Published Online
on May 28, 2008

A more recent version of this article appeared on July 1, 2008

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Original Article

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

Miriam T. Rademaker¹; Chris J. Charles; M. Gary Nicholls and A. Mark Richards

University of Otago, Christchurch

¹ E-mail: miriam.rademaker{at}chmeds.ac.nz

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 (HF) have not previously been investigated.

Methods and Results—Two incremental doses of human AM2 (10 and 100ng/kg/min for 90 minutes each) were given by intravenous infusion to eight sheep with pacing-induced HF. Compared to time-matched control infusions, AM2 produced dose-dependent increases in left ventricular dP/dt(max) (Control 1168+138mmHg/s versus AM2 high-dose 1402+130mmHg/s; p<0.01) and cardiac output (2.09+0.66L/min versus 3.81+0.30L/min; p<0.001), and reductions in calculated total peripheral resistance (40+6mmHg/L/min versus 21+4mmHg/L/min; p<0.001), mean arterial pressure (74.4+2.4mmHg versus 66.2+2.5mmHg; p<0.001) and left atrial pressure (23.3+1.0mmHg versus 18.8+1.3mmHg; p<0.001). AM2 administration also induced significant elevations in plasma cyclic AMP (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, while the aldosterone/PRA 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), cyclic AMP (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 indices in HF, and identify the peptide as a potential therapeutic target in this disease.

Key Words: heart failure • hemodynamics • hormones • adrenomedullin 2 • heart failure • hemodynamics • hormones • renal function