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Cytological changes in the endocrine glands of alloxanized hypertensive diabetic rats Radford, Hugh William 1951

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CYTOLOGICAL CHANGES I N THE  ENDOCRINE  GLANDS OF ALLOXANIZED HYPERTENSIVE DIABETIC  RATS  BY HUGH WILLIAM RADFORD, B.A.  A THESIS SUBMITTED I N P A R T I A L FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF ARTS  in  t h e Department of  BIOLOGY AND  We  accept  standard  this  BOTANY  t h e s i s as conforming t o the  r e q u i r e d from candidates  f o rthe  d e g r e e o f MASTER OF ARTS  Members o f t h e D e p a r t m e n t o f B i o l o g y  THE UNIVERSITY OF B R I T I S H A P R I L , 1951.  COLUMBIA  (ill  Abstract. R a t s made d i a b e t i c w i t h a l l o x a n a n d f e d h i g h and  salt  d i e t s showed h y p e r a c t i v i t y o f t h e p i t u i t a r y - a d r e n a l  systems, as i n d i c a t e d by a d r e n a l adrenal  hypertrophy, depletion o f  c h o l e s t e r o l and i n c r e a s e d  s i g n s "of h y p e r t e n s i o n  pituitary  acidophils.  such as a r t e r i o s c l e r o s i s ,  f a t t y degeneration o f the l i v e r Insulin  protein  Typical  nephrosclerosis,  and h e m o r r h a g e s were  common.  t h e r a p y and o m i s s i o n o f p r o t e i n f r o m t h e d i e t d i d n o t  lessen  the extent  cluded  t h a t t h e a n i m a l s were r e s p o n d i n g t o a l l o x a n a s a n a g e n t  of the  stress i n conformity high  resulting  salt  diet.  suggested that is  syndrome and t h a t  c o n t e n t o f t h e d i e t a g g r a v a t e d and s u s t a i n e d t h e  pathology o f alloxan diabetes,which d i f f e r s  that of diabetes salt  with the adaptation  I t was c o n -  hypertension. The  the  of the pathological conditions.  m e l l i t u s , i s changed t o t h a t Because of the s a l t  the hypertension  l a r g e l y due t o t h e s a l t  o f the l a t t e r by  craving of diabetics, i t i s  often associated with  Intake.  from  diabetes  (i)  ACKNOWLEDGEMENTS  The  author  expresses h i s thanks  to the following  f a c u l t y members n o t o n l y f o r t h e i r a s s i s t a n c e but a l s o f o r the p e r s o n a l i n t e r e s t research  and a d v i c e  t h e y have shown i n t h e  problem: D r . A.H. H u t c h i n s o n . Dr.  John A l l a r d y c e  D r . W.C. G i b s o n ,  .  M.D.  D r . P. C o n s t a n t i n i d e s , M.D. I n a d d i t i o n , t h e author  i s indebted to Dr. A.L.  C h u t e f o r t h e t r e a t e d r a t s w h i c h he s u p p l i e d Children's Hospital  i n Toronto.  from t h e S i c k  (iii)  TABLE OE  CONTENTS PAGE  Acknowledgements.  (i)  Abstract. Table  (ii)  of Contents.  (iii)  I  I n t r o d u c t i o n to the Problem.  1  II  H i s t o r i c a l Background.  2  A.  Alloxan diabetes.  2  1.  History.  2  2..  Chemistry.  2  3.  Alloxan &  4,  Pathology.  4  5..  Comparison w i t h o t h e r d i a b e t o g e n i c methods.  5  6.  Effect  5  B.  C.  as  a disease of adaptation to  1.  The  adaptation  2.  The  catabolic  3.  A c t i v a t i o n of the p i t u i t a r y - a d r e n a l  Metabolic  3  o f a l l o x a n on humans.  Hypertension  Adrenal  D.  s u l f h y d r a l compounds.  stress.  syndrome.  6  impulse.  7  Changes I n d u c e d By P i t u i t a r y  system.  Functions  2.  The  of the  adrenal  pituitary-adrenal  M e t h o d s Of  Studying  cortex.  system.  Adrenal  8  And  Hormone A d m i n i s t r a t i o n .  1.  6  Cortex A c t i v i t y .  11 11 13 14  1.  Urinary excretion.  15  2.  17-Ketosteroids.  15  3.  Assay of adrenal blood.  15  4.  Hormone c o n t e n t  16  of the gland.  (iv)  T A B L E OF CONTENTS 5.  (cont'd)  PAGE  Associated metabolic  changes.  I  (a)  Cholesterol & Ascorbic Acid.  16  (b)  Biogenesis  18  (c)  Effect  of steroid  hormones.  o f A.C.T.H. o n a d r e n a l  choles-  terol & ascorbic acid. (d)  Adrenal  The e f f e c t  19  cholesterol & ascorbic acid  precursors 6.  6  of cortical  of various  E . The C h e m i c a l C y t o l o g y  21  hormones.  s t r e s s e s on a d r e n a l  c h o l e s t e r o l and a s c o r b i o  as  22  acid.  Of The P i t u i t a r y  and  23  Adrenals. 1..  The p i t u i t a r y  2.  The a d r e n a l s .  gland.  IT. H i s t o l o g y Of The A d r e n a l  24 27 Gland.  31  III  Methods.  34  IV  Results.  41  V  Discussions & Conclusions.  56  VI  Summary.  60  1  I.  Introduction An  salt  and  vided Dr.  T O The  Problem:  e x p e r i m e n t on  alloxan  p r o t e i n diets,conducted  the  source of  by  Dr.  the  high  d i a b e t i c human p a t i e n t s .  i n rats given  used i n t h i s problem.  dietary salt  D u r i n g the  lication the  e x c e e d i n g l y f r u i t f u l and o f one  adaptation  logical brain and  W.A.  Mr.  Rivers.  be  r e f e r r e d to  It  will  in  the  be  diet  as  had  shown by  a direct  aspects of  former •  conditions.  the  since  case w i l l  the  alloxan  a  work c o n s i s t i n g o f  r e s u l t s of  syndrome due  i n d i r e c t agent o f on  the  dup-  the  the  author  a n i m a l s were  to the  Because o f t h i s ,  the  the  action  of  that  the  accompanying  hypertensive  r e c e i v e more e m p h a s i s t h a n t h e s e r v e d d i r e o t l y as  will  this thesis.  s t r e s s and  s e v e r i t y of  and  histo-  f i n d i n g s of t h i s i n v e s t i g a t i o n  adaptation or  problem,  concerning stress  c y t o c h e m i o a l methods t h a t  a d i r e c t bearing  pathological  betio,  The  the  was  done a t t h i s u n i v e r s i t y by  i n c o n n e c t i o n w i t h the  throes of the  alloxan  Preliminary  s t u d i e s was  the  i n t e r e s t i n g one,  o f S e l y e ' s many p r o j e c t s syndrome.  require-  oourse of  e x p e r i m e n t , i t s o o n became a p p a r e n t , however, t h a t t h o u g h an  high  Chute i n T o r o n t o , p r o -  experimental animals  Chute's i n t e r e s t i n v o l v e d  ments o f  diabetes  a vehicle  dia-  for  the  2.  II.  Historical  Background.  A. A l l o x a n 1.  Diabetes.  History. Alloxan  i s the ureide  of mesoxalic  acid.  When i n -  j e c t e d i n t o many l a b a n i m a l s i t p r o d u c e s a . s e l e c t i v e n e c r o s i s of the beta This  cells  i s followed  i n the I s l e t s o f Langerhans o f the pancreas. i n 24-48 h o u r s b y d i a b e t e s  mellitus.  b e e n f o u n d t h a t most a n i m a l s a r e s u s c e p t i b l e - , w i t h i o n o f t h e g u i n e a p i g , duck, o w l , c h i c k e n , Symptoms o f d i a b e t e s  I t has  the except-  f r o g and t o a d .  m e l l i t u s are p o l y d i p s i a , polyurea,  (3)  hyper-  g l y c e m i a and g l u o o s u r l a . A short  summarizing h i s t o r y o f a l l o x a n i s as f o l l o w s :  1838  - synthesized  1862  - discovered  1866  - f o u n d i n human u r i n e  1931  - excretory  1937  - a c t i o n on sugars n o t e d by Jacobs ( 4 2 ) .  1943  - islet  1943  - alloxan diabetes  i n r a b b i t s by B a i l e y ( 4 ) .  1943  - alloxan diabetes  i n r a t s b y Dunn ( 6 0 ) .  1943  - alloxan diabetes  i n dogs b y G o l d n e r ( 3 6 ) .  2.  route  by Lang.  studied  by C e r e c e d o ( 1 4 ) .  discovered  b y Dunn e t a l ( 2 7 ) .  Chemistry o f Alloxan. a pyrimidine-,  i s w h i t e i n c o l o u r , w a t e r and  s o l i b l e and i s a c i d i n s o l u t i o n .  l i z e d without vates  i n I n t e s t i n a l mucus o f humans b y L i e b i g .  necrosis  Alloxan, alcohol  b y W o e h l e r and L e l b i g .  Inactivating i t .  it.\ I t s f o r m u l a i s :  I t c a n n o t be  (Human b l o o d  plasma  neutra-  inacti-  a.  HN  CO  I  I  CO  CO  HN  CO  I t may act either as an oxidizer or a reducing agent. As an oxidizer i t i s i t s e l f reduced to d i a l u r i c acid whereas acting as a reducing agent i t i s ozldized to parabanic acid. In v i t r o , alloxan i n h i b i t s the conversion of glucose - 1 - P0 to glucose - 6 - P0 . 4  metabolism of glycogen.  4  This i s the second step i n the accepted This i n h i b i t i o n i s believed to be  due  to the action of alloxan as an enzyme destroyer. (48) Alloxan can be detected i n the blood and i n the pancreas immediately  after i t s intravenous i n j e c t i o n but i t has  a l l been destroyed or removed from the blood within f i v e minutes of i t s i n j e c t i o n . (47)  The fate of alloxan i n the body was  thought by Cerecedo (14) to be a chemical"combination  with s u l -  f u r i c acid with a subsequent excretion i n the b i l e as ethereal sulfate.  A small amount of alloxan i s converted to alloxantin  and excreted i n the urine as murexlde. 3.  Alloxan and Sulfhydral Compounds. Lab.es and Friesburger were the f i r s t to suggest that  alloxan might react with sulfhydral compounds. (45)  Leech and  Bailey (47) discovered that non-gluoose reducing substances i n the blood as well as glucose were markedly decreased after the i n j e c t i o n of alloxan into r a b b i t s .  Since glutathione, a s u l f -  hydral compound, comprises most of the reducing substance of the blood, an interaction i s indicated. Glutathione remained below normal l e v e l s for 18-24  hours, at which time diabetes  began to appear. The exact way  i n which alloxan produces i s l e t  crosis and diabetes i s not known.  ne-  I t has been suggested that  i s l e t o e l l destruction i s a r e s u l t of an action by the alloxan on c e l l u l a r enzymes,possibly sulfhydral enzymes, whioh are known to react with alloxan.(46) suggest that alloxan may (i)  Bruckmann and Wertheimer  (11)  act i n one of three ways:  By a selective accumulation of alloxan i n toxic amounts i n the beta c e l l s ,  (ii)  By competing with a s t r u c t u r a l l y s i m i l a r compound f o r an enzyme with r e s u l t i n g disorganization of the  cell  metabolism and eventual destruction of the c e l l , (iii)  By a s p e c i f i c reaction of alloxan on the i s l e t with or without an accumulation.  cell,  Such a reaction would  probably consist i n the i n a c t i v a t i o n of an enzyme system intimately connected with i n s u l i n synthesis. That the i s l e t c e l l necrosis i s due to the d i r e c t action of the alloxan was (37), who  shown neatly, by Gomori and Goldner  temporarily l i g a t e d the a r t e r i e s to one half of the  dogs'pancreas, injected alloxan and then released the l i g a t u r e f i v e minutes l a t e r .  This half remained normal.  Hypophyseotomy  does not affeot the destructive action, (5) (6) (31).  A diet  r i c h i n l a r d increases a r a t ' s s e n s i t i v i t y to alloxan, while protein decreases i t . 4.  Pathology. The course of alloxan diabetes d i f f e r s somewhat from  n a t u r a l l y occurring diabetes i n the following ways. (26)  5  (i)  There i s a s e l e c t i v e d e s t r u c t i o n of the B c e l l s i n the I s l e t s o f Langerhans.  (ii)  There i s no e f f e c t on alpha or non-granular the  (iii)  c e l l s of  pancreas.  F i b r o s i s or h y a l i n i z a t i o n i s m i s s i n g when a l l o x a n i s used as c o n t r a s t e d to t h a t seen i n n a t u r a l l y o o c u r r i n g diabetes.  (iv)  There i s a c i d o s i s , coma, c a t a r a c t s and r e t i n a l hemorrhage i n the experimental d i a b e t e s ,  (v)  T  here  i s temporary damage t o the l i v e r , a d r e n a l s , p i t -  u i t a r y and (vi) 5.  kidney.  