Beneficial hemodynamic and renal effects of adrenomedullin in an ovine model of heart failure

Background Adrenomedullin is a recently discovered endogenous peptide with hypotensive and natriuretic actions in normal animals. Circulating and ventricular adrenomedullin are elevated in congestive heart failure, suggesting a possible role in the pathophysiology of this disease. No studies have previously examined the effects of adrenomedullin in heart failure. Methods and Results Eight sheep with pacing-induced heart failure received human adrenomedullin (1-52) at 10 and 100 ng.kg(-1).min(-1) IV for 90 minutes each. Compared with vehicle control data, adrenomedullin increased plasma cAMP (high dose, P < .05) in association with dose-dependent falls in calculated peripheral resistance (13 mm Hg.L-1.min(-1), P < .001), mean arterial pressure (9 mm Hg, P < .001), and left atrial pressure (5 mm Hg, P < .001) and increases in cardiac output (0.5 L/min, P < .001). Adrenomedullin increased urine sodium (threefold, P < .05), creatinine (P < .05) and cAMP excretion (P < .01), creatinine clearance (P < .05), and renal production of cAMP (P < .05), whereas urine output was maintained during infusion and raised after infusion (P < .05). Adrenomedullin reduced plasma aldosterone levels (P < .05), whereas plasma atrial and brain natriuretic peptide concentrations were unchanged during infusion and rose after infusion (P < .01 and P < .05, respectively). Plasma catecholamine, cortisol, renin, calcium, and glucose concentrations were not significantly altered. Conclusions Adrenomedullin reduced ventricular preload and afterload and improved cardiac output in sheep with congestive heart failure. Despite the clear fall in arterial pressure, adrenomedullin increased creatinine clearance and sodium excretion and maintained urine output. These results imply an important pathophysiological role for adrenomedullin in the regulation of pressure and volume in heart failure and raise the possibility of a new therapeutic approach to this disease.