Dissociation of coronary vascular tolerance and neurohormonal adjustments during long-term nitroglycerin therapy in patients with stable coronary artery disease

Medizinische Klinik III, Division of Cardiology, University of Freiburg, Germany.

OBJECTIVES. We sought to examine whether long-term nitroglycerin treatment causes tolerance in large coronary arteries and whether the loss of vascular effects parallels neurohormonal adjustments. BACKGROUND. Nitroglycerin therapy is associated with increased plasma renin activity and aldosterone levels and a decrease in hematocrit. It is assumed that nitroglycerin tolerance results in part from these neurohormonal adjustments and intravascular volume expansion. METHODS. Three groups were studied: group I (n = 10), no prior nitroglycerin therapy; and group II (n = 10) and group III (n = 8), 24- and 72-h long-term nitroglycerin infusion (0.5 micrograms/kg body weight per min), respectively. Coronary artery dimensions were assessed using quantitative angiography. Plasma renin activity, plasma aldosterone and vasopressin levels and hematocrit were monitored before and during nitroglycerin infusions. RESULTS. In group I, increasing intravenous concentrations of nitroglycerin caused a dose-dependent increase of the midportion of the left anterior descending coronary artery (baseline diameter 2.13 +/- 0.07 mm [mean +/- SEM], maximally by 22 +/- 2%) and left circumflex coronary artery (baseline diameter 2.08 +/- 0.07) mm, maximally by 22 +/- 3%). An intracoronary nitroglycerin bolus (0.2 mg) caused no further significant increase in diameter, indicating maximal dilation. In group II (n = 10), the baseline large coronary artery diameter under ongoing nitroglycerin was significantly larger than that in group I (left anterior descending artery 2.61 +/- 0.08 mm, left circumflex artery 2.57 +/- 0.08 mm). Additional intravenous and intracoronary nitroglycerin challenges did not cause further dilation, indicating maximally dilated vessels. At the same time, plasma renin activity, plasma aldosterone and vasopressin levels were significantly increased, and hematocrit significantly decreased. In group III patients, the baseline diameter of the left anterior descending artery and the left circumflex artery did not differ from that in patients without nitroglycerin pretreatment, indicating a complete loss of nitroglycerin coronary vasodilative effects. These patients showed no significant increase in circulating neurohormonal levels but a significant decrease in hematocrit. CONCLUSIONS. Within 24 h of continuous nitroglycerin treatment, the coronary arteries were maximally dilated despite neurohormonal adjustments and signs of intravascular volume expansion. Within 3 days of nitroglycerin infusion, tolerance developed in the absence of neurohormonal activation. The dissociation of neurohormonal adjustments and tolerance in large coronary arteries indicates that after long-term nitroglycerin treatment, true vascular tolerance, perhaps from an intracellular tolerance step, may have developed.

This article has been cited by other articles:

				T. Munzel, A. Daiber, and T. Gori Nitrate Therapy: New Aspects Concerning Molecular Action and Tolerance Circulation, May 17, 2011; 123(19): 2132 - 2144. [Full Text] [PDF]

				T. Gori, S. Dragoni, G. Di Stolfo, S. Sicuro, A. Liuni, M. C. Luca, G. Thomas, M. Oelze, A. Daiber, and J. D. Parker Tolerance to nitroglycerin-induced preconditioning of the endothelium: a human in vivo study Am J Physiol Heart Circ Physiol, February 1, 2010; 298(2): H340 - H345. [Abstract] [Full Text] [PDF]

				S. E. Petersen, F. Wiesmann, L. E. Hudsmith, M. D. Robson, J. M. Francis, J. B. Selvanayagam, S. Neubauer, and K. M. Channon Functional and Structural Vascular Remodeling in Elite Rowers Assessed by Cardiovascular Magnetic Resonance J. Am. Coll. Cardiol., August 15, 2006; 48(4): 790 - 797. [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]

				U. Hink, M. Oelze, P. Kolb, M. Bachschmid, M.-H. Zou, A. Daiber, H. Mollnau, M. August, S. Baldus, N. Tsilimingas, et al. Role for peroxynitrite in the inhibition of prostacyclin synthase in nitrate tolerance J. Am. Coll. Cardiol., November 19, 2003; 42(10): 1826 - 1834. [Abstract] [Full Text] [PDF]

