Resistance of cholestatic rats against epinephrine-induced arrhythmia: the role of nitric oxide and endogenous opioids

Abstract

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(ω)-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 μg/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.