Adrenal Gland Hormones and the Vascular System

Abstract

The corticosteroid hormones (glucocorticoids and mineralocorticoids), via their effects on mineralocorticoid receptors (MR) and glucocorticoid receptors (GR), play an important role in cardiovascular inflammation. Endogenous glucocorticoids (cortisol in humans) bind to both MR and GR. Large randomized controlled trials (RALES, Randomized Aldactone Evaluation Study, and EPHESUS, Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study) have demonstrated the benefits on mortality and morbidity of MR antagonist treatment in symptomatic heart failure, implicating MR signalling as a key mediator of heart disease. However, the circulating levels of aldosterone in these patients were normal, indicating the possibility that the cardiovascular benefits conferred by aldosterone antagonists were at least partly independent of aldosterone itself and lend support to a role for cortisol in pathological states such as heart failure. The regulation of cortisol metabolism in humans is not only centrally determined. Two key enzymes in cortisol metabolism have been identified that influence the effects of cortisol at the peripheral level: 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1, which converts inactive cortisone to active cortisol) and type 2 (11β-HSD2, which converts active cortisol to inactive cortisone). Any therapy based on manipulation of glucocorticoid metabolism should inhibit 11β-HSD1 activity while preserving 11β-HSD2 activity. The net effect of 11β-HSD1 inhibitors appears to be atheroprotective and beneficial after myocardial infarction in mice. These findings offer the promise of therapeutic potential for tissue-specific manipulation of glucocorticoid action in the prevention and treatment of cardiovascular disease in humans.