Involvement of endogenous opioid peptides and nitric oxide in the blunted chronotropic and inotropic responses to beta-adrenergic stimulation in cirrhotic rats.
It is well known that chronotropic and inotropic responses to beta-adrenergic stimulation are impaired in cirrhosis, but the exact reason is not clear. Considering the inhibitory effect of endogenous opioid peptides and nitric oxide (NO) on beta-adrenergic pathway, we examined their roles in hyporesponsiveness of isolated atria and papillary muscles to isoproterenol stimulation in cirrhotic rats. Cirrhosis was induced by chronic bile duct ligation. Four weeks after ligation or sham operation, the responses of the isolated atria and papillary muscles to isoproterenol stimulation were evaluated in the absence and presence of naltrexone HCl (10(-6) m), N(omega)-nitro-L-arginine methyl ester (L-NAME, 10(-4) m), and naltrexone plus L-NAME in the organ bath. Considering the role of inducible NOS (iNOS) in hemodynamic abnormalities of cirrhotic rats, the chronotropic and inotropic responses of cirrhotic rats to isoproterenol stimulation were also assessed in the presence of aminoguanidine (a selective inhibitor of iNOS, 3 x 10(-4) m). Sham operation had no significant effect on basal atrial beating rate, contractile force, and maximal time derivatives for the development and the dissipation of papillary muscle tension. The basal atrial beating rate of cirrhotic rats did not show any significant difference compared with the sham-operated ones; however, the basal contractile parameters were significantly decreased in cirrhosis. Although the maximum effects of isoproterenol on chronotropic and inotropic responses were significantly reduced in cirrhotic rats, there was no difference in half-maximal effective concentrations of isoproterenol in these concentration-response curves. The basal abnormalities and the attenuated chronotropic and inotropic responses to isoproterenol were completely corrected by the administration of naltrexone, L-NAME and aminoguanidine. Concurrent administration of naltrexone and L-NAME also restored to normal the basal abnormalities and the blunted responses to isoproterenol in cirrhotic rats, and did not show any antagonistic effect. Based on these findings, both the endogenous opioid peptides and NO may be involved in the attenuated chronotropic and inotropic responses to beta-adrenergic stimulation in cirrhosis. It seems that the iNOS activity results in NO-induced hyporesponsiveness to beta-adrenergic stimulation in cirrhosis.
Ebrahimi
Farzad
F
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, PO Box 13145-784, Tehran, Iran.
Tavakoli
Sina
S
Hajrasouliha
Amir Reza
AR
Sadeghipour
Hamed
H
Dehghani
Mehdi
M
Ahmadi
Seyed Hossein
SH
Dehpour
Ahmad Reza
AR
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D001652:Bile Ducts / Q000601:surgery; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D006325:Heart Atria / Q000187:drug effects / Q000503:physiopathology; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology*; D008026:Ligation; D008105:Liver Cirrhosis, Biliary / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009271:Naltrexone / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D018847:Opioid Peptides / Q000378:metabolism*; D010210:Papillary Muscles / Q000187:drug effects / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley
D000318:Adrenergic beta-Agonists; D004791:Enzyme Inhibitors; D006146:Guanidines; D018847:Opioid Peptides; D009569:Nitric Oxide; D009271:Naltrexone; D052247:Nitric Oxide Synthase Type II; D007545:Isoproterenol; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester