plomestane and Hypertension

Rats susceptible to the hypertensive effect of dietary salt (SS/Jr) have excess urinary 19-nordeoxycorticosterone compared with salt-resistant control rats (SR/Jr). 19-Nordeoxycorticosterone is a hypertensinogenic mineralocorticoid, but whether it contributes to the salt sensitivity of SS/Jr is unknown. This study sought to evaluate the contribution of 19-nordeoxycorticosterone to the salt sensitivity of SS/Jr by lowering its production with an aromatase inhibitor, 10-propargyl-androst-4-ene,3,17-dione (19-acetylenic-androstenedione, 19-AA). This aromatase inhibitor also preferentially inhibits nonaromatizing adrenal 19-hydroxylation, an essential step in the formation of 19-nordeoxycorticosterone. To test this hypothesis, inhibitor (120 mg) or vehicle pellets were implanted into male and female weanling SS/Jr at 42 days of age. A high salt diet (8% NaCl) was started and two additional pellets were implanted at 52 and 62 days of age. Systolic blood pressure was measured in all animals and urinary corticosteroids in males. Compared with vehicle, the inhibitor lowered blood pressure at 50 days of age (when it could first be measured) until 64 days of age in females and 71 days of age in males. Corticosterone and aldosterone levels were not different between 19-AA- and vehicle-treated SS/Jr. 19-Nordeoxycorticosterone levels, however, were mildly reduced with the inhibitor (0.05 less than p less than 0.10). After 28 days of high salt diet all 23 of the 19-AA-treated SS/Jr were alive, whereas almost one half of the control animals had died. These data demonstrate that 19-AA attenuates the hypertension in SS/Jr; this effect may be through reduction in 19-nordeoxycorticosterone production.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aldosterone; Androstenedione; Animals; Antihypertensive Agents; Aromatase Inhibitors; Cortisone; Desoxycorticosterone; Female; Hypertension; Male; Pargyline; Rats; Rats, Inbred Strains; Sodium Chloride

Recent studies from this laboratory have demonstrated that 19-nor-deoxycorticosterone, a potent mineralocorticoid, has been excreted in excess in the urine of young spontaneously hypertensive rats (SHR). Although urinary 19-nor-deoxycorticosterone levels decline before the onset of hypertension, preliminary evidence suggests that 19-nor-deoxycorticosterone is further oxygenated to other steroid products in older SHR. Since 19-hydroxylation is the essential first step in the formation of 19-nor-deoxycorticosterone from deoxycorticosterone and since the mechanism-based aromatase inhibitor 10-propargyl-androst-4-ene,3,17-dione preferentially inhibits 19-hydroxylation, this agent was administered to weanling SHR to determine whether inhibition of 19-nor-deoxycorticosterone formation could modify or prevent hypertension. Accordingly, either 10 mg of 10-propargyl-androst-4-ene,3,17-dione or vehicle (control) was injected daily for several weeks in 4.5 week-old SHR. Injection of 10-propargyl-androst-4-ene,3,17-dione reduced urinary free 19-nor-deoxycorticosterone and retarded the development of hypertension compared with the effect of vehicle injection (p less than 0.05). Mean blood pressure levels in SHR receiving 10-propargyl-androst-4-ene,3,17-dione were lower than those in SHR receiving vehicle for each of the first 8 weeks of treatment (p less than 0.05). These data support the importance of 10-nor-corticosteroids in the pathogenesis of hypertension in SHR.

Topics: Aging; Androstenedione; Animals; Blood Pressure; Desoxycorticosterone; Hypertension; Male; Pargyline; Rats; Rats, Inbred SHR