Rapid Nongenomic Effects of Aldosterone on Human Forearm Vasculature

Abstract

Abstract-The impact of aldosterone in cardiovascular disease and hypertension has recently gained new interest.Aldosterone is now suggested to be a more common cause of hypertension than previously believed and has been linked to myocardial fibrosis, independent of its hypertensive effects. Finally, rapid nongenomic aldosterone effects have been proposed to be important in hypertension, in addition to its genomic effects. Forty-eight healthy male volunteers were examined in a randomized, placebo-controlled, double-blind crossover trial to elucidate the rapid nongenomic, vascular effects of aldosterone in humans. Forearm blood flow was measured by venous occlusion plethysmography. First, aldosterone (500 ng/min) and placebo were infused into the brachial artery for 8 minutes. The volunteers then received ascending doses of acetylcholine, N G -monomethyl-L-arginine (L-NMMA), sodium nitroprusside, or phenylephrine. Aldosterone increased forearm blood flow (PϽ0.001, ANOVA). The maximum effect was an increase in forearm blood flow with aldosterone of 7.9Ϯ2.6% compared with 0.1Ϯ1.9% with placebo treatment after 8 minutes. With aldosterone, L-NMMA induced a greater vasoconstriction (PϽ0.05, ANOVA), sodium nitroprusside induced an attenuated vasoconstriction (PϽ0.01, ANOVA), and phenylephrine induced an exaggerated vasoconstriction (PϽ0.01, ANOVA) within minutes as compared with placebo. These data suggest that aldosterone acts through rapid nongenomic effects at the endothelium by increasing NO release and at the vascular smooth muscle cells by promoting vasoconstriction. This is consistent with in vitro data showing an increase in intracellular calcium in both cell types. Disturbances of these aldosterone effects on both levels might be important in promoting hypertension.

Nongenomic Effects of Aldosterone in the Human Heart

“…In the rat aorta, 3 as well as the human forearm, 6 aldosterone has been reported to enhance vasoconstriction and vasodilation. The latter was endothelium dependent, whereas the former could only be observed during NO synthase blockade.…”

“…Second, similar diametrically differing effects of aldosterone have been observed on flow, either because such effects involve different cells or because different second messengers are activated depending on the experimental circumstances. 5,6,12,17 Finally, the consequences of PKC-induced regulation of Na ϩ -K ϩ pump activity are tissue specific and range from stimulation to inhibition or no change. 12,18 Hydrocortisone mimicked the inotropic effects of aldosterone at lower potency.…”

“…The nonrenal actions of aldosterone include inotropic effects in the heart and vasoconstrictor as well as vasodilator effects in various vascular beds. [3][4][5][6][7] Unexpectedly, these effects occurred within minutes rather than hours and could not always be blocked by MR antagonists. Consequently, they are now known as "nongenomic" effects of aldosterone.…”

“…Furthermore, because aldosterone exerts its effects, at least in part, via Ang II or Ang II type 1 (AT 1 ) receptors, 7,11 and vice versa, 10 we evaluated the interaction with Ang II in our experimental setup. Finally, we looked into the mediators of the effects of aldosterone in this study, focusing on those that have already been coupled to the nongenomic actions of aldosterone (protein kinase C [PKC], Ca 2ϩ , NO, and mitogen-activated protein kinases), 3,6,7,10,12 and we determined the aldosterone levels in normal and failing human hearts to put our findings into a physiological perspective.…”

Aldosterone Enhances Ligand-Stimulated Nitric Oxide Production in Endothelial Cells

“…Liu et al (9) could not detect any [Ca 2+ ]i changes in VSMCs and found that aldosterone acutely stimulated endothelial NO production that was blocked by an MR antagonist. Studies of the nongenomic actions of aldosterone on vasculature, specifically on rabbit afferent arterioles (17,18) or human forearm blood flow (19,20), have led to inconsistent conclusions as to whether aldosterone is constrictive or dilatory…”