Vascular and cardiac actions of aldosterone and spironolactone.
Classical pharmacology confines the mechanism of action of aldosterone and its antagonists to the modulation of ion transport in the distal tubule of the nephron. The purpose of this overview is to examine the evidence for the presence of extrarenal and, namely, vascular and cardiac sites of action for aldosterone and spironolactone. Beside its specific action in primary and secondary hyperaldosteronism, spironolactone is effective in lowering blood pressure in essential hypertension, despite normal levels of aldosterone production, and without necessarily producing significant changes in Na+ and K+ urinary excretion. This is particularly the case when therapy is applied chronically and at relatively low doses. This suggests that spironolactone may act by antagonizing the effects of aldosterone directly on the cardiovascular system. Electrophysiological studies have shown that spironolactone may reduce contractions of rat portal vein strips. This action was found to be mediated by the inhibition of the slow calcium channels. Spironolactone binds to the calcium channels, at sites different from those of dihydropyridines and phenylalkylamines. It interacts at these binding sites in vascular membranes by decreasing their density and accelerating the rate of dissociation of the ligand. In humans, spironolactone 50 mg and 75 mg o.d. produced a dose-dependent decrease of total vascular resistance and in vascular reactivity to vasopressor agents. In the heart, spironolactone produces a direct inotropic action in the mammalian myocardium with an increase of both the amplitude and duration of action potential. Finally, the direct role of aldosterone in promoting fibroblast growth producing cardiac hypertrophy in models of experimental hypertension have been recently emphasized.(ABSTRACT TRUNCATED AT 250 WORDS)
Zannad
F
F
Service de Cardiologie, Hôpital Central, Nancy, France.
D000450:Aldosterone / Q000502:physiology*; D000818:Animals; D004562:Electrocardiography / Q000187:drug effects*; D006801:Humans; D006973:Hypertension / Q000503:physiopathology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000503:physiopathology*; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology*; D013148:Spironolactone / Q000494:pharmacology*
D013148:Spironolactone; D000450:Aldosterone