Beneficial myocardial metabolic effects of insulin during verapamil toxicity in the anesthetized canine

OBJECTIVE Myocardial depression from verapamil toxicity may result from alterations in carbohydrate metabolism as well as calcium-channel antagonism. We hypothesized that pharmacologic doses of insulin may be effective in reversing both of these deficits. DESIGN Randomized, controlled, prospective study. SETTING Laboratory of an urban hospital. SUBJECTS Thirty mongrel dogs. INTERVENTIONS Thirty mongrel canines were anesthetized with alpha-chloralose. Toxicity was induced by the administration of 0.1 mg/kg/min iv of verapamil, until there was a 50% reduction in mean arterial pressure, for 30 mins (titration), followed by a continuous verapamil infusion of 1 mg/kg/hr. Animals (n = 6 per group) were randomized to the control group (saline only) or to one of four treatment protocolsa) calcium chloride (20 mg/kg), then 0.6 mg/kg/hr; b) hyperinsulinemia-euglycemia (4.0 U/min of recombinant insulin, with arterial glucose concentration clamped to +/-10 mg/dL [+/-0.5 mmol/L] of the basal value); c) epinephrine, with a starting rate of 1.0 micro gram/kg/min, titrated to maintain left ventricular pressure at basal values; or d) glucagon, a 0.2-mg/kg bolus, followed by a 150-micro gram/kg/hr infusion. Animals were monitored until death or 240 mins; infusate volumes were held constant for all groups. MEASUREMENTS AND MAIN RESULTS During verapamil titration, the myocardial respiratory quotient increased from 0.84 +/- 0.05 to 1.07 +/- 0.11 (p < .05, paired t-test) and myocardial glucose uptake doubled, despite a reduction in cardiac work (p < .05, paired t-test). Net myocardial lactate uptake also increased significantly, excluding myocardial ischemia. In controls, this trend continued, indicating preferential carbohydrate metabolism during untreated verapamil toxicity. Despite hyperglycemia, the plasma insulin concentration was not significantly different in controls (basal value 11 +/- 2 vs. 39 +/- 21 mu U/mL at 30 mins). Hyperinsulinemia-euglycemia increased both myocardial glucose and lactate uptake five-fold, and significantly increased the ratio of myocardial oxygen delivery/work, along with superior improvements in maximal left ventricular elastance at end systole compared with other treatments (p < .05 vs. other treatments, contrast analysis). CONCLUSIONS Verapamil toxicity renders the heart dependent on carbohydrate metabolism. Inasmuch as the positive inotropic effects of all treatments were coincident with increased indices of myocardial carbohydrate uptake, a