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The role of endothelin in the multihormonal regulation of fluid retention in congestive heart failure

University of British Columbia

Abnormal fluid retention is characteristic of congestive heart failure (CHF). The mechanisms responsible for this phenomenon are unclear. Recently, the role of endothelin (ET) in the pathophysiology of CHF has been given much attention. Studies were conducted to elucidate how ET may contribute to salt and water retention. Cardiomyopathic (CM) hamsters with a moderate degree of heart failure were employed for in vivo and in vitro trials. Clearance methods were used to determine the level of renal function in CM hamsters in comparison with age- and sex-matched control animals. Plasma and urine samples were collected for determination of haematocrit, plasma protein concentration, glomerular filtration rate (GFR), and sodium and water excretion while mean arterial blood pressure (MAP) was monitored intermittently. Radioligand binding studies were carried out to determine ET receptor distribution in the inner medullary collecting duct (IMCD) of CM and control hamsters. The effects of chronic enalapril therapy on renal function and ET receptors were investigated to deduce any interaction between the renin-angiotensin-aldosterone system (RAAS) and the ET hormonal system. Studies were also performed to measure the stimulation response of IMCD cells to ET-1 or to angiotensin II administration. The results demonstrated that renal excretion of sodium and water was diminished in the CHF hamsters in response to atrial natriuretic peptide (ANP) infusion and the fractional excretion of these variables decrementally decreased with increasing severity of heart failure. Binding studies revealed an equal distribution of ETA and ETB receptor subtypes in the IMCD of the hamsters and these receptors, particularly the B variety, were downregulated in the diseased animals. A similar negative correlation was apparent between the receptor density and the degree of cardiac dysfunction — the number of ET receptors declined as heart failure became more pronounced. Following chronic treatment with the angiotensin converting enzyme (ACE) inhibitor, enalapril, an improved renal excretory response to ANP was observed with simultaneous restoration of ET receptor density in the IMCD cells. Furthermore, the correlations of the severity of heart failure, fractional excretion of electrolytes, and receptor density, were abolished with enalapril. Cells of the IMCD in CM hamsters exhibited lower basal levels of cGMP accumulation than those of the normal controls. Stimulation of the IMCD cells with ET-1 showed a dose-dependent increase in cGMP production in both CM and healthy animals, but the responses were attenuated in the former. This blunted response may represent a reduction in ET receptor number in the CM hamster kidneys. Incubation of rat IMCD cells with low-concentration angiotensin II displayed a downregulation of ET receptors with an increase in receptor affinity. Co-incubation with the angiotensin receptor antagonist, saralasin, prevented this downregulation and the ET-1 binding affinity remained constant. These results suggest that angiotensin II may participate in the regulation of ET receptor expression. When the data are taken together, there is a strong implication that ET, in combination with angiotensin II, contributes to the regulation of salt and water homeostasis. That renal excretory function is improved with concomitant restoration of ET density after enalapril therapy is convincing evidence that these two hormones interact to promote abnormal fluid retention in the setting of CHF. In conclusion, in the CM hamster model, it is the insufficient ET receptor density, secondary to angiotensin II activation, that results in the unchecked reabsorption of electrolytes by the kidneys in CHF.

Thesis/Dissertation

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2009-02-11

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http://hdl.handle.net/2429/4470

Experimental Medicine

University of British Columbia

UBCV

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