Contribution of endogenous opioids and nitric oxide to papillary muscle contractile impairment in cholestatic rats

Farzad Ebrahimi, Sina Tavakoli, Amir Reza Hajrasouliha, Hamed Shafaroodi, Hamed Sadeghipour, Kiarash Riazi, Amir Ali Borhani, Golbahar Houshmand, Seyed Hossein Ahmadi, Ahmad Reza Dehpour*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Attenuated responsiveness to adrenoceptor stimulation has been proposed as an important factor underlying cardiovascular complications of cholestasis. We examined isolated papillary muscle responsiveness to α (phenylephrine) and β-adrenoceptor (isoproterenol) agonists in 7-day bile duct-ligated rats. We investigated the role of nitric oxide (NO) and endogenous opioids in papillary muscle hyporesponsiveness to isoproterenol stimulation. In order to evaluate the effect of NO and endogenous opioids, animals were treated with chronic subcutaneous injections of N (ω)-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg/day) or naltrexone (20 mg/kg/day), or isolated papillary muscles were exposed acutely to the same drugs (10- 4 and 10 - 6 M, respectively) in an organ bath. The basal contractile force of papillary muscle, + dT / dtmax and - dT / dtmax, was significantly decreased in bile duct-ligated rats compared to sham-operated ones (P < 0.05, for each value). The concentration-response curve for phenylephrine and isoproterenol demonstrated a reduced maximum effect in bile duct-ligated rats compared to the sham-operated group (P < 0.01 and 0.05, respectively). Basal contractile abnormalities of bile duct-ligated rats were corrected by L-NAME or naltrexone treatment, either acute or chronic. While chronic L-NAME treatment resulted in a left-ward shift (P < 0.05), it had no effect on the maximum effect in bile duct-ligated rats. Acute L-NAME treatment did not influence isoproterenol responsiveness. Acute and chronic naltrexone treatment resulted in partial and complete correction of the hyporesponsiveness of bile duct-ligated rats, respectively (P < 0.05). This investigation demonstrates that the papillary muscles of 7-day bile duct ligated-rats have an impaired basal contractility and hyporesponsiveness to both α and β-adrenoceptor stimulation. It also provides evidence for the involvement of increased opioidergic tone and NO overproduction in cholestasis-induced cardiac impairment.

Original languageEnglish (US)
Pages (from-to)93-100
Number of pages8
JournalEuropean Journal of Pharmacology
Volume523
Issue number1-3
DOIs
StatePublished - Oct 31 2005
Externally publishedYes

Keywords

  • Adrenoceptor
  • Cardiomyopathy
  • Cholestasis
  • Endogenous opioid peptide
  • NO (Nitric oxide)
  • Papillary muscle

ASJC Scopus subject areas

  • Pharmacology

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