Resistance of cholestatic rats against epinephrine-induced arrhythmia: the role of nitric oxide and endogenous opioids.
Short-term ligation of bile duct has been used as a model to study acute cholestasis and is associated with various cardiovascular abnormalities. We examined the role of nitric oxide (NO) and endogenous opioids on epinephrine-induced arrhythmia in 7-day bile duct-ligated (BDL) rats. Six groups of rats, each of which was subdivided into two subgroups (sham-operated and BDL), were examined. First group of animals were chronically treated with normal saline. In the second and third groups, single intraperitoneal administration of N(omega)-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg) or naltrexone (20 mg/kg) was performed 30 min before evaluation of epinephrine-induced arrhythmia. Two groups received chronic administration of low dose (3 mg/kg/day) or high dose (10 mg/kg/day) L-NAME; and the last group was treated chronically with naltrexone (20 mg/kg/day). Chronic drug administration was performed subcutaneously for 6 consecutive days following BDL or sham operation. After induction of arrhythmia by intravenous injection of 10 microg/kg epinephrine, mean arterial pressure and electrocardiogram were recorded for 1 min. Heart rate and mean arterial pressure were significantly lower in BDL rats (P<0.01). Chronic injection of naltrexone increased heart rate and mean arterial pressure in BDL (P<0.05). Chronic low dose L-NAME administration had no effect on baseline hemodynamic parameters. High dose L-NAME injection corrected hypotension in BDL rats, but not bradycardia (P<0.05). Epinephrine induced less arrhythmia in BDL rats (P<0.05). Acute and chronic injection of naltrexone had no effect on the resistance of BDL rats against epinephrine-induced arrhythmia. Although acute L-NAME administration enhanced arrhythmias in sham-operated rats (P<0.001), it had no effect on BDL animals. Chronic injection of low dose or high dose L-NAME, without having any effect on sham-operated animals, increased arrhythmias in BDL rats (P<0.01). This study showed that BDL animals are resistant against epinephrine-induced arrhythmia and this resistance depends on long-term NO overproduction.
Hajrasouliha
Amir Reza
AR
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran.
Tavakoli
Sina
S
Jabehdar-Maralani
Pejman
P
Shafaroodi
Hamed
H
Borhani
Amir Ali
AA
Houshmand
Golbahar
G
Sadeghipour
Hamed
H
Dehghani
Mehdi
M
Dehpour
Ahmad Reza
AR
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000503:physiopathology*; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002779:Cholestasis / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004837:Epinephrine / Q000008:administration & dosage / Q000633:toxicity; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D007275:Injections, Intravenous; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley
D004791:Enzyme Inhibitors; D009292:Narcotic Antagonists; D009271:Naltrexone; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester; D004837:Epinephrine