Chronic Administration of Adrenomedullin Attenuates Transition From Left Ventricular Hypertrophy to Heart Failure in Rats

Abstract

Acute administration of adrenomedullin (AM) exerts beneficial hemodynamic, renal, and neurohormonal effects in heart failure (HF). However, chronic effects of AM administration on HF remain unknown. This study sought to examine the effect of chronic infusion of AM on progression of HF in rat. Human recombinant AM was administered by osmotic minipump for 7 weeks in the HF model of Dahl salt-sensitive rats. The effect was compared with vehicle and diuretic treatment group. Chronic AM infusion significantly decreased left ventricular end-diastolic pressure, right ventricular systolic pressure, right atrial pressure, and left ventricular weight/body weight (P<0.01 for all). AM significantly attenuated the increase in circulating renin-aldosterone, endogenous rat AM, and atrial natriuretic peptide levels (P<0.01 for all). AM also inhibited the myocardial tissue levels of angiotensin II and atrial and brain natriuretic peptide (P<0.01 for all). These changes were associated with the improvement of cardiac output and systemic vascular resistance (both P<0.05). Furthermore, AM improved left ventricular end-systolic elastance (P<0.01). These improvements were greater in the AM than in the diuretic group, although both drugs similarly decreased systolic blood pressure and increased urinary sodium excretion. Kaplan-Meier survival analysis showed that AM significantly prolonged survival time compared with diuretic (P<0.05) and vehicle (P<0.01) treatment groups. These results suggest that endogenous AM plays a compensatory role in HF and that chronic AM infusion attenuates progression of left ventricular dysfunction and improves survival, at least in part, through inhibition of circulating and myocardial neurohormonal activation.