Prostanoids and aldosterone-induced mild experimental hypertension in rats.

Abstract

The goal of this study was to determine the role of prostanoids in a new model of mineralocorticoid-dependent hypertension induced by the subcutaneous infusion of aldosterone (1 fig/hT) to normal male Sprague-Dawley rats. This regimen caused a mild and gradual increase in systolic pressure over a period of 4 weeks (113±1 vs. 137±3 mm Hg) and was associated with an increase in the in vivo formation of prostaglandins I 2 and Ej and of thromboxane A 2 in the kidney. High sodium intake induced a fall in the urinary levels of prostaglandin E? aQ d a rise in the arterial pressure of control rats (126±1 vs. 113±1 mm Hg) but did not influence aldosterone-induced hypertension. Indomethacin (3.0 nig/kg/day) caused a profound inhibition of the in vivo synthesis of prostaglandin I 2 and thromboxane A 2 without modifying the renal production of prostaglandin E 2 . Although indomethacin exerted no effect on aldosterone-induced hypertension in rats fed a normal diet, it caused a further rise in systolic pressure in aldosterone-treated rats fed a high sodium diet (157±6 vs. 140±4 mm Hg). The results of this study in a model of aldosterone-induced mild hypertension in the rat indicate that 1) aldosterone exerts a stimulatory effect on the renal synthesis of prostanoids, particularly prostaglandin E?; 2) thromboxane A 2 and prostaglandin I 2 do not seem to play a role in aldosterone-induced hypertension under conditions of normal dietary salt intake, whereas the role of prostaglandin E 2 is unclear; 3) there is enough sodium in a normal diet to allow for the maximal expression of the hypertensive effect of aldosterone; 4) prostaglandin I 2 seems to play a significant role in modulating the cardiovascular impact of a high sodium diet in aldosteronetreated rats; and 5) the renal biosynthesis of prostaglandin E 2 is particularly resistant to the inhibitory effect of indomethacin in vivo. induced a further fall in blood pressure, suggesting that the concomitant formation of a pressor prostanoid could contribute to mineralocorticoid-induced severe hypertension. However, these models, which combine mineralocorticoid administration with uninephrectomy or the addition of sodium chloride to drinking water at an isosmolar or hyperosmolar concentration, are situations rarely encountered in clinical medicine.The objective of the present study was to investigate the role of prostanoids in a model of mineralocorticoidinduced hypertension that resembles more closely human primary aldosteronism. The results include the influence of aldosterone, dietary salt, and indomethacin on the systolic arterial pressure and the in vivo biosynthesis of PGI 2 and PGE2 and of TXA 2 , in a model of hypertension induced by the chronic subcutaneous administration of aldosterone in normal Sprague-Dawley rats.

(S)-N-{3-[1-Cyclopropyl-1-(2,4-difluoro-phenyl)-ethyl]-1H-indol-7-yl}-methanesulfonamide: A Potent, Nonsteroidal, Functional Antagonist of the Mineralocorticoid Receptor

“…In salt-loaded, uninephrectomized Sprague-Dawley rats, 14 was more potent than 1 on a dose basis. 8 After 14 days (po, qd), a 3 mpk dose of 14 showed equivalent blood pressure lowering to 1 at 30 mpk, as shown in Figure 2. Interestingly, indole 3 was not active at 3 mpk (data not shown).…”