There i s no d i a b e t i c n e u r i t i s o r a r t e r i o s c l e r o s i s . Comparison w i t h other d i a b e t o g e n i c methods: There are t h r e e other commonly used methods f o r p r o -  ducing experimental d i a b e t e s . (i) (ii) (iii)  I n j e o t i o n of a n t e r i o r p i t u i t a r y e x t r a c t (A.p.E.) Depanoreatization. I n j e c t i o n s of glucose. A.P.E. i s e f f e c t i v e on dogs and p a r t l y d e p a n c r e a t i z e d  r a t s and oats..  A p r e v i o u s hyperglycemia  i s n e c e s s a r y and i n -  j e c t i o n s must be repeated over s e v e r a l days or weeks. a c t s on beta c e l l s .  Depancreatization i s d i f f i c u l t  gland i s o f t e n v e r y d i f f u s e . i v e on c a t s o n l y . the beta 6.  Glucose  I t also  s i n c e the  administration i s effect-  I t s a c t i o n i s v e r y slow and a g a i n Involves  cells. E f f e c t of a l l o x a n on humans: I t was  hoped that h y p e r i n s u l i n i s m due t o tumours or  6  o t h e r causes c o u l d be t r e a t e d w i t h a l l o x a n .  Unfortunately, r e -  s u l t s were poor, s i n c e a l l o x a n i s too t o x i c to humans.  Gonn  (15) had no good r e s u l t s and found a f t e r removing the pancreas s u r g i o a l l y t h a t no damage had been done to tumour c e l l s  but  i n s t e a d the normal c e l l s had been a f f e c t e d . B.  Hypertension As A D i s e a s e Of A d a p t a t i o n To S t r e s s . 1.  The  a d a p t a t i o n syndrome.  The p r o d u c t i o n of n e p h r o s c l e r o s i s and i n the absence o f s e x u a l anomalies,  hypertensionj  i n experimental  animals  t r e a t e d w i t h D.C.A. l e d to the theory t h a t a s e l e o t i v e i n c r e a s e i n the endogenous mineral©- c o r t i o o i d s might be the cause o f corresponding  syndromes i n man.  of a d a p t a t i o n was  S e l y e ' s concept  o f the d i s e a s e s  l a r g e l y based upon t h i s o b s e r v a t i o n , s i n c e i t  i s known that c e r t a i n c o r t i o o i d s are produced i n excess a d a p t a t i o n and defence  during  to any type of damaging agent.  As p r e v i o u s l y mentioned i n the i n t r o d u c t i o n , the p r o blem was  seen to resemble one of S e l y e ' s s t r e s s  experiments.  Under the i n f l u e n c e o f s t r e s s , occasioned by a v a r i e t y of nons p e c i f i c damaging agents, the organism responds w i t h the g e n e r a l a d a p t a t i o n syndrome, whose m a n i f e s t a t i o n s are e s s e n t i a l l y i n dependent of the s p e c i f i c nature o f the s t r e s s employed and pend mainly on the degree and d u r a t i o n of the exposure.  de-  The  syndrome evolves i n three d i s t i n c t phases, (1) the alarm r e a c t i o n , (2) the stage of r e s i s t a n c e , and haustion.  Hypertension  resistance.  (3) the stage o f  ex-  i s e s s e n t i a l l y a d i s e a s e of the stage o f  2.  The  catabolic  Certain exposure to  during  the  types of h y p e r t e n s i o n are  stress,  changes, the  impulse.  A v a r i e t y of  so-called  *catabolic  shock phase o f the  of  the  thymus and  the  protein,  and  action,  tension  the  the  D i r e c t l y or  l i b e r a t i o n of  causes  produce  increased involution  c e r t a i n metabolio  of alpha 2  from  globulin  i n d i r e c t l y t h r o u g h t h e i r metcause a r e n a l  type of  hyper-  factors  adrenalinJ, may  s u c h as and  sympathetic  possibly  contribute  to  even a  the  dis-  raised  pressure. It  specific  has  i n the  teolytic weight  b e e n f o u n d t h a t many e n t i r e l y u n r e l a t e d  damaging a g e n t s p r o d u c e t h e  characterized  crease  of  catabolic  p i t u i t a r y to  resulting in as  prominent  (73)  charge of p i t u i t a r y v a s o p r e s s i n  is  liver  corticoids also  During s t r e s s , other  blood  latter  This  sodium, g l u c o n e o g e n e s i s  with nephrosclerosis.  stimulation,  The  adrenal.:,  of  p r o d u c t i o n by  (hypertensinogen). abolic  anterior  lymph n o d e s a s w e l l  c h a n g e s , s u c h as r e t e n t i o n  metabolio  impulse', which are  the  e x c e s s i v e amount o f A.C.T.H.  c o r t i c o i d p r o d u c t i o n by  elicit  alarm reaction.  impulse apparently influences an  stresses  c a u s e d by e x c e s s i v e  by  cells.  by  impulse,  a breakdown o f b o d y p r o t e i n s  concentration  enzymes i n t h e  and  catabolic  of p r o t e i n  blood.  This  oatabolites  etc.,  an  inpro-  i s a c c o m p a n i e d by  loss  a generalized  at t h i s time.  of  breakdown  characteristic adrenal-cortical  largement, g a s t r o i n t e s t i n a l u l c e r s , i n v o l u t i o n of organs,  which  and  h i s t o l o g i c a l evidence of  There i s a l s o  and  non-  en-  lymphatio  Prolonged stress leads  to  hyper-  8.  tension by  and  nephrosclerosis,  e s p e c i a l l y i n animals s e n s i t i z e d  u n i l a t e r a l n e p h r e c t o m y and 3.  A c t i v a t i o n of  S a y e r s and the  high  sodium, h i g h p r o t e i n d i e t s .  the p i t u i t a r y - a d r e n a l system.  Sayers  (62)  consumption or u t i l i z a t i o n  believe  of  corticoid  and-that the  r e s u l t i n g decrease i n t h e i r  discharge  c o t i o o t r o p h i n by  sponsible  of  f o r the  production so t h a t  of  cortical  t h e r e must be  an  this  stress  hormones by  and  tissues  i s thus  T h e r e i s an  t i m e however,  increased  increases  b l o o d - l e v e l causes  the p i t u i t a r y  enlargement.  cortiooids at  that  a  re-  excessive  (73)  (81)  (82)  utilization.  C.N.H. L o n g b e l i e v e s t h a t t h e p i t u i t a r y - a d r e n a l s y s t e m i s a c t i v a t e d by maintain that levels  i s an  o f A.C.T.H. and  secretory the  there  epinephrine  a o t i v i t y of  e f f e c t of  i n blood  each gland.  of  as  Long d e v i s e d  the  The  l a t t e r workers  to i t s c a p a c i t y  In order  of p i t u i t a r y  eyes.  The  s e l e c t e d as  eosinophil an  o f A.C.T.H. r e l e a s e of epinephrine  index of  decline adrenal  increase their  from the -grafts.  experiments.  produced  three  a n t e r i o r chamber o f  i n the p e r i p h e r a l  A  levels  his  t i s s u e from r a t s  cortical  blood  regard  to f u r t h e r  f o l l o w i n g s e r i e s of  same s t r a i n were i n s e r t e d i n t o t h e  right  to  r a t s were h y p o p h y s e o t o m i z e d and  l a t e r homologous t r a n s p l a n t s  Sayers  relative  c o r t i c a l hormones, t h u s r e d u c i n g  A group o f  was  determines the  t r a v e r s i n g the p i t u i t a r y .  contentions,  the  due  w h i l e S a y e r s and  r e l a t i o n s h i p between the  A.C.H. t h a t  epinephrine  the u t i l i z a t i o n  inverse  (52)  aotivity  days of the  blood and  hence  subcutaneous i n j e c t i o n  s u c h a r e s p o n s e , as  did direct injection  9.  of epinephrine into  the treated  e y e chamber.  d o s e g i v e n i n t o t h e chamber o f t h e i n t a c t the r e a c t i o n .  T h e same m i n u t e  eye d i d n o t cause  When t h e a n i m a l s were s u b j e c t e d t o s t r e s s ,  again responded by e o s i n o p e n i a .  they  A f t e r removal o f t h e eye con-  t a i n i n g t h e t r a n s p l a n t , e p i n e p h r i n e c a u s e d no r e s p o n s e .  The  g r a f t s were a s s a y e d a f t e r r e m o v a l and f o u n d t o c o n t a i n A.C.T.H. T h i s s e t o f experiments proved c o n c l u s i v e l y that has a d i r e c t  stimulatory effect  adrenaline  on t h e p i t u i t a r y .  E i t h e r hypophysectomy o r a d r e n a l e c t o m y p r e v e n t s s t r e s s from causing hypertension or nephrosclerosis, while of e i t h e r gland administered i n excess w i l l  extracts  cause h y p e r t e n s i o n .  The h y p e r t e n s i o n o f t h e s h o c k phase-may--so d e o r e a s e t h e b l o o d supply o f the kidney that r e n i n production i s increased as i t is  after  the Goldblatt  clamp.(33)  (34) S e l y e h a s shown  further  t h a t m i n e r a l o - o o r t i o o i d s s u c h a s D.C.A. c a u s e h y a l i n i z a t i o n o f i n d i v i d u a l glomeruli, thus diminishing blood supply i n the kidney after linized  corticoid  overdosage.  He b e l i e v e s t h a t  g l o m e r u l i may p r o d u c e t h e p r e s s o r  such hya-  substance o f hyper-  tension. T h e r e i s a w e a l t h o f d a t a showing type of nonspecific  damage o r s t r e s s c a u s e s e s s e n t i a l l y t h e  same a l a r m r e a c t i o n  symptoms.  I t i s n o t e w o r t h y , however,  upon p r o l o n g e d exposure t o s t r e s s , not always produced. different  t h a t almost any  end r e s u l t s ,  Different  that  diseases of adaptation are  t y p e s o f s t r e s s - may y i e l d  e.g. exposure  t o c o l d tends t o produce  n e p h r o s c l e r o s i s , w h i l e f o r c e d muscular  e x e r c i s e o r subcutaneous  10.  i n j e c t i o n s o f f o r m a l d e h y d e a r e more a p t t o c a u s e Yet,  i f t h e mechanism t h r o u g h w h i c h s t r e s s p r o d u c e s n e p h r o s c l e r -  o s i s and it  h y p e r t e n s i o n i s the l i b e r a t i o n o f m i n e r a l o - c o r t i c o i d s ,  is difficult  i n v a r i a b l y the nonspecific  to understand same.  effect  The  agent  and  why  excess  the r e s u l t s of s t r e s s  are  production of cortiooids  of s t r e s s , but perhaps the c a t a b o l i c  i s more d e p e n d e n t upon t h e  specific  nature  of the  i n t e r m e d i a t e m e t a b o l i s m p l a y s an  d e t e r m i n i n g whether the sult  hypertension.  excess  i n n e p h r o s c l e r o s i s and  is a  impulse  damaging  important  role  in  m i n e r a l o - c o r t i c o i d s produced  hypertension.  I t can r e a d i l y  nephrectomy. may  i n s o d i u m and  p r o t e i n o r by  Perhaps the s p e c i f i c metabolic  similarly,  sensitize  the organism  sen-  partial  e f f e c t s of  to excess  rebe  shown t h a t A.P.E. o r D.C.A. a r e made more damaging a f t e r s i t i z a t i o n by d i e t s r i c h  not  stress  mineralo-  corticoids. Recent p u b l i c a t i o n s i n d i c a t e adaptation develop experimental  i n man  animals.  t h a t the d i s e a s e s  i n e s s e n t i a l l y the  Increased  corticoid  been demonstrated by b i o a s s a y ,  width  a c t i v i t y o f t h e a d r e n a l c o r t e x has  l o g i c a l methods (Zamchek) and r e n a l v e i n has lation found  t h a t low  that diets  likewise  increased  b e e n shown b y  of  of  (39)  histo-  the In re-  sodium, i t h a s  w i t h ammonium  been  chloride  i n depressing the blood p r e s s u r e  c o n s i s t i n g mainly  tend to depress  (82)  i n h y p e r t e n s i v e humans.  sodium d i e t s o r t r e a t m e n t e ffectlve  (81)  Increased r e n i n content  to the p r e v i o u s l y mentioned e f f e c t  sometimes p r o v e and  been p r o v e n  same manner a s i n  e l i m i n a t i o n i n the  u r i n e has and  of  the  of r i c e  and  blood pressure  fruit  juices  (72) (43)  i n hypertensive  11  patients.  I t i s b e l i e v e d t h a t the l a t t e r  of a pressor  substance  but  r a t h e r by  do n o t  their  a c t b y means  l o w sodium  and  p r o t e i n content. M e t a b o l i c Changes I n d u c e d by A d m i n i s t r a t i n g A.C.T.H. & A.C.H. 1. Functions of the adrenal c o r t e x . At present, a p p e a r t o be  the f u n c t i o n s o f the  adrenal  cortex  the f o l l o w i n g :  1.  Regulation of electrolyte  metabolism.  2.  Regulation of carbohydrate,  p r o t e i n , and  fat  metabolism. 3.  R e g u l a t i o n o f lymphoid  t i s s u e and  circulating  leukocytes. 4.  Androgenic  function.  5.  Regulation of  pigmentation.  Electrolyte-regulating adrenal 11 - d e s o x y c o r t i o o s t e r o n e ,  are  r e t a i n i n g hormones, s i n c e t h i s The  interrelation  of  steroids,  commonly r e f e r r e d  particularly  t o as  sodium-  i s t h e i r most c o n s p i c u o u s  carbohydrate,  f a t and  effect.  p r o t e i n metabolism,  p a r t i c u l a r l y u n d e r f a s t i n g . c o n d i t i o n s , i s most e f f e c t i v e l y trolled  by 11,  oxysteroids.  18 - o x y s t e r o i d s and The  11,  17  promoting gluconeogenesls l y m p h o l y s i s j and be  caused  to a l e s s e r  by 11  - o x y s t e r o i d s a r e t h e most p o t e n t and  eosinopenia.  i n causing The  by hormones r e s e m b l i n g  atrophy  androgenic  androsterone.  s p o n s i b l e f o r ohanges i n p i g m e n t a t i o n as  extent  have n o t  of the  effect The been  con-  in  thymus,  appears factors  to re-  identified  yet. It  o f the  has  always been the  adrenal medulla  custom to d i s c u s s the f u n c t i o n  s e p a r a t e l y from t h a t of the  cortex.  12  It  i s w e l l known t h a t  the  c o n t r o l of the  l i b e r a t i o n of  the  s e c r e t i o n of  epinephrine  i s under  autonomic nervous system whereas,  cortical  hormones i s d e p e n d e n t u p o n  the  pituitary  A.C.T.H. w h i c h i n t u r n . i s f u n c t i o n a l l y i n t e g r a t e d w i t h autonomic nervous system. possible a c t s as  a stimulator  Proof that  Long.  (See  the  previous  upon t h e  Excessive  e n l a r g e m e n t may  be  was  of  al.  s o d i u m and  the  of  of potassium,  and  chloride i n perspiration.  volume.  (78)  i s not  (55)  (35)  Excessive  effect,  r e t e n t i o n of  over l o n g p e r i o d s  (61)  (70)  o f t i m e may  s t u d i e s by may  exert  i n hypertensive  s o d i u m and  cause tendon o o n t r a o t i o n s  a s i o n a l l y reported  i n D.C.A. t r e a t e d human p a t i e n t s may  on  cardiac  detrimental  c o n d u c t i o n and  ssium d e f i c i e n c y are  effect  o f a low  contraction.  e n h a n c e d by  sudden d e a t h  serum p o t a s s i u m  (78)  Symptoms o f  administration  of  a  potassium  I t i s also possible  to the  et  patients.  depletion of  that  the  Schroeder  f l a c c i d paralyses.  lated  sodium  d e p e n d e n t s o l e l y on  Recent  particularly  cardiac  patients  w i t h D.C.A, i s enhanded by  s u g g e s t t h a t D.C.A. i n j e c t e d i n t r a v e n o u s l y  direct pressor  and  i n b o t h l a b . a n i m a l s and  but  by  renal retention  d o s e s o f D.C.A. (38)  associated  i n blood  provided  h y d r e m i a , edema, h y p e r t e n s i o n  observed  man.  B-3).  i t s e f f e c t by  chloride administration, increase  in  one  water, w i t h e x c r e t i o n  treated with excessive hypertension  epinephrine,  action i s a direct  concentration  (38)  m e d u l l a r y hormone,  secretion i n  discussion  s o d i u m , c h l o r i d e and  h i s t o l o g i c a l methods, i t i s  o f p i t u i t a r y A.C.T.H.  D.C.A. e x e r t s  The  by  to demonstrate t h a t the  (58)  (16)  Now,  the  and occbe  re-  level pota-  glucose.  13.  2.  The  pituitary-adrenal  system.  I n p a t i e n t s w i t h an i n t a c t stress  causes a r a p i d  depression of c i r c u l a t i n g  P a t i e n t s w i t h Addison's show t h i s  d i s e a s e and  change.(58)  of c i r c u l a t i n g  pituitary-adrenal  eosinophils  (30)  panhypopituitarism f a i l  Because of these f a c t s ,  e o s i n o p h i l s c a n be  system,  to  t h e measurement  used to i n d i c a t e  the  integrity  of the p i t u i t a r y - a d r e n a l r e l a t i o n s h i p ,  a b n o r m a l A.C.T.H. p r o -  duction,  as  etc.  ability  t o meet a s t r e s s  ( 7 6 ) - - T h e a p p l i c a t i o n o f s t r e s s has  epinephrine production T  he  in  the  Cannon.  e a r l y response (12)  At  that repeated adrenal  and  of the  the beginning  injections (2)  Only  and  the  (83) n o t e d  nervous  system  century,  i t was  to r a b b i t s  r e c e n t l y . (1945),  increased a c t i v i t y  has  an  adrenal  noted  the  of the  by h y p o p h y s e o t o m y .  eristic  of a r a t l e d to adrenal  of that induced  epinephrine  combination  being  (79)  entire.  Epinephrine hormones.  by A.C.T.H.  administered  in rapid-eosinopenia  Prolonged  cortical Recent  to either  by  caused  enlargement i n normal r a t s  prevented  ago  link adrenal stress.  given Long et a l  showed t h a t a c r y s t a l o f e p i n e p h r i n e p l a c e d d i r e c t l y  pituitary  that  of t h i s  with  action.  s t i m u l a t i o n of the a d r e n a l c o r t e x under  e p i n e p h r i n e ^ , w h i c h was (50)  eosinophilic  d e s c r i b e d some t i m e  of epinephrine  b e e n e s t a b l i s h e d between t h e medulla  been c o r r e l a t e d  sympathetic  t o s t r e s s was  enlargement.  a major o p e r a t i o n ,  i n explaining this  r o l e of epinephrine  Vogt  such  on  the  stimulation, characts t u d i e s have shown  dogs o r humans r e s u l t s  T h i s d e p e n d s on  the  pituitary-adrenal  (58)  a l s o causes i n c r e a s e d e x c r e t i o n of u r i n a r y  a d m i n i s t r a t i o n , however, does n o t  give  results  14.  in  t h e same-amount o r r a t e a s d i r e c t A.C.T.H.  This  suggests t h a t an e a r l y r e f r a c t o r i n e s s o f t h e p i t u i t a r y has  been a t t a i n e d . limited  It i s likely  to the l i b e r a t i o n  Although there capable of inducing  that the action of epinephrine  o f p r e f o r m e d A.C.T.H., w i t h o u t  w i s e s t i m u l a t i n g A.C.T.H.  is  administration.  i s ample e v i d e n c e t h a t  increased  epinephrine  i t i s the only a neural  activator.  mechanism, l o c a t e d  i n t h e hypothalamus i s a l s o a c t i v a t e d by e p i n e p h r i n e the p i t u i t a r y .  (41)  A.C.T.H. s e c r e t i o n i s s u s t a i n e d not  it  of i t s particular  Both the circumstances that method o f p r o d u c t i o n  at the present the  adrenal  synthesis time.  cause an i n c r e a s e d  and r e l e a s e  i s particularly  i n small  s e c r e t i o n and The m e c h a n i s m o f  o f any hormone i s i m p e r f e c t  corteac, whose c h a r a c t e r i s t i c  The  gland  hormone i s made a v a i l a b l e .  must b e . c o n s i d e r e d .  This  c e n t l y been s y n t h e s i z e d  true  i n the case o f  hormone h a s o n l y r e -  amounts b y a l a b o r i o u s  technic.  methods t h a t have b e e n d e v e l o p e d f o r t h e d e t e r -  m i n a t i o n o f an i n c r e a s e d tex  Activity.  t o d e t e r m i n e t h e c i r c u m s t a n c e s u n d e r w h i c h an  supply  the b i o l o g i c a l  would  epinephrine.  t h e s t u d y o f t h e f u n c t i o n o f an e n d o c r i n e  i s important  increased  the  f o r a prolonged period  M e t h o d s Of S t u d y i n g A d r e n a l C o r t e x In  and i n  The m e c h a n i s m w h e r e b y  a p p e a r t o be b a s e d on t h e c o n t i n u o u s a c t i o n o f D.  is  o u t p u t o f p i t u i t a r y A.C.T.H., i t  evidence suggests that  turn stimulates  other-  production.  b y no means e s t a b l i s h e d t h a t  Preliminary  i s  a r e as f o l l o w s :  secretory  a c t i v i t y of the adrenal  cor-  15.  1.  Urinary  Excretion.  C o r t i c a l hormones i n u r i n e ability and  of the  hormone t o i n c r e a s e  m i c e o r by  against  the  e f f e c t s of  q u e s , i t has creased  i t s capacity  infections.  use  t o man  The  or l a r g e  17  -  credit  on  (53)  cold.  cortin  i n man  an  the  c u l a r hormone.  are  Firstly,  parallel  formation  the  two the  value  approach w i l l with  Assay of  the  adrenal  of c o r t i c a l  a f t e r trauma, burns  use  limit its  has  suggested  aotivity  - ketosteroid level  devised  the  Secondly,  f o r more  C 11  in the  com-  testi-  specific  substitution,^the However  advantage t h a t  of operative  in  dis-  i n the male, i s a l s o  this  i t can  be  procedures.  blood.  o f dogs c o n t a i n s  hormone t o be  been  of c o r t i n .  shown r e c e n t l y t h a t  veins  cortical  remain u n c e r t a i n .  first,  adrenal  Vbgt has  17  ketosteroids with  performed without the  from the  techni-  i s an i n -  f a c t s t h a t throw  level  U n t i l methods a r e of the  method, a l o n g  animals  these  of these substances from the  determination of t h i s  there  - k e t o s t e r o i d s has  i n d i c a t i o n o f the  t h i s method.  p l i c a t e d by  using  rats  animals.  - ketosteroid excretion, at least  3.  By  l a r g e amounts o f u r i n e r e q u i r e d  However t h e r e  the u r i n e does not 17  exposure to  e x c r e t i o n o f 17  some w o r k e r s a s (49)  glycogen of  the  Ketosteroids.  The  man.  liver  been c l e a r l y demonstrated t h a t  and  by  the  a s s a y e d e i t h e r by  to p r o t e c t adrenalectomized  urinary excretion of  2.  are  d e t e r m i n e d by  the blood  p l a s m a drawn  sufficient the  quantities  Selye-Schenker  16  method o f a s s a y . in  dogs e q u a l  t o 250  greater outputs o r by  I n t h i s manner he has c.c.'s  of commercial e x t r a c t .  were o b t a i n e d  by  splanchnic nerve  Even  stimulation  epinephrine. 4.  Hormone C o n t e n t One  of the  actual  Gland.  o f t h e most w i d e l y u s e d methods f o r t h e  of v a r i a t i o n s i n endocrine  erent  shown a d a i l y s e c r e t i o n  activity  i s the  q u a n t i t i e s o f hormone p r e s e n t conditions.  One  content  determination  i n the gland under  general d i f f i c u l t y  decide whether a decreased  released  into  the  endocrine  any  one  time  the b l o o d . glands  o f hormone i n t h e  i n the  case  may  adrenal  Associated Metabolic  be  i n a gland by  C h o l e s t e r o l and  Even by u s i n g  and  t h a t o n l y has  oortex.  Changes,  ascorbic acid.  a small reserve, w i l l  Two  however.  particularly  be.accompanied  changes a s s o c i a t e d w i t h the  r e l e a s e o f t h e hormone.  when a p r e c u r s o r o r an present.  at  biological  assumed t h a t i n c r e a s e d hormone p r o d u c t i o n ,  c h a r a c t e r i s t i c metabolic  thesis  of  s m a l l amount o f hormone p r e s e n t  Another approach to the problem i s , a v a i l a b l e It  a  p o s s i b l e t o d i r e c t l y measure changes i n  hormone q u a n t i t y i n t h e  (aj  diff-  gland  formation,  A special difficulty  i s the  the  a c t u a l measurement o f hormone  i n the gland i t s e l f .  t e c h n i c s i t i s not  5.  by  of  o f t h i s method i s t o  i n d i c a t e s a g r e a t e r s e c r e t i o n or a decreased matter that i s u s u a l l y s e t t l e d  study  essential  instances of t h i s  T h i s i s even more  syn-  evident  c o n s t i t u e n t o f t h e hormone i s a r e known.  The  first  i s the  17.  r e l a t i o n o f iodine metabolism t o the t h y r o i d second i s - t h e presence substances,  both  to the formation  hormone and t h e  i n t h e a d r e n a l c o r t e x o f two  o f w h i c h a p p e a r t o be s p e c i f i c a l l y  any c h a n g e s i n t h e r a t e o f s e c r e t i o n .  stances  are cholesterol  outstanding  presence  chemical  and a s c o r b i c o f these  approximately  o f the adrenal cortex.  