UBC Theses and Dissertations
Role of aldosterone and the aldosterone binding globulin in experimental and spontaneous hypertension Nowaczynski, Mark John Joseph
It is known that the binding capacity of the plasma aldosterone binding globulin (ABG) for aldosterone is increased in 52% of subjects with essential hypertension (EH), but not in individuals with secondary forms of hypertension. It was also previously shown that this elevation in the ABG binding capacity for aldosterone is transmitted as an autosomal dominant trait in families with a history of EH, which suggested that augmented ABG binding capacity could serve as a genetic marker of EH. To examine whether or not ABG played a role in the development of EH, the urinary homologue of ABG (ABG-TsU) was isolated from pooled human urine and administered to normotensive Sprague-Dawley rats to see if hypertension could be induced. ABG-TsU was purified by differential ultrafiltration, ion exchange chromatography, and gel filtration to electrophoretic homogeneity and was shown to bind aldosterone and dehydroepiandrosterone sulfate with high affinity. ABG-TsU administered once daily i.p. produced a sustained increase in blood pressure (BP) in 5-8 days. After 12 days ABG-TsU treated rats were hypertensive and had increased heart weights but showed no changes in plasma electrolytes, aldosterone, or plasma renin activity (PRA). This hypertension was however aldosterone dependent since it was prevented by adrenalectomy or administration of a spironolactone but not by adrenalectomy when physiological amounts of aldosterone were concomitantly administered with ABG-TsU The elevated BP in rats treated with ABG-TsU for two weeks was due to increased cardiac output since total peripheral resistance remained inappropriately normal. ABG-TsU induced hypertension thus resembled borderline EH both hormonally and hemodynamicaily, which suggested that ABG may be playing a pathophysiological role in some subjects with EH. ABG-TsU was isolated from individual normotensive subjects (normal ABG binding capacity), from a patient with renovascular hypertension (normal ABG binding capacity), and from EH subjects with either high (EHH) or normal (EHN) ABG binding capacity in order to see if the hypertensinogenicity of ABG-TsU represented a qualitative difference in some EH subjects. Equivalent doses of ABG-TsU were administered over a two week period to Sprague-Dawley rats. Only ABG-TsU from subjects with EH having increased ABG binding capacity (EHH) induced hypertension. ABG-TsU may thus differ qualitatively in a subgroup of subjects with EH and may be of etiological importance in those with increased ABG binding capacity for aldosterone (EHH). The role of mineralocorticoids in the development and maintenance of hypertension in the spontaneously hypertensive rat (SHR) was investigated starting at 7,10. and 12 weeks of age by continuously administering spironolactone for one or two weeks. Spironolactone treatment of SHR from 7-9 weeks of age attenuated the rise in BP, but spironolactone treatment of , SHR starting at 10 or 12 weeks of age failed to affect BP. The importance of aldosterone in the initial development of the hypertension was examined in 7 week old SHR which were either sham operated (SHAM), adrenalectomized (ADRX), or adrenalectomized and given physiological amounts of aldosterone from 7-9 weeks of age (ADRX+ALDO). At 9 weeks of age SHAM rats were very hypertensive, ADRX rats were normotensive, and ADRX+ALDO rats were hypertensive (in ADRX+ALDO rats BP was half way back to SHAM levels). No difference in plasma aldosterone, Na⁺, K⁺, or PRA existed between SHAM and ADRX+ALDO rats, indicating that the replacement dose of aldosterone chosen was indeed physiological. It is concluded that mineralocorticoids play a role in the development but not in the maintenance of hypertension in the SHR since spironolactone attenuates the BP increase at 7-9 weeks of age but not once the hypertension is more established. Aldosterone therefore appears to be a major initiator of this hypertension, accounting for approximately half of the adrenal dependent component of spontaneous hypertension in the rat during its development.
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