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. Circulatin g and ventricular adrenomedullin are elevated in congestive heart fail ure, 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 he art 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 associat ion with dose-dependent falls in calculated peripheral resistance (13 mm Hg.L-1.min(-1), P < .001), mean arterial pressure (9 mm Hg, P < .00 1), and left atrial pressure (5 mm Hg, P < .001) and increases in card iac output (0.5 L/min, P < .001). Adrenomedullin increased urine sodiu m (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 le vels (P < .05), whereas plasma atrial and brain natriuretic peptide co ncentrations were unchanged during infusion and rose after infusion (P < .01 and P < .05, respectively). Plasma catecholamine, cortisol, ren in, 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. D espite the clear fall in arterial pressure, adrenomedullin increased c reatinine clearance and sodium excretion and maintained urine output. These results imply an important pathophysiological role for adrenomed ullin in the regulation of pressure and volume in heart failure and ra ise the possibility of a new therapeutic approach to this disease.