the corpus  of the adrenal  90$ o f i t i s p r e s e n t  luteum  and t h e 10$ f o u n d  these  substances.  cholesterol i s that  i n the gland  i n the b r a i n .  i n e s t e r form.  of both  i n the  I t i s g e n e r a l l y under-  stood that a high p r o p o r t i o n of e s t e r i f i e d a high r a t e o f turnover  No  approaches  T h i s i s t o be compared w i t h t h e 50$ o f the- e s t e r f o u n d liver  sub-  compounds i s t h e  the organ i n i t s h i g h c o n c e n t r a t i o n s o f both characteristic  T h e s e two  acid.  two o r g a n i c  characteristic  o t h e r o r g a n o f t h e body e x c e p t  Another  related  o f t h e hormone a n d b o t h o f w h i o h a p p e a r t o  reflect  The  chemical  cholesterol indicates  the s t e r o i d  and i t s a s s o c i a t e d  fatty acids. There has been c o n s i d e r a b l e s p e c u l a t i o n c o n c e r n i n g t h e p o s s i b l e r e l a t i o n s h i p between t h e a d r e n a l s c h o l e s t e r o l m e t a b o l i s m o f t h e b o d y , a l t h o u g h no a s s o c i a t i o n h a s y e t b e e n shown. cholesterol  i n the adrenal fluctuated  circumstances by  Sayers  adrenal  The f a c t  was known.  e t a l (67) who  This latter  definite  t h a t t h e amount o f  g r e a t l y under  different  s u b j e c t has been  reviewed  have p o i n t e d o u t t h a t a l o w e r i n g o f .  cholesterol i s associated with  to a v a r i e t y o f s t r e s s e s .  and t h e g e n e r a l  exposure o f t h e organism  18.  The adrenals  high  concentration  f u r n i s h e d the  pure form.  first  source  F l u c t u a t i o n s are  c u m s t a n c e s and  the  relation  in  which the  that the steroid  Compounds o f t h i s o f the  of the  vitamin  to the n a t u r a l r e -  information  concerning  steroid  important  chemical  s u b s t a n c e s had  s u b s t a n c e s as  Recently  i t has  s t u d i e s has The  (8)  and  pregnanediol  that  steroid  c o n t a i n i n g the  the very  i n the  composition  Rittenberg a constant  hypothesis  hormones and of  has  i s followed  deuterium content  by  bile  the  urine.  that  adrenal  such  acids. with  into  cholic  excretion (9) to  This  of last  similar  since pregnanediol  of progesterone,  reported  that  body i n t o  in relation  cortex,  to the  new  c h o l e s t e r o l tagged  interest  adrenal  u r i n a r y excretion product similar  given  demonstration  i n the  i s o t o p e i n the  e xperiment i s of p a r t i c u l a r transformations  activity  substance i s a c t u a l l y converted  i n women t h i s  (86)  s t r u c t u r e t o many b i o l o g -  l e d to the  b e e n shown b y u s e  deuterium t h a t t h i s acid  the  steroids  hormones.  c h o l e s t e r o l might undergo t r a n s f o r m a t i o n related  has  isolated.  an o l d b e l i e f .  a similar  biological  cir-  It  ascorbic acid.  whioh p o s s e s s the  of the  (56)  contains water-soluble  i n t r o d u c t i o n of isotope  c h o l e s t e r o l had ically  a l s o been s u g g e s t e d .  i s associated with  (b) B i o g e n e s i s  in  under v a r i o u s  c o r t i c a l hormones h a v e b e e n  The  for i t s isolation present  adrenal  type  the  again  s i s t a n c e o f t h e o r g a n i s m has been r e p o r t e d  of ascorbic acid i n  a substance  is of  cortical steroids.  e x p e r i m e n t s on m i c e i n w h i c h  o f 1.5  atom p e r c e n t  was  maintained.  19.  After  60  days the  c h o l e s t e r o l i n t h e s e m i c e showed a  between d e u t e r i u m and f o u n d i n body f l u i d s . h y d r o g e n atoms i n t h e w i t h the  h y d r o g e n c o n t e n t w h i c h was I t was  genesis.  The  synthesized  f a c t was  i n the  body f l u i d s  i n t e r p r e t e d t o mean t h a t  body f r o m s m a l l e r  greater  amount o f  than could  suggest that three  i n the  accounted f o r .  cholesterol i s f i r s t  c a r b o n compounds and  has  built  up  22  of  i t s bio-  cholesterol i s  molecules.  deuterium present t h u s be  that  exchangeable  i n some s t e p  o f h y d r o g e n - d e u t e r i u m exchange r e a c t i o n s since the  half  concluded that at l e a s t  c h o l e s t e r o l m o l e c u l e are  deuterium of the  relation  The  been  possibility  eliminated,  cholesterol i s  A l l these  findings  f r o m one,  two  subsequently degraded to the  or steroid  hormones. A  comparison of the m o l e c u l a r  nenolone to  that of  any  of the  relationship  i n biogenesis.  cholesterol,  this  parent  I f the  only  hormones a r e  a l l s t e r o i d hormones, as  i n i t s side chain.  gnenolone a l s o occupies a r a t h e r the  the  (o)  properties of  E f f e c t o f A.C.T.H. on ascorbic acid.. Studies  from pre-  unique p o s i t i o n i n that  I t appears t h a t  expense o f o t h e r  from  logical  i t differs  the  specialization for  the parent adrenal  i t is  independent s t e r o i d  c e r t a i n pharmacological action occurs gradually the  possible  derived  Pharmacologically,  compound known t o p o s s e s s a l l t h e  hormone a c t i o n s .  preg-  s t e r o i d hormones shows a  compound w o u l d ' a p p e a r t o be  substance of  cholesterol only  structure of  and  a  always  at  compound.  cholesterol  w i t h A.C.T.H. have p r o v e d t h a t  this  and pituitary  20  hormone c a u s e d in  d e p l e t i o n o f both  the adrenal cortex.  (51)  c h o l e s t e r o l and a s c o r b i c a c i d  In the r a t , a single  1-4 m g . / 1 0 0 g r . i s f o l l o w e d b y a r a p i d ascorbic acid (64)  and a  (65) (66) (67)  slower  i n adrenal  i n adrenal cholesterol.  Some t w e n t y m i n u t e s a f t e r  the adrenal a s c o r b i c a c i d h o u r b y 60$.  fall  fall  has been reduced  I t then begins  hour; h a s r e t u r n e d t o n o r m a l .  injection of  to r i s e  (63)  the i n j e c t i o n ,  by.30$ and i n an  a g a i n and b y t h e n i n t h  The c h o l e s t e r o l ,  on t h e o t h e r  hand, does n o t r e a c h i t s maximum f a l l  until  the t h i r d  and  until  24 h o u r s a f t e r t h e  the r e t u r n t o normal i s prolonged  injection.  T h e s e e f f e c t s o f A.C.T.H. upon t h e c o m p o s i t i o n o f  the g l a n d a r e accompanied b y d e f i n i t e creased output creased l i v e r their  indications  glycogen  (67) and maximum l y m p h o p e n i a  adrenal c o r t i c a l  The  hormone  I t has been f o u n d  acid  to  acid  diet  o f t h e v i t a m i n from  storage i n the c e l l s  cholesterol  causes  a fall in  i n the gland i s  T h i s slow r e t u r n o f a s c o r b i c a c i d  be due t o a w i t h d r a w a l  It  to synthesize  and c h o l e s t e r o l a s i n t h e p r e v i o u s l y . m e n t i o n e d  (64)  subsequent  effects  results.  r a t s but that the reformation o f ascorbic acid retarded.  (25) r e a c h  t h a t a d m i n i s t r a t i o n o f A.C.T.H.  a n i m a l when on a n o n - a s c o r b i c  ascorbic  Both i n -  Both these  g u i n e a p i g , l i k e man, i s u n a b l e  ascorbic acid. this  o f an i n -  o f t h e c o r t i c a l hormones t h e m s e l v e s .  h e i g h t between t h e 6 t h a n d 9 t h h o u r s .  are s p e c i f i c  to  hour  i sbelieved  t h e b l o o d and a  of the gland.  s h o u l d be e m p h a s i z e d t h a t c o m p a r a b l e c h a n g e s i n ascorbic acid levels  o f o t h e r t i s s u e s do n o t o c c u r  21.  w i t h A.C.T.H. a d m i n i s t r a t i o n . physiological cortex, and  e f f e c t other  we may  ascorbic  increased  Since  A.C.T.H. h a s no  than s t i m u l a t i o n o f t h e  known  adrenal  c o n c l u d e t h a t t h e changes i n a d r e n a l  cholesterol  a c i d f o l l o w i n g i t s i n j e c t i o n a r e i n d i c a t i v e o f an  rate of formation  and r e l e a s e o f t h e hormone f r o m t h e  gland. (d)  A d r e n a l c h o l e s t e r o l and a s c o r b i c Of c o r t i c a l hormones. The  cholesterol  cholesterol The  p r o b l e m o f whether o r n o t a s c o r b i c  combine t o f o r m c o r t i c a l  l a t i v e l y new.  a c i d and  hormones i s s t i l l r e -  C with the c o r t i c a l  s u g g e s t e d by Zwemer.and L o w e n s t e i n . ( 8 6 )  they b e l i e v e that t h e v i t a m i n steroid nucleus,  apparently  compound h a s a h i g h  hormones was These  a water s o l u b l e C i s attached  activity, plus  to r i n g D of the  by c a r b o n - t o - c a r b o n l i n k a g e .  degree o f i n s t a b i l i t y  This  vitamin  observed i n the adrenal  i n water and b r e a k s cortical  claim cortex  c l a r i f i e s the a l t e r a t i o n s a f t e r A.C.T.H. i n j e c t i o n s .  w o u l d a l s o a c c o u n t f o r t h e r a p i d and e a r l y d e p l e t i o n  by  i n response to s t i m u l a t i o n o f the gland,  a slower  It  of ascorbic  since this  may  o f p r e f o r m e d hormone w h i c h i s f o l l o w e d  change i n c h o l e s t e r o l c o n t e n t  hormone a r e f o r m e d .  The  C.  important  the discharge  workers  s t e r o i d i n which  down i n a n a c i d medium t o f o r m a s t e r o i d , w i t h o u t  represent  that  i s known t o be c o n v e r t i b l e t o p r o g e s t e r o n e i n man.  have i s o l a t e d from t h e a d r e n a l  acid  precursors  T h e e v i d e n c e i s s t r e n g t h e n e d by t h e f a c t  association of vitamin  first  a c i d as  a s new q u a n t i t i e s o f  22.  The  e f f e c t s of  various  stresses  burns,  c o l d , m u s c l e t r a u m a and  pheral  n e r v e s h a v e b e e n shown t o p a r a l l e l  on  adrenals.  the  both ascorbic rate now  i n the  acid  two  generally  an  increased  of  the  put.  Thus t h e and  of  the  mized animals. rapidity  of  discerned  one  of  demand f o r c o r t i c a l  Evidence f o r  stimulation  and  experiments.  that  g r a t i f i c a t i o n of  parison  falling  the  subsequent r i s i n g  (67)  the  hormones and  f a c t can  be  These experiments a l s o  adrenal response, since h a l f an  is  stress  is  f r o m a com-  hypophysectoI l l u s t r a t e the  c h a n g e s can  hour a f t e r the  initiation  A.C.T.H. o u t -  obtained  n o r m a l and  of  It  the  increased  (51)  (80)  on  that  A.C.T.H.  similar  (38)  e f f e c t s of  t h i s need i s an  this latter  (57)  stress  within  of p e r i -  e f f e c t s of  e f f e c t s of  the  hemorrhage,  c h o l e s t e r o l proceeds at a very  types of  accepted  painful  such as  s t r e s s has  be  easily  been  applied. S i n c e the ascorbic  acid  and  agents that  cause d e p l e t i o n  c h o l e s t e r o l are  so  of  adrenal  d i v e r s i f i e d , the  o f what common d e n o m i n a t o r i s p o s s e s s e d by  such s t i m u l i a r i s e s .  That the  a l t e r a t i o n s i n a d r e n a l c o m p o s i t i o n depend on  liminary  a c t i v a t i o n of  viously. of are in  the  p i t u i t a r y has  T h r e e mechanisms may  ( i ) e x c i t a t i o n of composition of  latter  (iii)  the  the  traversing  l e v e l of  view i s h e l d  by  pre-  activity  l i b e r a t i o n o f A.C.T.H.  a nervous secretory blood  apre-  been mentioned  c o n t r o l the. s e c r e t o r y  a n t e r i o r p i t u i t a r y i n the  secretion The  the  question  cortical  S a y e r s and  the  mechanism blood,  These  ( i i ) changes  causing  hormones i n t h e  blood.  Sayers  found  (68)  who  £3.  