(Circulation. 1996;93:2052-2058.)
© 1996 American Heart Association, Inc.
Articles |
Long-term Angiotensin-Converting Enzyme Inhibition With High-Dose Enalapril Retards Nitrate Tolerance in Large Epicardial Arteries and Prevents Rebound Coronary Vasoconstriction In Vivo
From the Medizinische Klinik III, Division of Cardiology (T.M.) and the Institute for Applied Physiology (E.B.), University of Freiburg (Germany).
Correspondence to Thomas Münzel, MD, Universitätsklinik Freiburg, Medizinische Klinik III, Hugstetterstr 55, 79106 Freiburg, Germany.
Background Rebound myocardial ischemia develops
in patients with unstable or stable angina pectoris after sudden
cessation of nitroglycerin therapy. Long-term
nitroglycerin infusion is associated with increases in
plasma renin activity and catecholamine release rates, both
of which may lead to excess angiotensin II and
-adrenergic–mediated vasoconstriction, particularly on
withdrawal of nitroglycerin.
Methods and Results Chronically instrumented dogs were treated for 5 days with nitroglycerin (1.5 µg·kg-1·min-1 IV) alone or in combination with the angiotensin-converting enzyme (ACE) inhibitor enalapril (0.1 mg/kg two times daily or 1 mg/kg). With long-term nitroglycerin therapy, the left anterior circumflex artery was maximally dilated 4 hours after the start of nitroglycerin infusion (9.5±0.6%) and returned to baseline levels within the third day of treatment (baseline, 2.52±0.07 mm; day 3, 2.55±0.07 mm; P=NS), indicating a complete loss of nitroglycerin-induced coronary vasodilatation. Nitroglycerin infusion also was accompanied by a transient increase in plasma renin activity. Sudden withdrawal of nitroglycerin infusion caused a progressive constriction of the left anterior circumflex artery, which peaked 4 hours after nitroglycerin infusion cessation (-7.8±0.2%). This occurred in the absence of elevated plasma renin activity. Concomitant treatment with high-dose enalapril (1 mg·kg-1·d-1) markedly reduced the degree of tolerance and prevented the rebound constriction on cessation of nitroglycerin therapy.
Conclusions Long-term ACE inhibition with high-dose enalapril reduces nitroglycerin tolerance and prevents rebound vasoconstriction in coronary arteries. These phenomena were not associated with an activated circulating renin-angiotensin system. This observation suggests that during long-term nitroglycerin treatment, intrinsic abnormalities of the vascular smooth muscle may have developed that are suppressed by concomitant ACE inhibitor therapy. The present study also favors a combination of nitroglycerin and ACE inhibitors to maintain nitrate sensitivity of the vasculature during long-term nitroglycerin treatment.
Key Words: nitroglycerin • circulation • pharmacology
This article has been cited by other articles:
 |
|
 |
|
  H. J. Knot Nitrate Tolerance in Hypertension: New Insight Into a Century-Old Problem Circ. Res., October 31, 2003; 93(9): 799 - 801. [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]
|
|
|
|
 |
|
 L. T. McGrath, L. Dixon, D. R. Morgan, and G. E. McVeigh Production of 8-epi prostaglandin F2{alpha} in human platelets during administration of organic nitrates J. Am. Coll. Cardiol., August 21, 2002; 40(4): 820 - 825. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Hebert and J. Y. T. Lam Nitroglycerin rebound associated with vascular, rather than platelet, hypersensitivity J. Am. Coll. Cardiol., December 1, 2000; 36(7): 2311 - 2316. [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]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 W. M. Weightman, N. M. Gibbs, M. R. Sheminant, E. G. Whitford, B. D. Mahon, and M. A. J. Newman Drug Therapy Before Coronary Artery Surgery: Nitrates Are Independent Predictors of Mortality and {beta}-Adrenergic Blockers Predict Survival Anesth. Analg., February 1, 1999; 88(2): 286 - 286. [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]
|
|
|
|
|
|
H. Watanabe, M. Kakihana, S. Ohtsuka, and Y. Sugishita Preventive effects of carvedilol on nitrate tolerance--a randomized, double-blind, placebo-controlled comparative study between carvedilol and arotinolol J. Am. Coll. Cardiol., November 1, 1998; 32(5): 1201 - 1206. [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]
|
|
|
|
|
|
H. Watanabe, M. Kakihana, S. Ohtsuka, and Y. Sugishita Randomized, Double-Blind, Placebo-Controlled Study of Ascorbate on the Preventive Effect of Nitrate Tolerance in Patients With Congestive Heart Failure Circulation, March 10, 1998; 97(9): 886 - 891. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D. Parker and J. O. Parker Nitrate Therapy for Stable Angina Pectoris N. Engl. J. Med., February 19, 1998; 338(8): 520 - 531. [Full Text] [PDF]
|
|
|
|
|
|
H. Watanabe, M. Kakihana, S. Ohtsuka, and Y. Sugishita Randomized, Double-Blind, Placebo-Controlled Study of Supplemental Vitamin E on Attenuation of the Development of Nitrate Tolerance Circulation, October 21, 1997; 96(8): 2545 - 2550. [Abstract] [Full Text]
|
|
|
|
|
|
D. Hebert, J.-X. Xiang, and J. Y.T. Lam Persistent Inhibition of Platelets During Continuous Nitroglycerin Therapy Despite Hemodynamic Tolerance Circulation, March 4, 1997; 95(5): 1308 - 1313. [Abstract] [Full Text]
|
|