Hemodynamic, Hormonal, and Renal Actions of Adrenomedullin 2 in Experimental Heart Failure

BACKGROUND: Adrenomedullin 2 (AM2) is a novel member of the calcitonin gene-related peptide family that is thought to play a regulatory role in circulatory homeostasis under normal physiological conditions. The effects of AM2 in heart failure have not been investigated previously. METHODS AND RESULTS: Two incremental doses of human AM2 (10 and 100 ng[kg.min] for 90 minutes each) were given by intravenous infusion to 8 sheep with pacing-induced heart failure. Compared with time-matched control infusions, AM2 produced dose-dependent increases in left ventricular dP/dt(max) (control 1168+/-138 mm Hg/s versus AM2 high-dose 1402+/-130 mm Hg/s; P<0.01) and cardiac output (2.09+/-0.66 L/min versus 3.81+/-0.30 L/min; P<0.001) and reductions in calculated total peripheral resistance (40+/-6 mm Hg(L.min) versus 21+/-4 mm Hg(L.min); P<0.001), mean arterial pressure (74.4+/-2.4 mm Hg versus 66.2+/-2.5 mm Hg; P<0.001), and left atrial pressure (23.3+/-1.0 mm Hg versus 18.8+/-1.3 mm Hg; P<0.001). AM2 administration also induced significant elevations in plasma cAMP (P<0.01) in association with rises in atrial (P<0.05) and brain (P<0.01) natriuretic peptides and plasma renin activity (P<0.01). Despite the increase in renin activity, plasma aldosterone levels were not significantly altered, whereas the aldosterone/plasma renin activity ratio was reduced (P=0.08). Plasma vasopressin, endothelin-1, and catecholamines levels were also unchanged by AM2. Renal effects of AM2 included increased excretion of sodium (P<0.05), cAMP (P<0.01), and creatinine (P<0.05), with augmented creatinine clearance (P<0.05), and a trend for urine output to rise (P=0.068). CONCLUSIONS: These results indicate that AM2 administration has favorable effects on cardiovascular, endocrine, and renal indexes in heart failure and identify the peptide as a potential therapeutic target in this disease.