The endothelin-aldosterone axis and cardiovascular diseases.

Abstract

The results of the Randomized Aldactone Evaluation Study (RALES) and of several experimental studies have indicated that excess aldosterone detrimentally affects cardiovascular morbidity and mortality by acting through both classical and non-classical mineralocorticoid receptors. The effects mediated through classical mineralocorticoid receptors entail enhanced sodium and water reabsorption, potassium loss and hypokalaemia, congestion, increased vascular resistance and hypertension. Those occurring through non-classical mineralocorticoid receptors located on myofibroblasts comprise cardiac hypertrophy and fibrosis, which may be due to a direct effect of aldosterone on collagen synthesis. Data obtained in primary aldosteronism patients demonstrated left ventricular hypertrophy, as well as changes in left ventricular filling that can be accounted for by cardiac fibrosis. Available clinical data indicate that in a considerable proportion of congestive heart failure (CHF) patients treated with angiotensin converting enzyme (ACE) inhibitors, aldosterone secretion can escape from blockade of the renin-angiotensin system, thus suggesting that additional mechanisms, besides angiotensin II, can play an important role in the regulation of aldosterone secretion. Compelling evidence indicates that endothelin (ET)-1 is overtly increased in severe CHF and thus is a likely candidate for the aldosterone 'escape' phenomenon in CHF. Endothelin-1 is expressed in the adrenal cortex, together with its receptor subtypes A (ETA) and B (ETB), and directly stimulates aldosterone secretion in different species, in humans by acting via both ETA and ETB receptor subtypes. Moreover, we have recently found that the novel endothelin peptide ET-1 (1-31), by acting as an ETA agonist, can also be involved in the regulation of growth of the adrenal cortex, as well as in the pathogenesis of Conn's adenoma. In this paper, we review the findings suggesting a relationship between activation of the ET-1 system, enhanced aldosterone secretion and cardiac fibrosis and discuss the implications of endothelin antagonism for cardiovascular disease.