Skip to main content
Log in

Comparison of effect between nitrates and calcium channel antagonist on vascular function in patients with normal or mildly diseased coronary arteries

  • Original Article
  • Published:
Heart and Vessels Aims and scope Submit manuscript

Abstract

The comparative long-term antianginal efficacy of long-acting nitrates versus calcium channel antagonists remains unclear. The goal of the present study was to compare the coronary endothelial cell function and coronary artery vasoconstriction between patients with normal or mildly diseased coronary arteries treated with long-acting nitrates or calcium channel antagonists. Forty-two patients suspected to have angina pectoris and with normal or mildly diseased coronary arteries underwent Doppler flow study of the left anterior descending coronary artery. All patients were suspected to have angina pectoris and were receiving either long-acting nitrates (n = 18; Nitrates group) or calcium channel antagonists (n = 24; Ca-antagonists group) for at least 1 year. Vascular reactivity was assessed by intracoronary administration of papaverine, acetylcholine (Ach), and nitroglycerin using a Doppler guidewire. Segments that showed the greatest constrictive response to Ach were used for assessment of vasoconstriction. The percent increase in coronary blood flow (CBF) and coronary artery diameter (CAD) induced by Ach was significantly smaller in the Nitrates group than in the Ca-antagonists group (33% ± 74% vs 83% ± 77%, P < 0.05; −3% ± 16% vs 11% ± 12%, P < 0.01, respectively). The percent diameter reduction in the region of greatest constrictive response to Ach was significantly greater in the Nitrates group than in the Caantagonists group (44% ± 39% vs 15% ± 32%, P < 0.02). Long-term treatment with long-acting nitrates may produce less favorable effects on coronary endothelial function and the constrictive response to Ach when compared with long-acting calcium channel antagonists in patients with normal or mildly diseased coronary arteries.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Yusuf S, Collins R, McMahon S, Peto R (1988) Effect of intravenous nitrates on mortality in acute myocardial infarction: An overview of the randomized trials. Lancet 1:1088–1092

    Article  PubMed  CAS  Google Scholar 

  2. Jugdutt BI (1992) Role of nitrates after acute myocardial infraction. Am J Cardiol 70:82B–87B

    Article  PubMed  CAS  Google Scholar 

  3. GISSI-3 (1994) Effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. Gruppo Italiano per lo Studio della Sopravvivenza nell’infarto Miocardico. Lancet 343:1115–1122

    Google Scholar 

  4. ISIS-4 (1995) A randomized factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. Lancet 345:669–685

    Google Scholar 

  5. Ishikawa K, Kanamasa K, Ogawa I, Takenaka T, Naito T, Kamata N, Yamamoto T, Nakai S, Hama J, Oyaizu M, Kimura A, Yamamoto K, Aso N, Arai M, Yabushita H, Katori R (1996) Long-term nitrate treatment increases cardiac events in patients with healed myocardial infarction. Jpn Circ J 60:779–788

    Article  PubMed  CAS  Google Scholar 

  6. Munzel T, Giaid A, Kurz S, Stewart DJ, Harrison DG. (1995) Evidence for a role of endothelin 1 and protein kinase C in nitroglycerin tolerance. Proc Natl Acad Sci USA 92:5244–5248

    Article  PubMed  CAS  Google Scholar 

  7. Zierhut W, Ball HA (1996) Prevention of vascular nitroglycerin tolerance by inhibition of protein kinase C. Br J Pharmacol 119:3–5

    PubMed  CAS  Google Scholar 

  8. Heitzer T, Just H, Meinertz T, Brockhoff C, Munzel T (1998) Chronic angiotensin converting enzyme inhibition with captopril prevents nitroglycerin induced hypersensitivity to vasoconstrictors in patients with stable coronary artery disease. J Am Coll Cardiol 31:83–88

    Article  PubMed  CAS  Google Scholar 

  9. Furberg CD, Psaty BM, Meyer JV (1995) Nifedipine: dose-related increase in mortality in patients with coronary heart disease. Circulation 92:1326–1331

    PubMed  CAS  Google Scholar 

  10. Thadani U, Glasser S, Bittar N, Beach CI (1994) Dose-response evaluation of once-daily therapy with a new formation of diltiazem for stable angina pectoris. Diltiazem CD Study Group. Am J Cardiol 74:9–17

    Article  PubMed  CAS  Google Scholar 

  11. Gibbs JS, McAlpine HM, Wright C, McLenachan JM, Sparrow J, Sutton G, Dargie HJ, Fox KM (1991) Double-blind randomized placebo-controlled dose-efficacy study of sustained release verapamil in chronic stable angina. Int J Cardiol 31:281–286

