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Eur J Pharmacol. 2004 Sep 24;499(3):307-13.

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

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Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran.


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.

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