Dual nitric oxide mechanisms of cholestasis-induced bradycardia in the rat


AR Dehpour, Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, PO Box: 13145-784, Tehran, Iran. Email: Dehpour@medscape.com


1. Cholestatic liver disease is associated with nitric oxide (NO) overproduction and bradycardia. Nitric oxide has a dual effect on sinoatrial node and its effects depend on its concentration. Nitric oxide can increase heart rate by activating hyperpolarization-activated pacemaker current (If) but, at high concentrations, it can potentially decrease heart rate by inhibition of L-type calcium current. In the present study, the responsiveness of isolated atria to CsCl (an inhibitor of the If current) and acetylcholine (ACh; which decreases L-type calcium current through a NO-dependent pathway) were evaluated in bile duct-ligated and sham-operated control rats.

2. Bile duct ligation induced a significant decrease in the negative chronotropic effect of CsCl (0.2–5 mmol/L), but increased the responsiveness of isolated atria to ACh (10−8 to 10−3 mol/L). These effects were restored after incubation of the atria in the presence of the NO synthase inhibitor NG-nitro-l-arginine methyl ester (0.1 mmol/L).

3. Anaesthetized bile duct-ligated rats showed bradycardia and the plasma levels of NO2/NO3 were significantly higher in bile duct-ligated rats compared with sham-operated animals.

4. Different and opposite responses of atria of cholestatic rats to CsCl and ACh can be explained by NO overproduction in bile duct-ligated animals. A dual role of NO in the regulation of the sinoatrial node may be responsible for this opposite effect and may have a role in the pathophysiology of cholestasis-induced bradycardia.