Short-term administration of
adrenomedullin, a recently discovered
peptide with potent
vasodilator, natriuretic, and
aldosterone-inhibitory actions, has beneficial effects in experimental and clinical
heart failure. The effects of prolonged
adrenomedullin administration have not previously been assessed in this setting. Consequently, in 16 sheep with pacing-induced
heart failure, we infused either
adrenomedullin (10 ng/kg per minute; n=8) or a vehicle control (
Hemaccel; n=8) for 4 days. Compared with control data, infusion of
adrenomedullin persistently increased circulating levels of the
peptide (by approximately 9.5 pmol/L; P<0.001), in association with prompt (15 minutes) and sustained (4 days) increases in cardiac output (day 4, 27%), and reductions in peripheral resistance (30%), mean arterial pressure (13%), and left atrial pressure (24%; all, P<0.001).
Adrenomedullin also significantly enhanced urinary
sodium excretion (day 4, 3-fold; P<0.05),
creatinine excretion (1.2-fold; P<0.001), and
creatinine clearance (1.4-fold; P<0.001) over the 4 days of treatment, whereas urine volume and cAMP excretion tended to be elevated (both, 0.1>P>0.05). Plasma
renin activity was increased (P<0.05), whereas
aldosterone levels were reduced in a sustained fashion (P<0.01). Plasma
endothelin rose transiently (hours 1 to 6) after initiation of treatment (P<0.05). Despite substantial cardiac unloading, plasma concentrations of the
natriuretic peptides were not significantly different from control. In conclusion, long-term administration of
adrenomedullin induces pronounced and sustained cardiovascular and renal effects in experimental
heart failure, including reductions in cardiac preload and afterload, as well as augmentation of cardiac output,
sodium excretion, and glomerular filtration. These findings support the concept of
adrenomedullin as a protective
hormone during hemodynamic compromise with therapeutic potential in
heart failure.