Development of Insulin Resistance by Nitrate Tolerance in Conscious Rabbits

Clinical evidence has been raised to suggest that transdermal nitroglycerin increases the sensitivity of peripheral tissues to the hypoglycemic effect of insulin. In this study we determined whether development of tolerance to the hypotensive effect of nitroglycerin also resulted in tolerance to the insulin-sensitizing effect in rabbits. Intravenous glucose disposal and hyperinsulinemic euglycemic glucose clamp studies were performed on naive and hemodynamic nitrate tolerant conscious New Zealand white rabbits. These rabbits were exposed to continuous "patch on" with nitroglycerin (0.07 mg/kg/h) or placebo patches over 7 days. Nitroglycerin treatment of 7 days produced a lack of hypotensive response to a single intravenous bolus of 30 microg/kg nitroglycerin, which caused a significant decrease in mean arterial blood pressure in control rabbits. A six-hour exposure to transdermal nitroglycerin significantly increased insulin sensitivity determined by hyperinsulinemic (100 microU/ml) euglycemic (5.5 mmol/l) glucose clamping as compared with that seen in rabbits treated with placebo patches. A significant decrease in insulin sensitivity was observed in the nitroglycerin patch-treated animals both in the presence and after the removal of the last patch when the patches were applied over 7 days. We conclude that acutely nitrate patches improve insulin sensitivity whereas a 7-day chronic treatment schedule that results in hemodynamic nitrate tolerance also produces insulin resistance.