Involvement of endogenous opioid peptides and nitric oxide in the blunted chronotropic and inotropic responses to β-adrenergic stimulation in cirrhotic rats

Farzad Ebrahimi, Sina Tavakoli, Amir Reza Hajrasouliha, Hamed Sadeghipour, Mehdi Dehghani, Seyed Hossein Ahmadi, Ahmad Reza Dehpour

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

It is well known that chronotropic and inotropic responses to β-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 β-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(ω)-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 × 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 β-adrenergic stimulation in cirrhosis. It seems that the iNOS activity results in NO-induced hyporesponsiveness to β-adrenergic stimulation in cirrhosis.

Original languageEnglish (US)
Pages (from-to)461-471
Number of pages11
JournalFundamental and Clinical Pharmacology
Volume20
Issue number5
DOIs
StatePublished - Oct 1 2006
Externally publishedYes

Keywords

  • Bile duct ligation
  • Cardiomyopathy
  • Cirrhosis
  • Endogenous opioid peptides
  • Nitric oxide
  • β-adrenergic receptor

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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