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

Dario Giugliano, MD; Raffaele Marfella, MD; Giovanni Verrazzo, MD; Rita Acampora, MD; Cosimo Donzella, MD; Antonio Quatraro, MD; Ludovico Coppola, MD; and Felice D'Onofrio, MD
[+] Article and Author Information

From the Second University of Naples and the Diabetic Clinic Lepanto, Naples, Italy; and the Diabetic Clinic Santa Rita, Taranto, Italy. Requests for Reprints: Dario Giugliano, MD, Via Emilia 1, 80021 Afragola, Italy. Current Author Addresses: Drs. Giugliano, Marfella, Verrazzo, Coppola, D'Onofrio: Department of Geriatrics and Metabolic Disease, Second University of Naples, Piazza L. Miraglia, 80138 Napoli, Italy.


Copyright ©2004 by the American College of Physicians


Ann Intern Med. 1995;123(5):338-343. doi:10.7326/0003-4819-123-5-199509010-00003
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Objective: To 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, rheologic 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 rheologic responses to glyceryl trinitrate in patients with diabetes.

Conclusions: Organic nitrates have beneficial effects on blood rheology in controls but not in patients with diabetes, in whom a paradoxical deterioration is seen. Antioxidant supplementation can normalize primary tolerance to the rheologic effects of nitrates in diabetes.

Figures

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Figure 1.
Blood filterability and viscosity and platelet aggregation at baseline and 15 and 60 minutes after administration of sublingual glyceryl trinitrate (0.PP

3 mg) in 20 controls and 20 patients with non–insulin-dependent diabetes. Patients with diabetes were also studied after vitamin E (vit E) supplementation and during glutathione administration (GSH). * equals significance between patients with diabetes and controls ( < 0.05 to 0.001); star equals significance compared with baseline values ( < 0.05 to 0.01).

Grahic Jump Location
Grahic Jump Location
Figure 2.
Left.PPRight.PP

Blood filterability and viscosity and platelet aggregation at baseline and 1 and 12 hours after transdermal glyceryl trinitrate patches (10 mg) in 20 controls and 20 patients with diabetes. Patients with diabetes were also studied after vitamin E (vit E) supplementation and during glutathione administration (GSH). * equals significance between patients with diabetes and controls ( < 0.05 to 0.001); star equals significance compared with baseline values ( < 0.05 to 0.01). Effects of glyceryl trinitrae on platelet aggregation and blood viscosity and filterability in vitro. Blood was taken from 10 patients with diabetes and 10 matched controls. * equals significance between patients with diabetes and controls ( < 0.05 to 0.01); star equals significance compared with baseline values ( < 0.01 to 0.02). Glutathione (GSH) was tested at the end concentration of 300 mg/mL.

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