that  a previous  administration of c o r t i c a l  e x p o s e d t o c o l d f o r one adrenal ascorbic The lobe  type  one  various stresses.  T h i s i s an the  hormone, e p i n e p h r i n e .  (51)  injections  there  but n o t its  Long  of epinephrine  is a fall  a t t h e moment, b u t  of nervous a c t i v i t y  p a t h e t i c n e r v o u s s y s t e m and  of  usual f a l l  of both  e x c i t a t i o n o f the  on  has  i n v e s t i g a t e d the  t h e a d r e n a l and  a c t i v a t i o n of the  phrine,  then  medullation be  so,  animals  (Epinephrine  i n hypophysectomized t h a t the  effect  the p i t u i t a r y that the  by g i v i n g E.  i s i n n e r v a t e d by  The  Chemical ideal  Cytology  retains  animals).  stress.  although t o be  sympathetic  i t does on  These on (84)  epineor  de-  This  such  may  animals  implied that  nervous  skeletal  system  muscle,  effect. Of The  goals of chemical  of biochemistry  intact  the p i t u i t a r y .  i n meeting (85)  that  of epinephrine  I t i s not  the  a c t s as  a s t r i k i n g metabolic  The those  to s t r e s s .  epinephrine  still  complete a d r e n a l d e n e r v a t i o n  s h o u l d have d i f f i c u l t y  very sensitive  found  a d r e n a l depends on r e l e a s e o f  as t h e w o r k o f Wyman s u g g e s t s  are not  but  with  has  results  cholesterol i n  t h e a d r e n a l c o n s t i t u e n t s i s a l s o m e d i a t e d by the  sym-  release of i t s s p e c i f i c  i n hypophysectomized r a t s .  glycogenolytic effect  there i s  associated with a l l  a s c o r b i c a c i d and  experiments would i n d i c a t e  If  in  acid.  s e c r e t i o n i s a debatable  the  the  rats  question of a d i r e c t nervous c o n t r o l of a n t e r i o r  d e f i n i t e l y one of  hour prevented  hormones t o  Pituitary  and  c y t o l o g y are  - to a s c e r t a i n q u a l i t a t i v e l y  Adrenals. similar  to  andquantit-  24.  , a t i v e l y the events  o f the v a r i o u s m e t a b o l i c p r o c e s s e s .  Cytology  possesses  the advantage o f p e r m i t t i n g exact l o c a t i o n of v a r i o u s  metabolic  substances.  valid  results  i f morphological  physiological 1.  E v e n n o n - s p e c i f i c methods may  pituitary  (1)  (74)  d e s c r i b e d , the a c i d o p h i l s  ratio  chromophobes.  their  sex,  with acid dyes. after and  kinds of granular c e l l s  and  b a s o p h i l s , and  I n humans, t h e s e  sexual maturity, etc.  The  c e l l s are  when s t a i n e d by one  Thus b a s o p h i l s s t a i n w i t h a n i l i n  cell  phils  Recently  classified  blue,  eosin-methylene  blue or  triacid  acidophils these  (1945) t h e b a s o p h i l i c  cells  found  that digestion of  and  of the Dempsey  Consequently  b a s o p h i l s a r e engaged i n r a p i d p r o t e i n  and  Thus the  baso-  cytoplasmic  such a c o n c e n t r a t i o n  engaged i n r a p i d  i t seems l i k e l y  anterior  sections with r i b -  I n many o t h e r l o c a t i o n s  ribonucleoprotein occurs i n c e l l s  (71)  hematoxylin  apparently contain a considerable quantity of  synthesis.  change  o f the  destroyed the cytoplasmic b a s o p h i l i a .  ribonucleoprotein. of  percent  t y p e s were f i r s t r e c o g n i z e d by Schonemann  (23) who  onuclease  physio-  have b e e n  chromophobes r e j e c t  l o b e have been i n v e s t i g a t e d by D e s c l i n (24) Wislocki  i n the  number may  staining with either  eosin.  are  the  nongranular  The  f u c h s i n o r a z o c a r m i n e and  The  one  (54)  s t a i n i n g behaviour  - procedures.  types with d i f f e r e n t  Two  o f 37:11:52 r e s p e c t i v e l y .  w i t h age, by  has b e e n made t o c o r r e l a t e  appearance o f the c e l l  states.  type, the  to  gland.  Considerable e f f o r t  logical  related  states.  The  cytological  c h a n g e s c a n be  yield  that the  formation.  protein  pituitary  25.  Although  t h e c h e m i c a l n a t u r e s o f most o f t h e  hormones o f t h e a n t e r i o r p i t u i t a r y it  has  been e s t a b l i s h e d t h a t  percentage  of carbohydrate  t h e r e f o r e may  be  identifying  detail,  s e v e r a l o f them c o n t a i n a h i g h  r e s i d u e s such as glucosamine  classified  b e e n made r e c e n t l y  a r e n o t known i n  protein  to l o c a t e  the c a r b o h y d r a t e  as g l y c o p r o t e i n s . the  site  and  Attempts  have  o f hormone p r o d u c t i o n  residue of these g l y c o p r o t e i n s .  Catchpole  (13) u t i l i z e d p e r i o d i c  w h i c h was  then  acid  stained with Schiff's  to f r e e the  carbohydrate  leucofuchsin reagent.  t h i s procedure  some o f t h e c e l l s o f t h e a n t e r i o r p i t u i t a r y  differentially  stained.  impregnating hydrolysis  oxidation.  been i n t r o d u c e d and There specific  Similarly,  cell  has  (21)  recently  f o r f u t u r e work.  s e c r e t i o n o f A.C.T.H. (1) and  nalectomy  reveal  phils  b a s o p h i l s . (44)  from  d i m i n u a t i o n and  which i s r e -  (75)  o f abnormal b a s o p h i l i c  C r o o k e and R u s s e l l  acidophils,  cells  adre-  degeneration of both acido(17)  and l a r g e  state  that  adrenal i n s u f f i c i e n c y  t h e e x t r e m e d e c l i n e i n t h e number o f b a s o p h i l i c r e d u c t i o n i n t h e number o f  P o s t mortems  terminal stages of t o t a l  the constant f e a t u r e s i n p a t h o l o g i c a l  that  in  b e e n a l a c k o f agreement r e g a r d i n g t h e  from Addison's-disease  bility  were  alkaline  S u c h methods h a v e o n l y  holdngreat promise  By  succeeded  after  type i n the a n t e r i o r hypophysis  sponsible f o r the  and  JJempsey h a s  such carbohydrates w i t h s i l v e r  and  by  cells,  the presence  of a  chromophobes.  s u c h a d i s e a s e m i g h t be p r i m a r y  or i n the a d r e n a l s w i t h o p p o s i t e appearances  i n the  a  The  are  variable series possi-  hypophysis  i n the c y t o l o g y of  26  the hypophysis  must a l w a y s be  studying p i t u i t a r i e s found  considered.  of b i l a t e r a l l y  d i m i n u a t i o n i n number and  adrenalectomized  size of a c i d o p h i l s  w i t h a p r o g r e s s i v e l o s s o f g r a n u l e s and in  the G o l g i apparatus.  The  a whole,  fibers  be r a i s e d  as  to  o r o f abnormal metabolism  of t h e body  as  (69)  found  and R o l f  (40)  i n s t u d i e s on  t h a t f o l l o w i n g hypophysectomy, p r o g r e s s i v e  atrophy of the made on  correlated  of a modification i n p i t u i t a r y -  . Conversely, Heinbecker t h e dog  rats  r e g r e s s i v e changes  q u e s t i o n may  w h e t h e r t h e c h a n g e s were a r e s u l t adrenal relationship  Reese e t a l ( 5 9 ) ,  adrenal cortex occurred.  "puncture"  dogs i n w h i c h t h e  S t u d i e s were  infundibular  also  s t e m and  running c a u d a l l y from the p a i r e d p a r a v e n t r i c u l a r  i n t h e h y p o t h a l a m u s were s e v e r e d . acidophils  are maintained,  the a d r e n a l c o r t e x remains t h y r o i d s atrophy.  Under  T h i s suggests  nuclei  such c o n d i t i o n s the  the b a s o p h i l s decrease normal,  the  i n number,  w h i l e t h e gonads  that the  and  a c i d o p h i l s may  be  the  s o u r c e o f A.C.T.H. w h i l e t h e b a s o p h i l s a r e t h e  s o u r c e o f 1T.S.H.  and  (1)  thyrotrophin.  However A l b r i g h t  o n l y E.S.H. t o t h e b a s o p h i l s .  and E l r i c k  Daughaday e t a l (18)  attribute correlate  t h e a c i d o p h i l s w i t h A.C.T.H. p r o d u c t i o n b e c a u s e o f i n c r e a s e d adrenal function  i n acromegaly,  a c i d o p h i l tumours o f t h e The  response  satory hypertrophy occur  a condition usually  by  hypophysis.  to u n i l a t e r a l  of the remaining  i n hypophysectomized  caused  animals  adrenalectomy gland.  i s compen-  Since t h i s  i t appears  t o be  does n o t  dependent  27  u p o n an  i n c r e a s e d A.C.T.H. p r o d u c t i o n .  ditions  there i s a concomitant r i s e  Hypertrophy i s Increased  by  Under t h e  former  i n a c i d o p h i l s . (1)  con(29)  s t r e s s , which also i n c r e a s e s  the  acidophils. 2.  The  adrenals..  A relatively have b e e n d e t e c t e d gland  does n o t  microscopic  l a r g e number o f  i n the  adrenals.  appear t o s t a i n  examination  of the  cells  philic  strands.  On  gross  This cytoplasmic  into  the  than  where t h e p r o t o p l a s m i c  are d i s t i n c t l y  on  droplets  h e a v i l y baso-  b a s o p h i l i a i s more  gland  suggests  lipid  thin,  i n the p e r i p h e r a l zones o f the  This observation  examination  seen that, the  cytoplasm  strands  components  h e a v i l y w i t h b a s i c dyes but  i t c a n be  compress t h e  cytochemical  i n the  intense  reticularis,  eosinophilic.  the p r e s e n c e o f n u c l e o p r o t e i n s  and  of rapid protein synthesis. The  adrenal  a l k a l i n e phosphatase. disappears  the  sex  adrenals  considerable  amounts o f  A f ^ e r hypophysectomy, phosphatase  f r o m .the p a r e n c h y m a b u t  f o r a time before scribed  cortex contains  i n c r e a s e s i n the  gradually decreasing.  d i f f e r e n c e s i n the o f m i c e , and  has  Elftman  rapidly  endothelium  (28)  has  de-  d i s t r i b u t i o n of phosphatase i n shown t h a t i n j e c t i o n s o f  sex  hor-  mones m o d i f y i t s l o c a t i o n . A s c o r b i c a c i d has c o r t e x by v i r t u e This  i s important  o f i t s r e d u c i n g power i n a c i d  the p r o d u c t i o n  adrenal  solutions  from a p h y s i o l o g i c a l viewpoint  linked metabolically with (51)  been demonstrated i n the  (32)-.  i n that i t i s  of c o r t i c a l  hormone.  28.  The intensive of  lipid  study.  the l i p i d  content  The  of the  a d r e n a l c o r t e x has  s u d a n o p h i l i c and b i r e f r i n g e n t p r o p e r t i e s  d r o p l e t s have l e d t o t h e  revelation that a  c o n c e n t r a t i o n o f c h o l e s t e r o l i s 'present More r e c e n t l y , t h e s t e r o i d s has  i d e n t i f i c a t i o n of  stimulated interest  pounds i n t h e a d r e n a l g l a n d . lipids  received  i n the a d r e n a l  the  l o c a t e d i n the outer l a y e r  cells.  a d r e n a l hormones  in locating  I n 1940,  high  the  Bennett  active  (7)  as  com-  showed t h a t  o f the f a s c i c u l a t a  i n the  c a t ' s a d r e n a l c o r t e x e x h i b i t e d a number o f r e a c t i o n s s i m i l a r those  demonstrated by  T h e s e were  a c t i v e hormones i n c h e m i c a l  ( i ) acetone  c a r b a z i d e and  phenylhydrazine,  r e d u c t i o n of a l k a l i n e digitonides.  solubility,  The  silver  lipids  array of reactions.  s t e r o i d s o f the ovary,  i . e . ketone r e a c t i o n s , and  (iv)  i n o t h e r r e g i o n s do  Later,  experiments.  ( i i ) r e a c t i v i t y with  salts,  (1943),  Dempsey and  (20)  of ,  exhibit  i n attempting Bassett  semi-  (iii)  formation not  to  this  to l o c a t e the  defined  the  f o l l o w i n g histoohemical c h a r a c t e r i z a t i o n s of k e t o s t e r o i d s : (i)  acetone  (iii)  solubility,  ( i i ) reactivity with  autofluoresconce,  with concentrated reaction.  (iv) birefrirgence,  sulfuric  Each of these  p h y s i c a l or chemical  acid  (v)  r e a c t i o n s depends u p o n a  p r o p e r t y of the  other  k e t o s t e r o i d s i s known t o e x h i b i t  most e x t e n s i v e r e s e a r c h o f t h i s n a t u r e  rat  b y Deane and  In  Burchardt  different  f o r k e t o s t e r o i d s , but  The  (19).  reactivity  s t e r o i d molecule.  o f them i s s p e c i f i c  Greep  and  reagents,  as i n t h e L i e b e r m a n n -  s i n g l e one than  carbonyl  no  No substance  a l l five reactions. has  the r a t , both  b e e n made on the  the  glomerulosa  29  and  outer f a s e i c u l a t a react p o s i t i v e l y with the entire  of k e t o s t e r o i d procedures.  A f t e r hypophysectomy, t h e k e t -  o s t e r o i d s o f the f a s e i c u l a t a glomerulosa remain. (exposure cause  disappear w h i l e those  t o cold, noxious  agents,  certain vitamin  Injections  a d i s u s e a t r o p h y and s u b s e q u e n t  glomerulosa  deficiencies)  ofcorticosterone  disappearance  becomes a t r o p h i c a n d d e p l e t e d o f k e t o s t e r o i d s  injections of desoxycorticosterone into rats.  bohydrate  i s markedly d e f i c i e n t  metabolism  r e l a t i v e l y unimpaired,  separate s i t e  either  these  experiments  but s a l t  car-  regulation  p o i n t towards a  o f o r i g i n o f t h e s e two p r i n c i p l e s .  The e v i d e n c e  desoxycortioosterone - l i k e  pounds w h i c h r e g u l a t e e l e c t r o l y t e b a l a n c e ently of the p i t u i t a r y  intact  S i n c e a f t e r hypophystectomy  supports the hypothesis that  oxygenated  o f the  On t h e o t h e r h a n d , t h e  or hypophysectomized  is  stimulation  augmented k e t o s t e r o i d r e a c t i o n s i n t h e f a s e i c u l a t a h u t  ketosteroids o f the faseiculata.  after  of the  Conditions leading to adrenal  do n o t a l t e r t h e g l o m e r u l o s a . cause  series  a r e formed  i n the zona g l o m e r u l o s a ,  com-  independ-  and t h e 11 -  s t e r o i d s which r e g u l a t e carbohydrate metabolism a r e  formed under t h e i n f l u e n c e  of the p i t u i t a r y  g l a n d i n the zona  faseiculata. In addition to the s t e r o i d s , adrenal cortex. fatty  acids.  of brownish  occur i nthe  This material i s mostly neutral f a twith  The r e t i c u l a r i s  also  contains variable  some  quantities  y e l l o w pigment which i s n o t r e a d i l y e x t r a c t a b l e  from the t i s s u e s . these  other l i p i d s  cytochromes.  Little  i s known c o n c e r n i n g t h e n a t u r e o f  30.  The  methods f o r i d e n t i f y i n g s p e c i f i c  s e c t i o n s l e a v e much t o be bilities but  of  lipids  since l i p i d s  with proteins indices.  desired.  enter  their  T h e y may  into both loose  solubilities be  of t h e i r The  introduced  oil  no  soluble  polar  s o l u t i o n i n t o the  first  i n 1901  and  not  lipid  Sudan I V ,  has  used  firm  frequently,  combinations trustworthy  stained with  Sudan  groups which s t a i n of the  of these o i l soluble  and  are  entirely  characteristically  by D a d d i i n 1896.  by M i c h a e l i s  are  in tissue  characteristic solu-  i n non-aqueous s o l v e n t s  d y e s - compounds p o s s e s s i n g virtue  The  lipids  tissue.  d y e s was was  by  Sudan I I I ,  later  introduced  s i n c e been t h e m o s t p o p u l a r o f  dyes.  Some l i p i d s p o s s e s s a c t i v e g r o u p s w h i c h a i d i n detection and  and  a number o f  biologically with carbonyl The  identification.  S u c h compounds as  s t e r o i d s have s u c h d i s t i n g u i s h i n g f e a t u r e s .  exhibit  characteristic features.  a c t i v e compounds c o n t a i n reagents  s u c h as  When t r e a t e d w i t h c o n c e n t r a t e d  of  a g e n t s s u o h as  colours  results.  nature of t h e i r for  ultraviolet  which are  sulfuric  Many o f  the  react  phenylhydrazine.  strongly birefringent.  a c i d together  T h i s phenomenon d e p e n d s on  polycyclic ring structures.  been a d a p t e d t o light,  steroids  with  de-  a c e t i c anhydride, a c h a r a c t e r i s t i c play  d e t e r m i n i n g c h o l e s t e r o l , the  r e a c t i o n has  The  (21)  and  their  phospholipins  k e t o n e g r o u p s and  leucofuchsin  s t e r o i d s form s p h e r o c r y s t a l s  hydrating  the  In  the  unsaturated  Schultz's  Liebermann - Burchardt  cytology.  method  sterol  When i r r a d i a t e d w i t h  some s t e r o i d s f l u o r e s c e , u s u a l l y  a  stable  31.  green  colour.  Under p o l a r i z e d  crystals of cholesterol l i g h t n a t e l y once i n each readily be  soluble  determined  dissolving b u t no (7)  i n acetone  i f each  and  the l o n g are  extinguished a l t e r -  Finally,  o r a l c o h o l and  out the l i p i d s .  Wo  one  displays  Adrenal  More t h a n  300  test  i s specific  for  by  steroids,  reactions.  differ  d e s c r i b e d by  i n their  He  is  chloride  immersed i n f e r r i c  Gland.  noted  that  staining  gave a r u s t  discovered that  ability  i f a slice  solution,  The  called  not d i f f i c u l t ,  from  structure  that o f the  although c e l l  the medulla  and  gonal  and m e a s u r e s 18  about  7 microns  in  bich-  chromaffin reaction.  histological  quite different  a  medulla  coloured p r e c i p i t a t e with d i l u t e potassium  r o m a t e , the so  adrenal  takes  Subsequently,  c e r t a i n granules i n the  the  from  a c r o s s an  the m e d u l l a  g r e e n i s h t i n g e , w h i l e the c o r t e x does n o t . Henle  Eustachius i n  years l a t e r , Vulpian discovered that  those o f the c o r t e x .  cords o f the The  - 30 m i c r o n s ,  i n diameter.  a good i n d e x o f t h e i r  of the adrenal medulla  cortex.  vice versa.  f e a t u r e s o f the m e d u l l a r y is  are  i t can, t h e r e f o r e ,  the e n t i r e b a t t e r y o f  a d r e n a l s were f i r s t  c e l l s o f the medulla  into  steroids  (22)  The  1865,  rhomboidal  o f t h e a b o v e phenomena i s d e s t r o y e d  F . H i s t o l o g y Of The  1856.  up  90° o f r o t a t i o n .  other substance  (20)  light,  One  cells  Differentiation i s c o r t e x may  medullary  cell  with a vesicular  o f t h e most  i s their  is  r e a c h deep i s polynucleus  characteristic  c h r o m a f f i n i t y , which  adrenaline content.  32.  The layers.  cortex  consists of three  The e x t e r n a l z o n e , i m m e d i a t e l y  tissue  capsule,  i s called  small,  irregularly  structurally  under t h e connective  t h e zona g l o m e r u l o s a .  arranged  cells  different  I t contains  that contain scanty  The  nuclei  the  z o n a f a s c i c u l a t a , w h i c h c o n s i s t s o f r e g u l a r rows o f l a r g e  polygonal arranged these The  c e l l s with  vesicular nuclei.  r a d i a l l y , with  The n e x t  The c e l l  s i n u s o i d s b e t w e e n them.  layer i s  columns a r e The w a l l s o f  s i n u s o i d s are studded w i t h r e t i c u l o - e n d o t h e l i a l  zona r e t i c u l a r i s ,  sists with  are small but r i c h i n chromatin.  cytoplasm.  of irregular dark n u c l e i .  t h e i n n e r m o s t l a y e r o f the. c o r t e x ,  con-  strands which form a network o f small Many m e l a n i n and i r o n - p i g m e n t  phagocytes are found erable variation,  cells.  i n t h i s zone  t  Although  the zona f a s c i c u l a t a  cells  containing  there  i s consid-  i s always the w i d e s t  layer. B e c a u s e o f t h e numerous l i p i d cells,  especially  granules,  the cortical  i n t h e f a s c i c u l a t a , have a v a c u o l i z e d  p l a s m and a r e c a l l e d  spongiocytes.  Around the c e n t r a l  cytovein,  the c o r t e x i s i n v a g i n a t e d towards t h e medulla. The to occur  r e g e n e r a t i o n o f t h e c o r t e x i s b e l i e v e d b y some  from the outer  unanimously  accepted.  Islets adrenals,  s u r f a c e inwards, but t h i s view i s n o t  o f lymphatic  tissue  a r e o f t e n found  within the  e s p e c i a l l y under c e r t a i n p a t h o l o g i o a l c o n d i t i o n s such  as A d d i s o n ' s The  disease. adrenal  arteries  enter the gland  at various  33.  p o i n t s on  i t s surface  of the,blood so  t h a t the  flows latter  and  t h r u the  important muscular  vein.  cortex before  the metabolites  sphincters  i n the  T h e i r p e r i o d i c c o n t r a c t i o n and  collect with  v e i n emerges a t t h e  the  and  release  reaching  i s exclusively supplied with  maximally saturated with are  the  the  organism.  the  wall  the  venous  of the  blood  in  All  medulla, blood,  cortex.  There  central  relaxation helps  hormone s a t u r a t e d  requirements o f the  of  hilum.  to  accordance  34.  III.  Methods. As mentioned p r e v i o u s l y ,  itially  by D r . C h u t e  controls,  received  i n Toronto.  as f o l l o w s :  PS B 4 0 $ p r o t e i n , 1 0 $ a subgroup  A l l animals, i n c l u d i n g the  a d i e t o f known p r o t e i n and  The r a t s a r e i d e n t i f i e d  B  t h e r a t s were t r e a t e d i n -  salt  salt  ( f o r example  content.  PS  3 B 11).  diet.  i n the experiment.  11 s t h e number o f t h e e x p e r i m e n t . a t h e number o f t h e r a t i n t h e  3 The  s u b g r o u p s a r e as A  - Alloxanized  B  =  Alloxanized  C  =  Normal  D  follows: d i a b e t i c , weighed d i a b e t i c , weighed  E  =  Alloxanized  F  =  Alloxanized,  G  =  Alloxanized  d i a b e t i c , ad l i b d i e t p l u s  insulin.  insulin.  n o t d i a b e t i c , ad l i b d i e t . d i a b e t i c , w e i g h e d p r o t e i n and  intravenously  the i n j e c t i o n ,  salt  diet  with kidney pedicles and t w e n t y m i n u t e s  with hot s a l i n e packs  applied  t h e abdomen.  F r o m t h e above  s u b g r o u p s i t c a n be  methods were u s e d t o e n s u r e t h a t salt  diet plus  d i a b e t i c , ad l i b d i e t .  c l a m p e d f o r 10 m i n u t e s b e f o r e  to  only.  ad l i b n o r m a l d i e t .  CO r . A l l o x a n i z e d  after  diet  c o n t r o l , ad l i b d i e t .  - Alloxanized  plus  sub-group.  and p r o t e i n .  The CO  seen t h a t  the r a t s ingested  g r o u p was  the  various given  used t o determine whether  o r n o t t h e k i d n e y s were a f f e c t e d d i r e c t l y  by t h e  alloxan.  35.  The two  animals  months age  sacrificed  kept  or dying The  Toronto  and  were p l a c e d on  test  there f o r 3 - 4  kidneys  laboratory, while  months b e f o r e  and  the  adrenals, p i t u i t a r i e s  autopsies performed here was  followed this  removed by r a i s i n g t h e  adjacent  surrounding  moved and  t h e g l a n d was  and  hypertrophy,  of 1.  tracts  and  carefully  re-  cranial  vault.  etc.  The  adrenals  signs of hyperplasia, hypoplasia,  were  atrophy,  etc.  The types  lifting  a d r e n a l s w e r e examined g r o s s l y  s i g n s o f hemorrhage, d e g e n e r a t i o n ,  weighed to f i n d  optic  g l a n d was  f r e e d from the  Both p i t u i t a r i e s for  the  brains  procedure:  calvarium,  b a c k w a r d t o expose t h e  dura  and  Columbia.  t h e b r a i n upward and areas;  being  h e a r t were e x a m i n e d i n t h e  were s t u d i e d a t t h e U n i v e r s i t y o f B r i t i s h  the hypophysis  approximately  spontaneously.  livers,  The  at  a d r e n a l s were e x a m i n e d m i c r o s c o p i c a l l y u s i n g  three  stains. General to  s t a i n s s u c h as  hematoxylin  and  e o s i n were used  show t i s s u e c h a n g e s , h e m o r r h a g e s , and  t h e number  of  mitosis. 