Local regulator adrenomedullin contributes to the circulatory disturbance in cirrhotic rats.
OBJECTIVE
To investigate whether adrenomedullin, a potent vasodilator peptide, plays a role in the circulatory disturbance in cirrhosis.


METHODS
Cirrhosis was induced in rats by weekly gavage of carbon tetrachloride. Hemodynamic studies were performed in vivo using radioactive microspheres and in vitro using isolated aortic rings. The adrenomedullin concentrations were measured by radioimmunoassay.


RESULTS
Acute administration of adrenomedullin to the control rats reduced the systemic arterial pressure along with an increase of serum levels of the stable metabolite of nitric oxide (NOx), in a dose-dependent manner. Chronic infusion of adrenomedullin reduced the vascular resistance and increased the blood flow in the systemic and splanchnic circulation. Intravenous administration of anti-adrenomedullin antibody did not affect any hemodynamic parameters in the cirrhotic rats, whereas this antibody ameliorated the blunted contractile response to phenylephrine, alpha-adrenergic receptor agonist, in the aortic rings of the cirrhotic rats. The adrenomedullin concentrations in the aorta were higher in the cirrhotic rats than in the controls, and correlated with the mean arterial pressure in the cirrhotic rats. Moreover, adrenomedullin blunted the contractile response to phenylephrine in both of the control aorta and cirrhotic aorta, but not in the presence of NG-nitro-L-arginine methyl ester, an NO synthase inhibitor.


CONCLUSIONS
Adrenomedullin overproduced in the vascular wall may contribute to the circulatory disturbance in cirrhosis as a local regulator of the vascular tonus rather than a circulating hormone.
Sakurai
Shinya
S
Third Department of Internal Medicine, Nara Medical University, Nara 634-8522, Japan.
Kojima
Hideyuki
H
Uemura
Masahito
M
Satoh
Hiroyasu
H
Fukui
Hiroshi
H
D053607:Adrenomedullin; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D016534:Cardiac Output, High / Q000209:etiology*; D007022:Hypotension / Q000209:etiology*; D008106:Liver Cirrhosis, Experimental / Q000150:complications / Q000503:physiopathology*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology; D010455:Peptides / Q000097:blood / Q000494:pharmacology*; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects
D010455:Peptides; D053607:Adrenomedullin; D010656:Phenylephrine; D009569:Nitric Oxide; D019331:NG-Nitroarginine Methyl Ester