Protective Effect of Digoxin on Impaired Chronotropic Responsiveness to Adrenergic Stimulation in Cholestatic Rats

Decreased cardiac responsiveness to adrenergic stimulation has been observed in cholestatic liver disease, but the cause remains unclear. Previous reports have suggested that nitric oxide overproduction might have a role in cholestasis-induced bradycardia via inhibition of L-type calcium channels. In the present study, the digoxin has been used to increase cardiac Ca2+ transient in male Sprague-Dawley rats with obstructive cholestasis and the chronotropic responsiveness to adrenergic stimulation was evaluated. Cholestasis was induced by surgical ligation of the bile duct under general anesthesia and sham-operated animals were considered as control. The animals were divided into two groups, which received either digoxin (10, 20 mg/kg/day) or saline. One week after the operation, spontaneously beating atria were isolated and chronotropic responses to epinephrine were evaluated in a standard oxygenated organ bath. The basal spontaneous beating rate of the atria in the cholestatic animals was not significantly different from that of sham-operated rats in vitro. Meanwhile, cholestasis induced a significant decrease in chronotropic effect of epinephrine. This effect was corrected by daily administration of digoxin (20 mg/kg/day). The results also showed that plasma alkaline phosphatase activity was increased by bile-duct ligation, and digoxin treatment had no effect in the elevation of this marker of liver damage. The protective effect of digoxin on impaired chronotropic responsiveness to adrenergic stimulation in cholestatic rats might be related to increase of Ca2+ transient. However, further studies are necessary to confirm the molecular basis of this effect