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(Circulation. 2000;102:2810.)
© 2000 American Heart Association, Inc.

Clinical Investigation and Reports

Nitroglycerin Tolerance in Human Vessels

Evidence for Impaired Nitroglycerin Bioconversion

Presented in part at the 72nd Scientific Sessions of the American Heart Association, Atlanta, Ga, November 7–10, 1999, and published in abstract form (Circulation. 1999;100:I-186).

Peter R. Sage, MBBS, FRACP; Ivan S. de la Lande, DSc; Irene Stafford, BSc; Catherine L. Bennett, BSc (Hons); George Phillipov, PhD; John Stubberfield, MBBS, FRACS; John D. Horowitz, MBBS, PhD

From the Departments of Cardiology (P.R.S., I.S.d.l.L., I.S., C.L.B., J.D.H.) and Endocrinology (G.P.), The Queen Elizabeth Hospital, North Western Adelaide Health Service, University of Adelaide, and Department of Cardiothoracic Surgery (J.S.), Royal Adelaide Hospital, Adelaide, Australia.

Correspondence to Prof John Horowitz, Dept of Cardiology, TQEH Campus, NWAHS, Woodville Rd, Woodville, South Australia 5011, Australia. E-mail john.horowitz{at}adelaide.edu.au

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 decreased release of nitric oxide (NO) from nitrates and/or increased NO clearance through a reaction with incrementally generated superoxide (O₂^–).

Methods and Results—Patients undergoing elective coronary artery bypass were randomized to receive 24 hours of intravenously infused nitroglycerin (NTG; 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 ionophore A23187; (2) bioconversion of NTG to 1,2- and 1,3-glyceryl dinitrate; and (3) the generation of O₂^–. Responses to NTG were reduced 3- to 5-fold in vessels from the nitrate group compared with control vessels (P<0.01 for both types of segments), whereas responses to sodium nitroprusside and A23187 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 the control group. O₂^– generation was greater (P<0.01) in internal mammary artery samples from the nitrate group than in those from the control group. However, incremental O₂^– generation induced by an inhibitor of superoxide dismutase did not affect NTG responses.

Conclusions—NTG tolerance in patients with coronary artery disease is nitrate-specific and is associated with evidence of impaired NTG bioconversion. Tolerance was associated with incremental O₂^– generation, but short-term elevation of O₂^– did not affect NTG responsiveness, suggesting increased NO clearance by O₂^– has a minimal contribution to tolerance.

Key Words: nitroglycerin • nitrate tolerance • superoxide

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