Long-term adrenomedullin administration in experimental heart failure.
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.
Rademaker
Miriam T
MT
Christchurch Cardioendocrine Research Group, Department of Medicine, The Christchurch School of Medicine, Christchurch, New Zealand. miriam.rademaker@chmeds.ac.nz
Charles
Chris J
CJ
Espiner
Eric A
EA
Nicholls
M Gary
MG
Richards
A Mark
AM
D053607:Adrenomedullin; D000450:Aldosterone / Q000097:blood; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D002304:Cardiac Pacing, Artificial / Q000009:adverse effects; D000242:Cyclic AMP / Q000097:blood; D004195:Disease Models, Animal; D016232:Endothelins / Q000097:blood; D005260:Female; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D006854:Hydrocortisone / Q000097:blood; D007262:Infusions, Intravenous; D007668:Kidney / Q000187:drug effects / Q000502:physiology; D020097:Natriuretic Peptide, Brain / Q000097:blood; D010455:Peptides / Q000008:administration & dosage* / Q000097:blood; D012083:Renin / Q000097:blood; D012756:Sheep; D013995:Time; D016896:Treatment Outcome; D014655:Vascular Resistance / Q000187:drug effects
D016232:Endothelins; D010455:Peptides; D020097:Natriuretic Peptide, Brain; D053607:Adrenomedullin; D000450:Aldosterone; D009320:Atrial Natriuretic Factor; D000242:Cyclic AMP; D012083:Renin; D006854:Hydrocortisone