Haemodynamic, endocrine and renal actions of adrenomedullin 5 in an ovine model of heart failure

Abstract

AM5 (adrenomedullin 5), a newly described member of the CGRP (calcitonin gene-related peptide) family, is reported to play a role in normal cardiovascular physiology. The effects of AM5 in HF (heart failure), however, have not been investigated. In the present study, we intravenously infused two incremental doses of AM5 (10 and 100 ng/min per kg of body weight each for 90 min) into eight sheep with pacing-induced HF. Compared with time-matched vehicle control infusions, AM5 produced progressive and dose-dependent increases in left ventricular dP/dt(max) [LD (low dose), +56 mmHg/s and HD (high dose), +152 mmHg/s] and cardiac output (+0.83 l/min and +1.81 l/min), together with decrements in calculated total peripheral resistance (−9.4 mmHg/min per litre and −14.7 mmHg/min per litre), mean arterial pressure (−2.8 mmHg and −8.4 mmHg) and LAP (left atrial pressure; −2.6 mmHg and −5.6 mmHg) (all P<0.001). HD AM5 significantly raised PRA (plasma renin activity) (3.5-fold increment, P<0.001), whereas plasma aldosterone levels were unchanged over the intra-infusion period and actually fell in the post-infusion period (70% decrement, P<0.01), resulting in a marked decrease in the aldosterone/PRA ratio (P<0.01). Despite falls in LAP, plasma atrial natriuretic peptide and B-type natriuretic peptide concentrations were maintained relative to controls. AM5 infusion also induced significant increases in urine volume (HD 2-fold increment, P<0.05) and urine sodium (2.7-fold increment, P<0.01), potassium (1.7-fold increment, P<0.05) and creatinine (1.4-fold increment, P<0.05) excretion and creatinine clearance (60% increment, P<0.05). In conclusion, AM5 has significant haemodynamic, endocrine and renal actions in experimental HF likely to be protective and compensatory in this setting. These results suggest that AM5 may have potential as a therapeutic agent in human HF.