Mineralocorticoid Resistance

David S. Geller

Disclosures

Clin Endocrinol. 2005;62(5):513-520. 

In This Article

Perspectives on Aldosterone Biology

A wide variety of clinical and experimental evidence suggests an important role of aldosterone in mediating cardiovascular disease. Of particular interest, a number of studies have focused on extrarenal roles of aldosterone, stemming from the finding that the MR is expressed in diverse tissues including the myocardium and the vascular endothelium. Recent progress has taught us much about mechanisms of aldosterone action, but it is clear that we have more to understand. Nevertheless, the insights gained from these studies have taught us much about aldosterone biology.

One interesting finding stemming from the study of these monogenic disorders of mineralocorticoid resistance is the uncertain correlation between aldosterone levels and cardiovascular disease. A wide variety of studies have suggested pathological effects of angiotensin II and aldosterone on cardiovascular tissue, mediating such effects as cardiac fibrosis and left ventricular hypertrophy.[9,11,59] The example of arPHA1 and adPHA1 make it clear that angiotensin II and aldosterone are not in and of themselves the primary mediators of the pathology observed. Patients with arPHA1 have lifelong elevation of renin, angiotensin II, and aldosterone levels many times above the norm (with a normal MR pathway in extrarenal tissues), and yet, left ventricular hypertrophy and cardiac fibrosis have never been observed in humans or in mice lacking ENaC. By contrast, patients with Liddle's syndrome, which is characterized by constitutive activation of ENaC, leading to hypertension and hypokalaemia despite lifelong suppression of renin, angiotensin II and aldosterone, have a high incidence of left ventricular hypertrophy and renal failure. Stated simply, excess renal sodium reabsorption is necessary and sufficient to produce cardiovascular disease, whereas angiotensin II and aldosterone are neither necessary nor sufficient. Whether aldosterone worsens cardiovascular pathology above and beyond its effect on renal sodium reabsorption remains an open question. Nevertheless, these findings lend support to the proposition that the principal culprit mediating cardiovascular disease in many of the widely cited experimental systems of cardiovascular disease is not angiotensin II or aldosterone, but the excess renal sodium reabsorption induced by these hormones. Similarly, while there has been much interest in so-called nongenomic effects of aldosterone on cardiovascular parameters,[60] the finding that arPHA1 patients have low blood pressure and no cardiovascular disease suggests that the proposed nongenomic effects of aldosterone have only a limited role on cardiovascular health independent of salt balance as well.

Can this notion that the principal effects of aldosterone in cardiac disease relate to salt balance be supported by the wide variety of studies suggesting a role of aldosterone itself in cardiovascular disease? Among the widely cited examples of aldosterone-mediated toxicity is the finding that mineralocorticoid antagonists such as spironolactone or eplerenone, given at doses that do not noticeably alter salt balance or blood pressure, markedly decrease the incidence of stroke and renal injury in stroke-prone spontaneously hypertensive rats;[61—63] the absence of a blood pressure lowering effect has been cited as evidence that aldosterone blockade must have an effect above and beyond its effect on renal salt reabsorption. However, recent studies have demonstrated that amiloride, an inhibitor of ENaC, also reduces the incidence of stroke in this model system, again in the absence of a change in blood pressure.[64] Importantly, it should be noted that amiloride, unlike spironolactone, is thought to work exclusively in the renal tubular lumen, because only there is the concentration of the drug sufficient for ENaC inhibition. Similarly, the demonstration that aldosterone administration leads to hypertrophy and fibrosis not only in the high-pressure left heart circulation but also in the low-pressure circulation encountered in the right heart circulation has been used to suggest that aldosterone must have direct effects on the heart independent of renal salt reabsorption.[10,11] Again, however, the replication of these data in a high-salt (and therefore low-aldosterone) model again suggests strongly that the true culprit is excess salt, not aldosterone.[65] Clarification of the true pathological effects will require further investigation, but given the importance of the renin—angiotensin—aldosterone pathway to sodium homeostasis and cardiovascular disease, it is clear that an improved understanding of aldosterone biology is likely to lead to improved treatment of cardiovascular disease.

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