Defense Date

1990

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Physiology and Biophysics

First Advisor

Mohammed Y. Kalimi

Abstract

Excess adrenocorticosteroid hormones such as glucocorticoids and mineralocorticoids is well known to induce hypertension in several animal species as well as in humans. Therefore, the development of potent and specific glucocorticoid and mineralocorticoid antagonists with antihypertensive effects is clinically necessary. steroid hormone antagonists being used therapeutically present serious endocrinology side effects such as the widely used antimineralocorticoid, spironolactone. The antiglucocorticoids available so far have been active only in vitro or only weakly in viva. Recently, three new exciting adrenocorticosteroid hormone antagonists have been synthesized. RU 486 is a potent antiglucocorticoid (and antiprogesterone with potential as an abortifacient), RU 26752 and mespirenone, are novel mineralocorticoid antagonists. I studied the antihypertensive effect of RU 486, RU 26752 and mespirenone in Sprague- Dawley rats with dexamethasone- or aldosterone-induced hypertension. In addition, the effect of these antagonists on the hypertension developed by genetic model, spontaneously hypertensive rats (SHR) were also studied. The SHR is the closest animal model to human essential hypertension and it is believed that adrenocorticosteroid hormones are involved in the induction and maintenance of the hypertension. The results obtained from my studies showed that RU 486 administered simultaneously with dexamethasone prevented the hypertension induced by dexamethasone treatment. However, RU 486 had no effect on mineralocorticoid-induced hypertension. The administration of the antimineralocorticoid RU 26752 or mespirenone in combination with aldosterone successfully presented aldosterone-induced hypertension but not dexamethasone- induced hypertension. Surprisingly, RU 486 caused a significant increase in the blood pressure of the SHR whilst mespirenone caused a slight decrease in blood pressure as compared to control SHR.

The effect of these antihormones on body/organ weights, fluid intake and urinary output was observed. Morphologically examination of the heart and kidney showed no abnormalities with treatment. These results suggest that 1) RU 486 is specific in preventing dexamethasone-induced hypertension; 2) RU 26752 and mespirenone are successful in preventing aldosterone-induced hypertension and 3) mineralocorticoids may be involved in the development and maintenance of hypertension in the SHR.

Comments

Scanned, with permission from the author, from the original print version, which resides in University Archives.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

8-1-2017

Included in

Physiology Commons

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