Nitroglycerin tolerance in human vessels - Evidence for impaired nitroglycerin bioconversion

Background-The basis for progressive attenuation of the effects of organic nitrates during long-term therapy (nitrate tolerance) remains controversial ; proposed mechanisms include impaired nitrate bioconversion resulting in d ecreased release of nitric oxide (NO) from nitrates and/or increased NO cle arance through a reaction with incrementally generated superoxide (O-2(-)). Methods and Results-Patients undergoing elective coronary artery bypass wer e randomized to receive 24 hours of intravenously infused nitroglycerin (NT G; nitrate group) or no nitrate therapy (control group). Discarded segments of the internal mammary artery and saphenous vein were used to examine (1) vascular responsiveness to NTG, sodium nitroprusside, and the calcium iono phore A23187; (2) bioconversion of NTG to 1,2- and 1,3-glyceryl dinitrate; and (3) the generation of O-2(-). Responses to NTG were reduced 3- to 5-fol d in vessels from the nitrate group compared with control vessels (P<0.01 f or both types of segments), whereas responses to sodium nitroprusside and A 23187 were unchanged. Tissue content of 1,2-glyceryl dinitrate was lower (P =0.012) in the saphenous veins from the nitrate group than in those from th e control group. O-2(-) generation was greater (P<0.01) in internal mammary artery samples from the nitrate group than in those from the control group . However, incremental O-2(-) generation induced by an inhibitor of superox ide dismutase did not affect NTG responses. Conclusions-NTG tolerance in patients with coronary artery disease is nitra te-specific and is associated with evidence of impaired NTG bioconversion. Tolerance was associated with incremental O-2(-) generation, but short-term elevation of O-2(-) did not affect NTG responsiveness, suggesting increase d NO clearance by O-2(-) has a minimal contribution to tolerance.