Published online before print May 28, 2008, doi: 10.1161/CIRCHEARTFAILURE.107.755504
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Original Articles |
Hemodynamic, Hormonal, and Renal Actions of Adrenomedullin 2 in Experimental Heart Failure
From the Christchurch Cardioendocrine Research Group, University of Otago, Christchurch, New Zealand.
Correspondence to Miriam T. Rademaker, Department of Medicine, University of Otago, Christchurch, P.O. Box 4345, Christchurch, New Zealand. E-mail miriam.rademaker{at}chmeds.ac.nz
Received November 25, 2007; accepted May 19, 2008.
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).
Conclusion— 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.
Key Words: adenomedullin 2 • heart failure • hemodynamics • hormones • renal function