2.  Trichrome connective  connective tissue  tissue  s t a i n s were u s e d t o  infiltration  and  show  t h i c k e n i n g of w a l l s  of blood v e s s e l s . 3.  The  most i m p o r t a n t  the  s t a i n o f c h o i c e b e i n g Sudan I V .  stain dicate  s t a i n s u s e d were t h e  the c h o l e s t e r o l o f the the m e t a b o l i c  adrenal  s t a t e o f the  fat  I t was  stains, used  to  c o r t e x to i n -  hormone-producing  36  cells.  The method, a d a p t e d f r o m L i l l i e ,  i s o p r o p a n o l method f o r S u d a n I V .  used the s a t u r a t e d  T h e a d r e n a l s were  o n a f r e e z i n g m i c r o t o m e a t 15 m i c r o n s , s t a i n e d and h e m a t o x y l i n a n d mounted i n A p a t h e ' s  Gum  sectioned  i n Sudan I V  Syrup.  The p i t u i t a r i e s were s t a i n e d w i t h h e m a t o x y l i n and eosin as a general s t a i n .  S e c t i o n s were a l s o  B r i s e n o - C a s t r e j o n method f o r d i f f e r e n t i a l Azocarmine  staining  immersion  P r e s t a i n i n g o f t h e n u c l e a r membranes  i n alum h e m a t o x y l i n b r i n g s o u t t h e n u c l e i  s h a r p l y , m a k i n g c o u n t i n g much e a s i e r . for  c e l l a n a l y s i s . (10)  o f acidophil granules i s excellent f o r  sharp d i f f e r e n t i a t i o n . by a s h o r t  s t a i n e d by the  The c o m p l e t e  procedure  t h e r a t h y p o p h y s i s i s as f o l l o w s : 1.  F i x i n Zenker-formol, 6 - IS hours. Potassium bichromate  25 g r .  Mercuric bichloride  50 g r .  Ringer's solution Add  1000 m l .  1 c c . neutral formalin  10 m l . s o l u t i o n b e f o r e  using. 2.  Wash 6 - 1 2  3.  Dehydrate 30, 100$  4.  hours  i n running water.  i n alcohols:  50, 70, 8 0 , 9 5 % - 2 changes  - | hour  - 1 hour  each.  each.  Clear: (a) a b s o l u t e a l c o h o l - oedarwood o i l ( e q u a l 1 hour.  .  (b) oedarwood o i l ,  1 hour.  parts),  37.  (c)  x y l e n e , 15  5. I n f i l t r a t e  min.  i n hard p a r a f f i n  (a)  1 change  into paraffin  (b)  3 ohanges  (c)  embed.  (56 - 58° 0 ) . (5 m i n . ) .  hour e a c h ) .  6. S e c t i o n a t 4 m i c r o n s . 7. Remove p a r a f f i n w i t h ;xylene, 2 c h a n g e s , 3 m i n . 8. Two  changes a b s o l u t e a l c o h o l ,  9. A l c o h o l , 10. D i s t i l l e d  95$,  water, 3  min*  (4 I : 6K I : 100 HgO),  t h i o s u l f a t e , 0.5$  13. D i s t i l l e d  each.  3 min.  11. L u g o l ' s s o l u t i o n 12. Sodium  3 min.  water, 3  aqueous,  3  3 min.  min.  min.  14. A l u m h e m a t o x y l i n , 30 s e c . 15. Tap w a t e r  wash.  16. D i s t i l l e d  water, 3  17. A l c o h o l , 18. A n i l i n  80$ 3 m i n .  alcohol,  aniline  15  o i l  95$ a l c o h o l 19. S t a i n  min.  min.  1 ml. 1000  ml.  i n a z o c a r m i n e G a t 6 0 ° C , 45  azocarmine G  1 gr.  Distilled  100  water  Warm and a l l o w t o c o o l  ml. t o room t e m p e r a t u r e .  F i l t e r with f i l t e r  paper  Add  a c i d , 4 ml.,  glacial  acetic  min.  ( a l l day).  P l a c e i n oven 1 hour b e f o r e  to  using.  filtrate.  each.  38.  30.  Rinse  in distilled  21.  Differentiate 2-3  22.  water.  in anilin  (solution  18)  min.  Wash i n a c i d Glacial  alcohol,  acetic  Alcohol,  g - 1  acid  Phosphotungstic  24.  Dehydrate  in  acid,  5$,  1  ml.  hour.  alcohols: 2  A l c o h o l 95$,  2 min.,  min.  . Absolute alcohol, Counterstain i n acid green  not  longer.  2 min. green  o r more. solution,  0.1  gr.  G  0.5  gr.  Clove O i l  100  ml.  Orange  ml.  1000  A l c o h o l 70$,  Acid  min.  10  95$  23.  25.  alcohol  5  min.  r  Use  fresh  26.  lylene,  27.  Two  28.  Mount.  red, beta c e l l  cells  alpha c e l l  granules  green,  orange,  Golgi  to p a l e  apparatus o r no  are  nuclear  d e f i n e d , m i t o c h o n d r i a are orange-red,  n e g a t i v e image, chromophobes show l i t t l e  The  each.  granules are l i g h t  are b r i l l i a n t  which i s c o l o u r l e s s  slides.  min.  t h e above s t a i n i n g ,  membranes a r e w e l l blood  20  c h a n g e s x y l e n e , 30 m i n .  After purplish  1  s t a i n f o r each  red  shows a s  cytoplasm,  green.  c o u n t i n g method was  m o d i f i e d f r o m Rasmussen,  a  39.  1922. All  The the  rat p i t u i t a r y i s sectioned i n  cells  are  three horizontal  counted i n every f i f t h sections  at  equidistant  Most v a r i a t i o n  in cell  and  r e g i o n s , which are  a  peripheral  center section.  u s i n g one  the  type of  investigators.  but  can  be  acid  the  with acetic  acid.  E a c h has  so cell  different  Zenker - formol type subsequent  counts of  be  be  divided  without bichloride osmic  disadvantages.  The  colour d i f f e r e n t i a t i o n i n  criticized  against  i t s use  cell  counts i n that  i t p r e s e r v e s m i t o c h o n d r i a , which' a r e  cult  to  from a c i d o p h i l  the  distinguish  least  tinctorial dissolves are  cellular  d i s t o r t i o n but  differentiation. out  excellent  granules. does n o t  acetic  m i t o c h o n d r i a from the for  cytological  a p p a r a t u s , but  are  of  of  and  tissue  variability  The  little  damage.  in diffi-  Bouin s  gives  p r o v i d e as  sharp  acid  scene.  detail, use  to  different  those which contain  excellent  I t can  use  i t i s important  t e c h n i q u e s can  a d v a n t a g e s and  gives  staining^  and  by  thus,  The  those without mercuric  acid{Bouin's); i t s own  central  hypophysis markedly i n -  i n comparing the  (Zenker - f o r m o l ) ;  gland.  counted  3 groups: those c o n t a i n i n g mercuric b i c h l o r i d e ,  acetic  of  counting.  acidophils,  by  between t h e  p i t u i t a r y gland.  f i x a t i o n of  Fixation  i n each  b o t h sampled a d e q u a t e l y  facilitates  percentage of  consider t h i s factor  into  of the  colour f i l t e r s The  fluences  percentage e x i s t s  section  field  plane.  l e v e l s i n the  About-1200-1400 c e l l s  central  of v a r i o u s  a horizontal  T  contained  therein  Osmic a c i d  methods  especially  in differential  for  Golgi  counts  because  40.  The t y p e o f f i x a t i o n determining different  t h e a p p r o x i m a t e c o n t r o l v a l u e as r e p o r t e d b y  investigators.  32-40$ a l p h a c e l l s , usingzenker found  seems t o be f u n d a m e n t a l i n  Thus W o l f e , u s i n g Regaud's  as d i d P f e i f f e r ,  Finerty  and B r i s e n o ,  - f o r m o l ; F i n e r t y , Meyer and M a r v i n ,  24 - 27$.  found  using  Bouins,  41.  IV  Results:  R a t No.  A d r e n a l Wt.  PS 3 A 11  i n mgm.  Gross  Observations.  27  7  41  9  32  12  31  13  34  14  20  16  22  17  29  18  28  Average  50  PS  2 B 11  34  3  27  i  4 5  52  Very f a t .  7  54  Pituitary hemorrhage.  •8  35  10  42  11  25  12  27  13  31  14  56 58  Average PS 1 C 2  11  34 16  42.  R a t . No.  A d r e n a l Wt.  3  39  4  20  5  39  6  17  Average  27  PS 2 D 11  35  4  45  i n mgm.  Gross  Observations.  Small  hemorrhage.  5 6  30  7  52  8  43  Dark  10  38  Spotty  11  40  12  24  Average  38  PS 1  T 11  31  3  33  4  40  6  50  7  44  8  37  9  51  Average  38  PS 1 0 11  35  2  33  3  38  discolouration. discolouration.  43  R a t . No.  A d r e n a l Wt.  5  36  6  49  Average  58  S I  £0  D 10  i n mgm.  Gross  Observations.  discolouration.  ,  5  £5  Dark  5  £4  Hemorrhage.  9  44  12  50  15  50  Average  28  S  55  2 E  7  5  45  Average C  40  0 10  50  12  30  15  40  25  56  Hemorrhage.  41  32  Dark  46  42  29  Average 2.  -  59-  S m a l l h e m o r r h a g e s were f r e q u e n t b o t h adrenals of a l l experimental ( F i g , 4)  discolouration.  i n the p i t u i t a r i e s  subgroups except the  A more common o c c u r a n c e  was  and  controls.  t h e engorgement o f  the  44  blood  sinuses of these glands  (Fig.  5).  3.  Several classical seen. one  Two  examples o f s e v e r e  examples o f  i n the  t o about twice  width.  arteriosclerosis  e n d a r t e r i t i s o b l i t e r a n s are  adrenal cortex  r e l a t e d p a r t o f the  t h e i r normal  ( F i g . 1) and  were  shown,,  t h e o t h e r i n an  body, t h e s a l i v a r y g l a n d  ( F i g , 2).  P r o l i f e r a t i o n o f the media w i t h complete disappearance the e l a s t i c a 4.  Mitotic  i n t e r n a was  w h i c h some a u t h o r s dant 5.  i n both  6,  drop  i n cholesterol. no  8)  apparent  except  showed t h e which the  and  i n the  to note  The  CO  i n c h o l e s t e r o l content.  c h o l e s t e r o l was  i n the p r o c e s s  F  adrenals. small  that there  extent of t h i s  given i n s u l i n therapy.  same d r o p  groups  i n the  animals w i t h those  decrease  t h a t had group Cells  of being  been  also in  utilized  i n t h e n o r m a l s were e a s i l y d i s c e r n a b l e  due  t o the f a c t  its  s p h e r i c a l g l o b u l e t h e r e was  t h a t a s t h e c h o l e s t e r o l was  crescent  shape  appeared  completely.  The  granules,  only a r e l a t i v e l y  I t i s important  difference  more q u i c k l y t h a n  6.  t h e c o n t r o l s and  G r o u p s F & A had  when c o m p a r i n g a l l o x a n i z e d alloxanized  Chromatin  depletion of cholesterol  Fig.  was  7 and  ( F i g . 3)  (Fig. 8).  animals  showed s e v e r e  of  r e f e r t o as p r o c h r o m o s o m e s , were abun-  glands.  A l l experimental & A  common i n t h e b r a i n .  f i g u r e s were s u r p r i s i n g l y r a r e .  un-  ( F i g . 7 and  8)  left  behind  removed a  from  characteristic  before the c h o l e s t e r o l  f o l l o w i n g t a b l e shows t h e p e r c e n t  r a t i o of the  dis-  three  45.  cell  types  method.  i n the p i t u i t a r y  a s shown by t h e B r i s e n o - C a s t r e j o n  (See F i g . 9) Ratio. beta  chrom.  47  6  47  46  7  47  52  7  41  7  67  6  27  8  54  7  39  41  7  52  3  40  7  53  4  40  7  53  50  7  43  54  6  40  43  6  51  45  6  49  55  6  39  53  7  40  56  6  38  3  52  7  41  6  56  7  37  13  55  6  39  S 5 E 7  57  6  37  GO  10  46  7  47  15  70  6  24  23  83  4  13  Rat.  No.  PS 3 A  11  9 PS 3 B 11  PS 1 0 11  PS 2 D  11  4 PS 1 F  11  3 PS 2 G 11 6 S 1 D  10  alpha  %  46.  7.  A comparison the p e r c e n t  of the percent  i n c r e a s e i n a d r e n a l weight  increase i n p i t u i t a r y  acidophils i s given i n  the f o l l o w i n g t a b l e : % Increase i n A d r e n a l Wt.  Group  % Increase i n P i t . acidophils  PS -  A  11.1  15  PS -  B  40.7  45  PS -  D  40.7  30  PS - V  40.7  10  PS -  G  40.7  35  S -  B  3.7  35  S -  E  48.1  43  44.4  65  CO  with  47.  Fig.  1. Endarteritis obliterans  c o r t e x o f r a t PS 12 A 11. is  almost non-existent, x  i n an a r t e r y o f t h e a d r e n a l  Note t h e s i z e o f t h e lumen, w h i c h 1000.  48.  Fig.  2. Endarteritis obliterans  of r a t S 9 D 10,  i n the s a l i v a r y gland  showing the laminated nature of the  oocluding t i s s u e , x  1000.  49.  Fig.  3. Proliferation  the of  cerebral  cortex  the elastica  o f the media  of rat S  3 D  interna, x 4 4 0 .  10.  i n three Note  the  arteries  of  disappearance  50.  Fig.  4.  Large i n t e r n a l hemorrhage i n the adrenal cortex of r a t PS IS A 11,  The hemorrhage was situated across the  junction of the zona f a s e i c u l a t a and the zona r e t i c u l a r i s .  x 800.  51.  mm %  F i g . 