				S. D. Rybalkin, C. Yan, K. E. Bornfeldt, and J. A. Beavo Cyclic GMP Phosphodiesterases and Regulation of Smooth Muscle Function Circ. Res., August 22, 2003; 93(4): 280 - 291. [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]

				T. Gori and J. D. Parker The Puzzle of Nitrate Tolerance: Pieces Smaller Than We Thought? Circulation, October 29, 2002; 106(18): 2404 - 2408. [Full Text] [PDF]

				T. Munzel, A. Mulsch, and A. Kleschyov Mechanisms Underlying Nitroglycerin-Induced Superoxide Production in Platelets: Some Insight, More Questions Circulation, July 9, 2002; 106(2): 170 - 172. [Full Text] [PDF]

				D. Kim, S. D. Rybalkin, X. Pi, Y. Wang, C. Zhang, T. Munzel, J. A. Beavo, B. C. Berk, and C. Yan Upregulation of Phosphodiesterase 1A1 Expression Is Associated With the Development of Nitrate Tolerance Circulation, November 6, 2001; 104(19): 2338 - 2343. [Abstract] [Full Text] [PDF]

				D. A. Zvara Treatment of Perioperative Myocardial Ischemia Seminars in Cardiothoracic and Vascular Anesthesia, July 1, 2001; 5(2): 166 - 183. [Abstract] [PDF]

				J. Chanda, I. Brichkov, and C. C. Canver Prevention of radial artery graft vasospasm after coronary bypass Ann. Thorac. Surg., December 1, 2000; 70(6): 2070 - 2074. [Abstract] [Full Text] [PDF]

				T. Munzel, H. Mollnau, M. Hartmann, C. Geiger, M. Oelze, A. Warnholtz, A. H. Yehia, U. Forstermann, and T. Meinertz Effects of a nitrate-free interval on tolerance, vasoconstrictor sensitivity and vascular superoxide production J. Am. Coll. Cardiol., August 1, 2000; 36(2): 628 - 634. [Abstract] [Full Text] [PDF]

				I Christiansen, H. Iversen, and J Olesen Induction of Nitrate Tolerance is not a Useful Treatment in Cluster Headache Cephalalgia, June 1, 2000; 20(5): 445 - 454. [Abstract] [Full Text] [PDF]

				T. Munzel, H. Li, H. Mollnau, U. Hink, E. Matheis, M. Hartmann, M. Oelze, M. Skatchkov, A. Warnholtz, L. Duncker, et al. Effects of Long-Term Nitroglycerin Treatment on Endothelial Nitric Oxide Synthase (NOS III) Gene Expression, NOS III-Mediated Superoxide Production, and Vascular NO Bioavailability Circ. Res., January 7, 2000; 86(1): e7 - e12. [Abstract] [Full Text] [PDF]

				S. Kurz, U. Hink, G. Nickenig, A. B. Borthayre, D. G. Harrison, and T. Munzel Evidence for a Causal Role of the Renin-Angiotensin System in Nitrate Tolerance Circulation, June 22, 1999; 99(24): 3181 - 3187. [Abstract] [Full Text] [PDF]

				H. Hupf, D. Grimm, G. A. J. Riegger, and H. Schunkert Evidence for a Vasopressin System in the Rat Heart Circ. Res., February 19, 1999; 84(3): 365 - 370. [Abstract] [Full Text] [PDF]

				P. R. A. Caramori, A. G. Adelman, E. R. Azevedo, G. E. Newton, A. B. Parker, and J. D. Parker Therapy with nitroglycerin increases coronary vasoconstriction in response to acetylcholine J. Am. Coll. Cardiol., December 1, 1998; 32(7): 1969 - 1974. [Abstract] [Full Text] [PDF]

				J. Zanzinger, J. Czachurski, and H. Seller Impaired Modulation of Sympathetic Excitability by Nitric Oxide After Long-term Administration of Organic Nitrates in Pigs Circulation, June 16, 1998; 97(23): 2352 - 2358. [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]