Dual nitric oxide mechanisms of cholestasis-induced bradycardia in the rat.
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.
Mani
Ali R
AR
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Nahavandi
Arezo
A
Moosavi
Maryam
M
Safarinejad
Reza
R
Dehpour
Ahmad R
AR
D000818:Animals; D001652:Bile Ducts / Q000187:drug effects / Q000378:metabolism; D001919:Bradycardia / Q000378:metabolism* / Q000503:physiopathology; D002779:Cholestasis / Q000378:metabolism* / Q000503:physiopathology; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D009569:Nitric Oxide