Contribution of endogenous opioids and nitric oxide to papillary muscle contractile impairment in cholestatic rats.
Attenuated responsiveness to adrenoceptor stimulation has been proposed as an important factor underlying cardiovascular complications of cholestasis. We examined isolated papillary muscle responsiveness to alpha (phenylephrine) and beta-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(omega)-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 alpha and beta-adrenoceptor stimulation. It also provides evidence for the involvement of increased opioidergic tone and NO overproduction in cholestasis-induced cardiac impairment.
Ebrahimi
Farzad
F
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran.
Tavakoli
Sina
S
Hajrasouliha
Amir Reza
AR
Shafaroodi
Hamed
H
Sadeghipour
Hamed
H
Riazi
Kiarash
K
Borhani
Amir Ali
AA
Houshmand
Golbahar
G
Ahmadi
Seyed Hossein
SH
Dehpour
Ahmad Reza
AR
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001652:Bile Ducts / Q000601:surgery; D009202:Cardiomyopathies / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D002779:Cholestasis / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D008026:Ligation; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D018847:Opioid Peptides / Q000378:metabolism; D010210:Papillary Muscles / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D000316:Adrenergic alpha-Agonists; D000318:Adrenergic beta-Agonists; D004791:Enzyme Inhibitors; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D010656:Phenylephrine; D009569:Nitric Oxide; D009271:Naltrexone; D019001:Nitric Oxide Synthase; D007545:Isoproterenol; D019331:NG-Nitroarginine Methyl Ester