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

Clinical and Experimental Pharmacology and Physiology - Tập 29 Số 10 - Trang 905-908 - 2002
Ali R. Mani1, Arezo Nahavandi2, Maryam Moosavi2, Reza Safarinejad1, Ahmad Reza Dehpour1
1Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences and
2Department of Physiology, Iran University of Medical Sciences, Tehran, Iran

Tóm tắt

Summary1. 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.

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Clinical and Experimental Pharmacology and Physiology

Tập 29 Số 10

905-908

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