Abnormal Rheologic Effects of Glyceryl Trinitrate in Patients with Non-Insulin-Dependent Diabetes Mellitus and Reversal by Antioxidants

Abstract

Objective: io evaluate 1) the hemorrheologic and hemodynamic effects of glyceryl trinitrate in patients with non-insulin-dependent diabetes mellitus and 2) the influence of antioxidants on these effects. Design: Case-control study. Setting: University hospital clinic. Patients: 40 patients with diabetes and no evidence of cardiovascular complications and 40 controls matched for demographic variables and body habitus. Interventions: Sublingual glyceryl trinitrate (0.3 mg) and transdermal glyceryl trinitrate patches (10 mg/d). Vitamin E, 300 mg/d orally for 7 days, and glutathione, 600 mg intravenously or intramuscularly, were given to test the effects of antioxidant supplementation. Measurements: Systolic, diastolic, and mean arterial pressure and heart rate; left ventricular ejection fraction; platelet aggregation, blood viscosity, and blood filterability in vitro and ex vivo. Results: Compared with controls, patients with diabetes had increased platelet aggregation to adenosine diphosphate (P < 0.005), increased blood viscosity (P < 0.001), and decreased blood filterability (P = 0.041) at baseline; blood pressure, heart rate, and ejection fraction were similar in the two groups. In controls, both sublingual glyceryl trinitrate and transdermal glyceryl trinitrate patches significantly reduced platelet aggregation (-38%; 95% CI, -49% to -27%) and blood viscosity (-8%; CI, -11% to -5%) and increased blood filterability (10%; CI, 7.0% to 13.1%). Slight but significant decreases in blood pressure and ejection fraction and an increase in heart rate were also seen in controls after administration of glyceryl trinitrate (both preparations). In patients with diabetes, glyceryl trinitrate paradoxically increased platelet aggregation (24%; CI, 15% to 33%) and blood viscosity (6%; CI, 2.9% to 8.8%) and decreased blood filterability (-7%; CI, -9.5% to -4.4%); hemodynamic values did not change significantly. In both groups, theologic responses to glyceryl trinitrate (end concentration, 100 and 200 ng/mL) in vitro were similar to those seen in ex vivo studies. Vitamin E and glutathione normalized theologic responses to glyceryl trinitrate in patients with diabetes. Conclusions: Organic nitrates have beneficial effects on blood theology in controls but not in patients with diabetes, in whom a paradoxical deterioration is seen. Antioxidant supplementation can normalize primary tolerance to the theologic effects of nitrates in diabetes.