Reduced susceptibility to epinephrine-induced arrhythmias in cirrhotic rats: the roles of nitric oxide and endogenous opioid peptides.
OBJECTIVE
The clinical relevance of QT prolongation, the most widely recognized cardiac electrophysiological abnormality of cirrhosis, is still undefined. The aim of this study is to examine the susceptibility of chronic (4-week) bile duct-ligated rats to epinephrine-induced arrhythmias. The roles of nitric oxide and endogenous opioids were also evaluated.


METHODS
Sham-operated and cirrhotic rats were treated with daily subcutaneous administrations of normal saline (1 ml/kg/day), L-NAME (a non-selective nitric oxide synthase inhibitor, 3mg/kg/day), and naltrexone (20mg/kg/day) during the fourth week after operation. In order to evaluate the effects of acute nitric oxide synthesis inhibition, additional groups of animals were treated by acute intraperitoneal L-NAME injections (3mg/kg). Arrhythmias were induced by intravenous injections of 10 microg/kg epinephrine.


RESULTS
Despite QT prolongation (P<0.001), epinephrine induced fewer arrhythmias in cirrhotic rats compared to sham-operated animals (P<0.05). Chronic, but not acute, L-NAME administration corrected the QT prolongation in cirrhotic rats (P<0.001), and restored the susceptibility of cirrhotic rats to arrhythmias (P<0.05). Naltrexone injection without a significant effect on epinephrine-induced arrhythmias corrected QT interval in cirrhotic rats (P<0.001).


CONCLUSIONS
This study shows that despite QT prolongation, cirrhotic animals are resistant against epinephrine-induced arrhythmias. This resistance is mediated by chronic nitric oxide overproduction.
Tavakoli
Sina
S
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran.
Hajrasouliha
Amir Reza
AR
Jabehdar-Maralani
Pejman
P
Ebrahimi
Farzad
F
Solhpour
Amirreza
A
Sadeghipour
Hamed
H
Ghasemi
Mehdi
M
Dehpour
Ahmad R
AR
D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D004198:Disease Susceptibility / Q000503:physiopathology*; D004562:Electrocardiography; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004837:Epinephrine; D006339:Heart Rate / Q000502:physiology; D008106:Liver Cirrhosis, Experimental / Q000150:complications* / Q000503:physiopathology; D008133:Long QT Syndrome / Q000139:chemically induced / Q000209:etiology* / Q000517:prevention & control*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000187:drug effects; D018847:Opioid Peptides / Q000502:physiology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012307:Risk Factors
D004791:Enzyme Inhibitors; D018847:Opioid Peptides; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester; D004837:Epinephrine