(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).
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
This article has been cited by other articles:
 |
|
 |
|
  P.-S. Tsou, V. Addanki, and H.-L. Fung Dissociation between Superoxide Accumulation and Nitroglycerin-Induced Tolerance J. Pharmacol. Exp. Ther., October 1, 2008; 327(1): 97 - 104. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Hink, A. Daiber, N. Kayhan, J. Trischler, C. Kraatz, M. Oelze, H. Mollnau, P. Wenzel, C. F. Vahl, K. K. Ho, et al. Oxidative Inhibition of the Mitochondrial Aldehyde Dehydrogenase Promotes Nitroglycerin Tolerance in Human Blood Vessels J. Am. Coll. Cardiol., December 4, 2007; 50(23): 2226 - 2232. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. MacPherson, T. D. Gillespie, H. A. Dunkerley, D. H. Maurice, and B. M. Bennett Inhibition of Phosphodiesterase 5 Selectively Reverses Nitrate Tolerance in the Venous Circulation J. Pharmacol. Exp. Ther., April 1, 2006; 317(1): 188 - 195. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Munzel, A. Daiber, and A. Mulsch Explaining the Phenomenon of Nitrate Tolerance Circ. Res., September 30, 2005; 97(7): 618 - 628. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. S. Mackenzie, K. M. Maki-Petaja, C. M. McEniery, Y. P. Bao, S. M. Wallace, J. Cheriyan, S. Monteith, M. J. Brown, and I. B. Wilkinson Aldehyde Dehydrogenase 2 Plays a Role in the Bioactivation of Nitroglycerin in Humans Arterioscler Thromb Vasc Biol, September 1, 2005; 25(9): 1891 - 1895. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Chen, M. W. Foster, J. Zhang, L. Mao, H. A. Rockman, T. Kawamoto, K. Kitagawa, K. I. Nakayama, D. T. Hess, and J. S. Stamler An essential role for mitochondrial aldehyde dehydrogenase in nitroglycerin bioactivation PNAS, August 23, 2005; 102(34): 12159 - 12164. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Wei, C.-Q. Yang, A. Furnary, and G.-W. He Greater vasopressin-induced vasoconstriction and inferior effects of nitrovasodilators and milrinone in the radial artery than in the internal thoracic artery J. Thorac. Cardiovasc. Surg., January 1, 2005; 129(1): 33 - 40. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Elkayam, F. Bitar, M. W. Akhter, S. Khan, S. Patrus, and M. Derakhshani Intravenous Nitroglycerin in the Treatment of Decompensated Heart Failure: Potential Benefits and Limitations Journal of Cardiovascular Pharmacology and Therapeutics, October 1, 2004; 9(4): 227 - 241. [Abstract] [PDF]
|
|
|
|
 |
|
 J. DiFabio, Y. Ji, V. Vasiliou, G. R. J. Thatcher, and B. M. Bennett Role of Mitochondrial Aldehyde Dehydrogenase in Nitrate Tolerance Mol. Pharmacol., November 1, 2003; 64(5): 1109 - 1116. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Muller, U. Laber, J. Mullenheim, W. Meyer, and G. Kojda Preserved endothelial function after long-term eccentric isosorbide mononitrate despite moderate nitrate tolerance J. Am. Coll. Cardiol., June 4, 2003; 41(11): 1994 - 2000. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Horowitz Amelioration of nitrate tolerance: matching strategies with mechanisms J. Am. Coll. Cardiol., June 4, 2003; 41(11): 2001 - 2003. [Full Text] [PDF]
|
|
|
|
|
|
K. Yamahara, H. Itoh, T.-H. Chun, Y. Ogawa, J. Yamashita, N. Sawada, Y. Fukunaga, M. Sone, T. Yurugi-Kobayashi, K. Miyashita, et al. Significance and therapeutic potential of the natriuretic peptides/cGMP/cGMP-dependent protein kinase pathway in vascular regeneration PNAS, March 18, 2003; 100(6): 3404 - 3409. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.R. Willoughby, S. Stewart, Y.Y. Chirkov, J.A. Kennedy, A.S. Holmes, and J.D. Horowitz Beneficial clinical effects of perhexiline in patients with stable angina pectoris and acute coronary syndromes are associated with potentiation of platelet responsiveness to nitric oxide Eur. Heart J., December 2, 2002; 23(24): 1946 - 1954. [Abstract] [PDF]
|
|
|
|
 |
|
 T. Gori and J. D. Parker Nitrate Tolerance: A Unifying Hypothesis Circulation, November 5, 2002; 106(19): 2510 - 2513. [Full Text] [PDF]
|
|
|
|
 |
|
 T. Csont, C. Csonka, A. Onody, A. Gorbe, L. Dux, R. Schulz, G. F. Baxter, and P. Ferdinandy Nitrate tolerance does not increase production of peroxynitrite in the heart Am J Physiol Heart Circ Physiol, July 1, 2002; 283(1): H69 - H76. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. J. Ignarro After 130 years, the molecular mechanism of action of nitroglycerin is revealed PNAS, June 11, 2002; 99(12): 7816 - 7817. [Full Text] [PDF]
|
|
|
|
|
|
Z. Chen, J. Zhang, and J. S. Stamler From the Cover: Identification of the enzymatic mechanism of nitroglycerin bioactivation PNAS, June 11, 2002; 99(12): 8306 - 8311. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Wei, H. S. Floten, and G.-W. He Interaction between vasodilators and vasopressin in internal mammary artery and clinical significance Ann. Thorac. Surg., February 1, 2002; 73(2): 516 - 522. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Parker and T. Gori Tolerance to the Organic Nitrates: New Ideas, New Mechanisms, Continued Mystery Circulation, November 6, 2001; 104(19): 2263 - 2265. [Full Text] [PDF]
|
|
|
|
|
|
T. Munzel Does nitroglycerin therapy hit the endothelium? J. Am. Coll. Cardiol., October 1, 2001; 38(4): 1102 - 1105. [Full Text] [PDF]
|
|
|
|
|
|
S. P. Didion, C. A. Hathaway, and F. M. Faraci Superoxide levels and function of cerebral blood vessels after inhibition of CuZn-SOD Am J Physiol Heart Circ Physiol, October 1, 2001; 281(4): H1697 - H1703. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Jurt, T. Gori, A. Ravandi, S. Babaei, P. Zeman, and J. D. Parker Differential effects of pentaerythritol tetranitrate and nitroglycerin on the development of tolerance and evidence of lipid peroxidation: a human in vivo study J. Am. Coll. Cardiol., September 1, 2001; 38(3): 854 - 859. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Schulz, N. Tsilimingas, R. Rinze, B. Reiter, M. Wendt, M. Oelze, S. Woelken-Weckmuller, U. Walter, H. Reichenspurner, T. Meinertz, et al. Functional and Biochemical Analysis of Endothelial (Dys)function and NO/cGMP Signaling in Human Blood Vessels With and Without Nitroglycerin Pretreatment Circulation, March 12, 2002; 105(10): 1170 - 1175. [Abstract] [Full Text] [PDF]
|
|