Dissociation of Vascular Tolerance and Plasma Norepinephrine Adjustment during Long-term Nitrate Therapy in Human Coronary Arteries

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Objective We examined whether changes in plasma norepinephrine (NE) concentration contribute to the development of nitrate tolerance in human coronary arteries. Methods Patients with stable angina were randomized to receiving nitrate (isosorbide dinitrate: ISDN or nitroglycerin: TNG) infusion for 30 minutes (group A), 48 hours (group B), or 78 hours (group C). Coronary diameters were measured angiographically at baseline (CT), during maximum dilation by ISDN (Nl), at the end of nitrate infusion (N2) and after additional ISDN (1 mg) injection (N3). Results In groups A and B, Nl, N2, and N3 were greater than CT, and there was no significant difference between Nl, N2, and N3 for each group. In group C, Nl and N3 were greater than CT, but there was no difference between CT and N2, in the development of nitrate tolerance. In group A, NE increased significantly during nitrate infusion (304±163 vs. 418±273 pg/ml). NE did not change in groups B and C. Conclusion The change in NE concentration is not a primary contribution to the development of nitrate tolerance.
(Internal Medicine 38: 773-779, 1999)