5. A low power view of the adrenal cortex of r a t PS 5 D 11 showing the greatly expanded blood sinuses.  Note  the r e l a t i v e d i s t r i b u t i o n of blood to the three layers. (Mallory-Heidenhain rapid connective tissue s t a i n ) , x 180.  r  52.  F i g . 6. Low power view of the adrenal cortex of r a t PS 4 0 11 stained with Sudan IV i n isopropanol to show the normal d i s t r i b u t i o n of l i p i d material, x 400.  53.  Fig. 7. Greatly magnified view of nearly exhausted adrenal cortex of r a t PS 5 G 11 stained with Sudan IT.  Note the  t y p i c a l crescent shaped structure formed as cholesterol i s u t i l i z e d from the globule i n which i t i s stored, x  3 5 0 0 .  54.  Fig.  8. A similar condition to that  s l i g h t l y more s e v e r e . upper  centre  Note the t y p i c a l  o f the photograph.  nuclei  i s also  R a t CO  10.  s e e n i n F i g . 7,  clearly visible  crescent  but  i h the  Chromatin m a t e r i a l  of the  i n many o f t h e c e l l s , x  2500.  55.  A typical  basophil c e l l with p l e n t i f u l l i g h t l y stained  cytoplasm  i s seen near  have d a r k e r little of  the centre.  The numerous  acidophils  s t a i n e d c y t o p l a s m w h i l e t h e chromophobes h a v e  o r none.  alphas: betas:  The a o i d o p h i l c o u n t chromophobes •  i s high, the %  55: 6: 39, x,  1700.  ratio  56.  Discussion  and It  Conclusions:  i s apparent from t h e r e s u l t s obtained  pituitary-adrenal  systems o f t h e experimental  a state of hyperactivity. unilateral the  I n many t y p e s o f e x p e r i m e n t s , a s i n  regains  function thru hypertrophy. c e r n e d , however, t h e r e  I n the case w i t h  depletion o f adrenal  increased p i t u i t a r y  a c i d o p h i l count.  At this point,  three  f a c t s should  be n o t e d ,  that a l l animals, i n c l u d i n g the c o n t r o l s , received a  protein,  high  salt  diet,  ( i i ) that a l l o x a n i z e d animals  o n l y one d o s e o f a l l o x a n and t h a t stroyed that  t h e r e was no d i f f e r e n c e i n t h e r e s u l t s o b t a i n e d a n i m a l s when i n s u l i n was g i v e n  c a n be s e e n t h e n t h a t t h e d i a b e t e s  pathological the  diet  logical  That  i s not a s u f f i c i e n t  aided  and a b e t t e d  such a small  de-  and ( i i i ) for all-  i s not a factor i n the  stimulus.  that the alloxan i s the i n i t i a l  sequently  received  t o remedy t h e d i a b e t e s .  c o n d i t i o n s w i t h w h i c h we a r e c o n c e r n e d .  alone  high  such a dose i s c o m p l e t e l y  i n t h e body f i v e m i n u t e s a f t e r i t s i n j e c t i o n ,  oxanized It  w h i c h we a r e c o n -  t h e demand f o r c o r t i c a l hormones must be c o n t i n -  uously high. (i)  t o n o r m a l when  the necessary l e v e l o f c o r t i c a l  i s a sustained  c h o l e s t e r o l and a oonstant Therefore,  a n i m a l s were i n  adrenalectomy, the p i t u i t a r y r e t u r n s  remaining adrenal  that the  Similarly,  I t therefore  seems  a g e n t o f s t r e s s , sub-  by t h e d i e t a r y p r o t e i n and s a l t .  f a c t o r a s a s i n g l e dose o f a l l o x a n  acting  o v e r s u c h a s h o r t p e r i o d o f time c o u l d have such a g r e a t  effect  i s made p l a u s i b l e b y two f a c t s .  short  One i s t h a t d u r i n g  time, the a l l o x a n i s capable o f destroying beta  c e l l s of the i s l e t s  o f Langerhans.  that  the insulin-producing  The o t h e r  i s that  57  hypertension, has  been p r o d u c e d by a former s t u d e n t  only a single The  c o m p a r a b l e t o what i s p r o d u c e d i n t h e s e  nature  at this university  t h e same a s t h a t o f t h e h o s t  agents o f s t r e s s .  But i t i s tempting  could attack the adrenals i n which i t destroys i s l e t  syndrome  o f other n o n - s p e c i f i c  to speculate that alloxan  d i r e c t l y i n a s i m i l a r manner t o t h a t tissue.  Since the adrenal  one o f t h e h i g h e s t g l u t a t h i o n e c o n t e n t s  gland  o f any t i s s u e i n  t h e body and because o f t h e f a c t t h a t a l l o x a n removes thione from t h e blood a direct case,  using  s m a l l d o s e o f d e s o x y c o r t i c o s t e r o n e a c e t a t e . (70)  of the action o f alloxan i n the adaptation  i s probably  has  animals,  and a t t a c k s s u l f h y d r a l s i n g e n e r a l ,  action i s a definite possibility.  t h e p r o b l e m w o u l d be a l m o s t  adrenalectomy-salt  glutasuch  I f t h i s was t h e  i d e n t i c a l with the f a m i l i a r  experiments t h a t are a l s o concerned  with  stress. The  effect  of the diet  on t h e e x p e r i m e n t a l  r e c e i v e s some p o s s i b l e c l a r i f i c a t i o n PS-A, tein  and S-D & 33. i n the d i e t  of these did  T h e method o f s u p p l y i n g t h e s a l t  o f group A d i d n o t g i v e t h e a n i m a l s  t h e more a c c u r a t e methods u s e d i n t h e l a t e r g r o u p G.  difficult  contained  i n groups and p r o a s much  two components a n d a s much a d r e n a l h y p e r t r o p h y  especially is  by t h e r e s u l t s  animals  as  experiments,  There i s a d i s c r e p a n c y between A & B t h a t  to explain.  i n the i n s u l i n  There i s a p o s s i b i l i t y t h a t t h e z i n c c o u l d have o a u s e d an a l l e r g i c o r  p o i s o n i n g a c t i o n a s i t o c c a s i o n a l l y does i n some human p a t i e n t s . On t h e o t h e r h a n d , t h e l o w v a l u e s o b t a i n e d which the a l l o x a n f a i l e d  i n g r o u p 3?, i n  to produce d i a b e t e s , a r e probably  only  58.  due  to a high l e v e l of c i r c u l a t i n g  at the  time  of i n j e c t i o n of the  i n w h i c h s a l t was with  those  factor  and  then  supply  and  established fact  hormones i n t h i s  important  stress,  i s a sustained  experiment, then  salt  coming i n t o CI  content  t o t h a t seen i n t h e If this  retaining  of the  blood.  sequence o f events  i s prolonged,  out,  be  t h e r e may occurs.  the animals  and,  d i e d a spontaneous  adaptation the  horpoints  e v i d e n t , s i n c e some o f  method b y w h i c h t h e  The  cholesterol  death.  p r o d u c e t h e h y p e r t e n s i o n may  a direct  i s com-  as S e l y e  showed a c o m p l e t e a b s e n c e o f a d r e n a l  following paths.  the  a l a c k o f t h e s e hormones when t e r m i n a t i o n o f  T h i s e x h a u s t i o n p h a s e was  The  hor-  critical  This r i s e  r e s i s t a n c e phase o f the  over-  there  hormones on  t h e b o d y must c a u s e a  mechanism becomes e x h a u s t e d  exert  more  t h a t t h e r e i s an i n -  that there  mone p r o d u c i n g  and  The  S-E,  parallel  demand f o r c o r t i c a l hormones d u r i n g  a c t i o n of these  content  syndrome.  life  and  salt.  been c o n f i r m e d  i n c r e a s e i n t h e Na parable  G r o u p s S-D  an i n c r e a s e d amount o f c i r c u l a t i n g D.C.A. t y p e  The  high salt  the  i t i s an  p r o d u c t i o n of these s h o u l d be  animals  a d d e d b u t n o t p r o t e i n , gave r e a d i n g s  i s probably  s i n c e i t has  mones.  alloxan.  obtained with p r o t e i n included.  Since creased  sulfhydrals i n the  high  salt  and m i n e r a l o - c o r t i c o i d s  i n v o l v e one  or both of the  sodium l e v e l i n the  a c t i o n on t h e w a l l s o f t h e  blood  arteries  two  might  due  to  the  t e n d a n c y o f sodium t o cause s u s t a i n e d muscular c o n t r a c t i o n therein.  Again,  the m i n e r a l o - o o r t i c o i d s c o u l d cause a  nephritic  59.  t y p e o f h y p e r t e n s i o n b y t h e i r h y a l i n i z i n g a c t i o n on There are important pathology o f alloxan to  the d i e t .  differences  diabetes  The c o n d i t i o n s  and t h a t  between t h e u s u a l  s e e n when s a l t  seen i n the l a t t e r  and r e m a r k a b l e p a r a l l e l i s m t o t y p i c a l ,  occurring  diabetes  the  salt  alone. betic  mellitus  naturally  T h u s one f i n d s a r t e r i o s c l e r o s i s ,  f a t t y degeneration of the l i v e r , i n both diabetes  i s added  show a n i n -  teresting  mellitus.  glomeruli.  nephrosclerosis  and i n t h e a l l o x a n i z e d  and f i b r o s i s animals  having  d i e t i n t h i s experiment, but not i n a l l o x a n i z e d D r . C h u t e h a s made t h e c l i n i c a l  c h i l d r e n consume a b n o r m a l l y l a r g e  observation  animals  that  dia-  quantities of salt.  From t h i s f a c t and from t h e r e s u l t s o f t h i s t h e s i s i t appears likely  that  diabetes  the only  reason that alloxan  mellitus pathologically i s that  diabetes  differs  l a b animals kept  a l l o x a n i z a t i o n do n o t n o r m a l l y g e t t h e c h a n c e t o i n g e s t salt  a s w o u l d human d i a b e t i c s .  alloxan the  diabetes  f a c t that  diabetes by  the lab. animals a r e f e d a b e t t e r  that  d i e t than t h e i r  Conversely, the complications  of salt.  extra  mellitus lies i n  must be due t o a s e c o n d a r y h y p e r t e n s i o n  the craving  after  I n o t h e r words, t h e r e a s o n  i s n o t t h e same a s d i a b e t e s  human c o u n t e r p a r t s .  from  o f human caused l a r g e l y  60.  Summary. The  pituitaries  and a d r e n a l s o f a l l o x a n i z e d d i a b e t i c  r a t s f e d h i g h p r o t e i n and s a l t adrenal  systems o f t h e s e  activity,  diets  animals  were i n a s t a t e o f h y p e r -  a s shown b y a d r e n a l h y p e r t r o p h y ,  c h o l e s t e r o l and i n c r e a s e d p i t u i t a r y insulin  showed t h a t t h e p i t u i t a r y -  acidophils.  t o remedy t h e d i a b e t e s a n d t h e o m i s s i o n  the d i e t  d i d not a l t e r  showed t y p i c a l  signs of hypertension  It  was c o n c l u d e d  that the animals  an  agent o f s t r e s s i n conformity w i t h  tained  the r e s u l t i n g Normally,  degeneration  such  fatty  that the high salt  content  variety.  only reason  o f p r o t e i n from The  animals  as a r t e r i o s c l e r o s i s ,  were r e s p o n d i n g  and h e m o r r h a g e s . t o a l l o x a n as  the adaptation  syndrome  aggravated  and sus-  hypertension. the pathology  of alloxan diabetes However o n t h e s a l t  differs diet the  o f d i a b e t e s was t h e same a s t h e n a t u r a l l y o c c u r r i n g  S i n c e D r . Chute has observed  abnormally  The u s e o f  o f the l i v e r  of the diet  from t h a t o f diabetes m e l l i t u s . a l l o x a n type  adrenal  the extent o f t h i s response.  nephrosclerosis,  and  depleted  large quantities of s a l t ,  that diabetics  i t i s proposed that the  t h a t a l l o x a n d i a b e t e s does n o t resemble  mellitus pathologically r e g u l a t i o n foods  i s that l a b animals  t h a t do n o t p e r m i t  a d o u b t f u l luxury enjoyed the hypertension bably l a r g e l y  by t h e i r  diabetes  are u s u a l l y kept  t h e i n g e s t i o n o f excess human c o u n t e r p a r t s .  t h a t so o f t e n c o m p l i c a t e s  due t o t h e s a l t  consume  intake.  on salt,  Conversely,  human d i a b e t e s i s p r o -  61.  References: 1.  Albright, E. & Elriek, D i s o r d e r s Of The  H;  An A t t e m p t To C l a s s i f y Hormone  Hypophysis.  T r a n s . A s s o c . Am. P h y s i c i a n s . , 61, 4 2 , 1948. 2.  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