Hemodynamic, hormonal, and renal actions of adrenomedullin 2 in experimental heart failure.
BACKGROUND
Adrenomedullin 2 (AM2) is a novel member of the calcitonin gene-related peptide family that is thought to play a regulatory role in circulatory homeostasis under normal physiological conditions. The effects of AM2 in heart failure have not been investigated previously.


RESULTS
Two incremental doses of human AM2 (10 and 100 ng[kg.min] for 90 minutes each) were given by intravenous infusion to 8 sheep with pacing-induced heart failure. Compared with time-matched control infusions, AM2 produced dose-dependent increases in left ventricular dP/dt(max) (control 1168+/-138 mm Hg/s versus AM2 high-dose 1402+/-130 mm Hg/s; P<0.01) and cardiac output (2.09+/-0.66 L/min versus 3.81+/-0.30 L/min; P<0.001) and reductions in calculated total peripheral resistance (40+/-6 mm Hg(L.min) versus 21+/-4 mm Hg(L.min); P<0.001), mean arterial pressure (74.4+/-2.4 mm Hg versus 66.2+/-2.5 mm Hg; P<0.001), and left atrial pressure (23.3+/-1.0 mm Hg versus 18.8+/-1.3 mm Hg; P<0.001). AM2 administration also induced significant elevations in plasma cAMP (P<0.01) in association with rises in atrial (P<0.05) and brain (P<0.01) natriuretic peptides and plasma renin activity (P<0.01). Despite the increase in renin activity, plasma aldosterone levels were not significantly altered, whereas the aldosterone/plasma renin activity ratio was reduced (P=0.08). Plasma vasopressin, endothelin-1, and catecholamines levels were also unchanged by AM2. Renal effects of AM2 included increased excretion of sodium (P<0.05), cAMP (P<0.01), and creatinine (P<0.05), with augmented creatinine clearance (P<0.05), and a trend for urine output to rise (P=0.068).


CONCLUSIONS
These results indicate that AM2 administration has favorable effects on cardiovascular, endocrine, and renal indexes in heart failure and identify the peptide as a potential therapeutic target in this disease.
Rademaker
Miriam T
MT
Christchurch Cardioendocrine Research Group, University of Otago, Christchurch, New Zealand. miriam.rademaker@chmeds.ac.nz
Charles
Christopher J
CJ
Nicholls
M Gary
MG
Richards
A Mark
AM
D000450:Aldosterone / Q000097:blood*; D000818:Animals; D003404:Creatinine / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects*; D007262:Infusions, Intravenous; D045265:Natriuretic Peptides / Q000097:blood*; D036361:Peptide Hormones / Q000008:administration & dosage / Q000627:therapeutic use*; D012083:Renin / Q000097:blood*; D012756:Sheep; D016896:Treatment Outcome; D014655:Vascular Resistance / Q000187:drug effects
C484330:ADM2 protein, human; D045265:Natriuretic Peptides; D036361:Peptide Hormones; D000450:Aldosterone; D003404:Creatinine; D012083:Renin