Extra-adrenal mineralocorticoids and cardiovascular tissue

In experimental models where chronic inappropriate (relative to sodium inta ke and intravascular volume) elevations in circulating mineralocorticoids ( aldosterone or deoxycorticosterone) are created, a reactive fibrosis with v ascular remodeling is observed in systemic organs and the heart. Until rece ntly, it was assumed that aldosterone was derived solely from adrenal gland s via the circulation; however, there is now convincing evidence that cells of the heart and vasculature express genes responsible for the formation o f both aldosterone and corticosterone and are capable of producing these st eroids. Vascular endothelial and smooth muscle cells express CYP11B1 and CY P11B2, genes responsible for 11 beta-hydroxylase and aldosterone synthase, respectively. Furthermore, smooth muscle cells elaborate aldosterone. There is evidence that similar regulatory mechanisms operate in vascular cells a s in adrenal cortex, since aldosterone synthase and 11 beta-hydroxylase exp ression are differentially modulated by low sodium/high potassium, angioten sin II and ACTH. It is likely that such localized corticosteroid production also occurs at sites of tissue repair, where populations of collagen-produ cing myofibroblasts, nourished by a neovasculature, predominate. Using a su bcutaneous pouch model of granulation tissue we have obtained compelling da ta which would support such a notion. The mineralocorticoid receptor antago nist, spironolactone, severely attenuates pouch formation over a 2-week per iod and significantly reduces pouch wall hydroxyproline concentration. This effect is apparent even following adrenalectomy, when circulating corticos teroids are undetectable; however, with adrenalectomy alone, pouch formatio n is barely affected. This we took to be a possible indication of an effect of local, non-adrenal steroids in maintaining pouch tissue, Spironolactone inhibits angiogenesis. A recent clinical study demonstrates the efficacy o f low-dose spironolactone in enhancing survival in patients with advanced c hronic cardiac failure, Although it is not known how spironolactone brings about such an improvement in survival, we would propose that inhibition of fibrous tissue formation and/or angiogenesis might be important contributor y factors. Further studies are required to address the relative contributio ns of circulating vs local aldosterone in promoting normal vs pathologic co nnective tissue formation. (C) 1999 Academic Press.