Aldosterone, salt and cardiac fibrosis.
The classical effects of aldosterone are mediated via epithelial mineralocorticoid receptors (MR), protected against cortisol/corticosterone occupancy and activation by the enzyme 11 beta hydroxysteroid dehydrogenase. The pathophysiological effects of aldosterone on non-epithelial tissues, in contrast, are mediated via unprotected MR in which occupancy by cortisol/corticosterone antagonises the effect of aldosterone. Aldosterone raises blood pressure by occupying MR in the circumventricular region of the brain, an effect antagonised by concomitant intracerebroventricular (ICV) infusion of similar doses of corticosterone. Peripheral infusion of aldosterone to salt loaded rats causes hypertension, cardiac hypertrophy and cardiac fibrosis; concomitant ICV infusion of the MR antagonist RU28318 abolishes the aldosterone-induced hypertension, but does not affect cardiac hypertrophy or fibrosis. These peripheral effects of aldosterone are presumably via cardiac MR; high glucose/PKC modulated, aldosterone-specific effects on protein synthesis have recently been demonstrated as direct MR-mediated actions on cultured neonatal rat cardiomyocytes. The pathophysiologic effects of aldosterone via nonepithelial MR have a time course of days/weeks rather than hours, reflect occupancy of only a small percentage of such receptors, and require salt loading. How the effects of salt loading are transduced in such circumstances remains to be explored.
Funder
J W
JW
Baker Medical Research Institute, Prahran, Victoria, Australia.
D042842:11-beta-Hydroxysteroid Dehydrogenases; D000450:Aldosterone / Q000008:administration & dosage / Q000494:pharmacology* / Q000502:physiology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D006332:Cardiomegaly / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D009202:Cardiomyopathies / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D005355:Fibrosis; D006913:Hydroxysteroid Dehydrogenases / Q000378:metabolism; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D051381:Rats; D018161:Receptors, Mineralocorticoid / Q000187:drug effects / Q000502:physiology; D012982:Sodium, Dietary / Q000008:administration & dosage*; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D013577:Syndrome
D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D012982:Sodium, Dietary; D013148:Spironolactone; D000450:Aldosterone; C041006:RU 28318; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases