The story of spironolactones from 1957 to now: from sodium balance to inflammation.

After the discovery of aldosterone (1953), many synthetic steroids were tested for their ability to block the sodium retaining and potassium excreting effect of synthetic mineralocorticoids in adrenalectomized rats. In the same years Kagawa discovered that 17-spirolactone steroids were effective to block mineralocorticoid effects, but when used alone they did not produce any effect in adrenalectomized rats. After the description of the first case of primary aldosteronism (1955), spironolactone (SP) was considered the main treatment before surgery to control blood pressure and kaliemia and for long-term treatment in patients with bilateral adrenal hyperplasia. SP was further used for various clinical situations, such as liver cirrhosis, idiopathic oedema, nephrosis and congestive heart failure. SP also shows an antiandrogen action, effective in polycystic ovary syndrome. In 1985 we demonstrated that human mononuclear leukocytes (MNL) possess mineralocorticoid receptors (MR) and lately we demonstrated that coincubation of MNL with canrenone blocked aldosterone mediated inflammatory, reducing the expression of PAI-1 and p22phox. It is well known that MNL and macrophages are mainly involved in vascular inflammation and atherosclerosis and we have hypothesized that the tissue invasion of MNL brings MR in the site of inflammation starting the process. Recently, aldosterone has been associated with the promotion of many organ-specific autoimmune diseases, inducing Th17 polarization of CD4+ T cells and suggesting new possible therapeutic targets for anti-mineralocorticoid drugs. In conclusion, considering all the benefits of MR-antagonists, their use should be reconsidered not only for the treatment but also for the prevention of many clinical situations.