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.