Do endogenous opioids contribute to the bradycardia of rats with obstructive cholestasis?

Abstract

Endogenous opioids have nitric oxide (NO)-dependent cardiovascular actions. In the light of biological evidence of accumulation of endogenous opioids in cholestasis and also existence of NO-dependent bradycardia in cholestatic subjects, this study was carried out to evaluate the role of endogenous opioids in the generation of bradycardia in a rat model of cholestasis. Male Sprague-Dawley rats were used to induce cholestasis by surgical ligation of the bile duct, with sham-operated animals serving as a control. The animals were divided into six groups which received naltrexone [20 mg/kg/day, subcutaneously (s.c.)], N(G)-L-nitro-arginine methyl ester (L-NAME, 3 mg/kg/day, s.c.), aminoguanidine (200 mg/kg/day, s.c.), L-arginine (200 mg/kg/day, s.c.), naltrexone + L-NAME (20 and 3 mg/kg/day, s.c) or saline. One week after the operation, a lead II electrocardiogram (ECG) was recorded and the spontaneously beating atria of the animals were then isolated and the chronotropic responses to epinephrine evaluated. The plasma L-nitro-tyrosine level and alanine amino transferase and alkaline phosphatase activities were also measured. The heart rate of cholestatic animals was significantly lower than that of control rats in vivo and this bradycardia was corrected with daily adminstration of naltrexone or L-NAME. The basal spontaneous beating rate of atria in cholestatic animals was not significantly different from that of sham-operated animals in vitro. Cholestasis induced a significant decrease in the chronotropic effect of epinephrine. This effect was corrected by daily injection of naltrexone or L-NAME, or concurrent administration of naltrexone + L-NAME, and was not corrected by aminoguanidine. L-arginine had an equivalent effect to L-NAME and increased the chronotropic effect of epinephrine in cholestatic rats but not in control animals. Bile duct ligation increased the plasma activity of liver enzymes as well as the level of L-nitro-tyrosine. L-arginine and naltrexone treatment significantly decreased the elevation of liver enzymes in bile duct-ligated rats. Pretreatment of cholestatic animals with naltrexone or L-NAME decreased the plasma L-nitro-tyrosine level. The results suggest that either prevention of NO overproduction or protection against liver damage is responsible for recovery of bradycardia after naltrexone administration.

Naltrexone attenuates endoplasmic reticulum stress induced hepatic injury in mice

“…Although opioid peptides were first recognized in brain, they are also found in other tissues such as gut, spleen, stomach, heart, pancreas and liver (38). Opioid peptides are up regulated in diseases states such as liver dysfunction, endotoxic shock, trauma and cholestasis (7,11,14). Morphine administration is shown to induce oxidative stress and increase superoxide dismutase and catalase activities and apoptosis in liver tissue (32).…”

Opioid Receptor Blockade Improves Mesenteric Responsiveness in Biliary Cirrhosis

“…Opioid peptides contribute partly to the manifestations of liver disease such as fatigue, pruritis, ascitis and hepatic encephalopathy. There are also emerging reports on the role of opioid system in the pathophysiology of cardiovascular hyporesponsiveness in short-term cholestasis [4,5]. However there is not any data regarding the contribution of endogenous opioid system to hyperdynamic circulation of cirrhosis which is a more common clinical situation with worldwide importance.…”

The Inflammatory Response to Cigarette Smoking Versus Inhaled Opium in the Liver: An Experimental Study

“…These destructive effects of opium have been also observed in biliary systems so that a significant increase in the range of the common bile duct diameter in comparison with normal bile ducts was shown following chronic opium addiction [3]. Besides, it has been suggested that opioid neurotransmission is increased in patients with liver disease, and therefore, administration of opioid antagonists decreases liver injury in animal models with acute biliary obstruction [4,5]. Moreover, the current data suggest that regular injection of opioids may lead to decreased hepatic glutathione levels [6].…”