Disopyramide induces insulin secretion and plasma glucose diminution: Studies using the in situ canine pancreas

The mechanism of disopyramide-induced hypoglycemia, a life-threatening complication in the antiarrhythmic drug treatment, is still controversial. To elucidate this, we have evaluated plasma insulin (IRI) and glucagon (IRG) responses in the pancreatic vein (PV) of the in situ pancreas as well as responses of plasma IRI, IRG, and glucose in the femoral artery (FA) to disopyramide phosphate administration in anesthetized dogs. First, infusion of disopyramide at a dose of 50 mg for ten minutes directly into the pancreatic artery, but not the vehicle, increased significantly plasma IRI concentration in the PV ( P < .05 or less), where the IRI response started within three minutes and reached a peak of 2.8-fold preinfusion value at 30 minutes after starting the infusion (n = 7). Plasma IRI concentration in the FA also increased slightly but significantly ( P < .05). Plasma IRG concentration in the PV initially decreased significantly ( P < .05 or less) and in the FA at one point ( P < .05) during the infusion, and then increased significantly after cessation of the infusion, showing a peak of 1.9-fold preinfusion value at 60 minutes in the PV and the FA ( P < .05). Plasma glucose concentration in the FA decreased slowly and significantly after the infusion ( P < .05 or less) and fell by 16% of the baseline value at 60 minutes ( P < .05). Second, infusion of disopyramide at a dose of 7 mg/kg body weight (BW) for ten minutes into the femoral vein induced a peak of serum disopyramide concentration of 13.7 ± 2.8 μg/mL at ten minutes, which corresponds to a twofold to threefold concentration of the human therapeutic level (n = 4). The disopyramide infusion, but not vehicle, induced a significant increment of plasma IRI concentration in the PV at ten minutes ( P < .05), accompanying a very slight IRI rise in the FA. Plasma IRG concentration in the PV again increased after the cessation of the infusion ( P < .05). Arterial plasma glucose level decreased significantly by 14% at 60 minutes ( P < .01). The present results indicate that disopyramide provokes a prompt and significant insulin secretion, and also induces a concomitant fall of plasma glucose level in face of an ongoing IRG secretion. The results thus suggest that the disopyramide-induced glucose fall is caused by decreased hepatic glucose output due to the hepatic action of insulin released by the drug rather than by increased peripheral glucose uptake due to the peripheral action of insulin. It may be an addi