    Article  PubMed  CAS  Google Scholar 

  12. Poole-Wilson PA, Lubsen J, Kirwan BA, van Dalen FJ, Wagener G, Danchin N, Just H, Fox KA, Pocock SJ, Clayton TC, Motro M, Parker JD, Bourassa MG, Dart AM, Hildebrandt P, Hjalmarson A, Kragten JA, Molhoek GP, Otterstad JE, Seabra-Gomes R, Soler-Soler J, Weber S; A Coronary disease Trial Investigating Outcome with Nifedipine gastrointestinal therapeutic system investigators (2004) Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): randomized controlled trial. Lancet 364:849–857

    Article  PubMed  CAS  Google Scholar 

  13. Nissen SE, Tuzcu EM, Libby P, Thompson PD, Ghali M, Garza D, Berman L, Shi H, Buebendorf E, Topol EJ; CAMELOT Investigators (2004) Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial. JAMA 292:2217–2225

    Article  PubMed  CAS  Google Scholar 

  14. Pitt B, Byington RP, Furberg CD, Hunninghake DB, Mancini GB, Miller ME, Riley W (2000) Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events. PREVENT Investigators. Circulation 102:1503–1510

    PubMed  CAS  Google Scholar 

  15. Egashira K (2002) Clinical importance of endothelial function in arteriosclerosis and ischemic heart disease. Circ J 66(6):529–533

    Article  PubMed  CAS  Google Scholar 

  16. Egashira K, Suzuki S, Hirooka Y, Kai H, Sugimachi M, Imaizumi T, Takeshita A (1995) Impaired endothelium-dependent vasodilation of large epicardial and resistance coronary arteries in patients with essential hypertension. Different responses to acetylcholine and substance P. Hypertension 25(2):201–206

    PubMed  CAS  Google Scholar 

  17. Zeiher AM, Schachinger V, Minners J (1995) Long-term cigarette smoking impairs endothelium-dependent coronary arterial vasodilator function. Circulation 92(5):1094–1100

    PubMed  CAS  Google Scholar 

  18. Matsuo T, Iwade K, Hirata N, Yamashita M, Ikegami H, Tanaka N, Aosaki M, Kasanuki H (2005) Improvement of atrial stiffness by the antioxidant and anti-inflammatory effects of short-term statin therapy in patients with hypercholesterolemia. Heart Vessels 20(1):8–12

    Article  PubMed  Google Scholar 

  19. Takagi A, Tsurumi Y, Ishizuka N, Omori H, Arai K, Hagiwara N, Kasanuki H (2006) Single administration of cerivastatin, an HMD-CoA reductase inhibitor, improves the coronary flow velocity reserve: a transthoracic Doppler echocardiography study. Heart Vessels 21(5):298–301

    Article  PubMed  Google Scholar 

  20. Nishimura RA, Lerman A, Chesebro JH, Ilstrup DM, Hodge DO, Higano ST, Holmes DR Jr, Tajik AJ (1995) Epicardial vasomotor responses to acetylcholine are not predicted by coronary atherosclerosis as assessed by intracoronary ultrasound. J Am Coll Cardiol 26:41–49

    Article  PubMed  CAS  Google Scholar 

  21. Lerman A, Holmes DR Jr., Bell MR, Garratt KN, Nishimura RA, Burnett JC Jr (1995) Endothelin in coronary endothelial dysfunction and early atherosclerosis in humans. Circulation 92:2426–2431

    PubMed  CAS  Google Scholar 

  22. Hasdai D, Gibbons RJ, Holmes DR Jr., Higano ST, Lerman A (1997) Coronary endothelial dysfunction in humans is associated with myocardial perfusion defects. Circulation 96:3390–3395

    PubMed  CAS  Google Scholar 

  23. Egashira K, Inou T, Hirooka Y, Kai H, Sugimachi M, Suzuki S, Kuga T, Urabe Y, Takeshita A (1993) Effects of age on endothelium-dependent vasodilation of resistance coronary artery by acetylcholine in humans. Circulation 88:77–81

    PubMed  CAS  Google Scholar 

  24. Fukuda Y, Teragawa H, Matsuda K, Yamagata T, Matsuura H, Chayama-K (2002) Tetrahydrobiopterin restores endothelial function of coronary arteries in patients with hypercholesterolemia. Heart 87:264–269

    Article  PubMed  CAS  Google Scholar 

  25. Ishida S, Hamasaki S, Kamekou M, Yoshitama T, Nakano F, Yoshikawa A, Kataoka T, Saihara K, Minagoe S, Tei C (2003) Advancing age is associated with diminished vascular remodeling and impaired vasodilation in resistance coronary arteries. Coronary Artery Dis 14:443–449

    Article  Google Scholar 

  26. Doucette JW, Corl PD, Payne HM, Flynn AE, Goto M, Nassi M, Segal J (1992) Validation of a Doppler guide wire for intravascular measurement of coronary artery flow velocity. Circulation 85:1899–1911

    PubMed  CAS  Google Scholar 

  27. de Simone G, Devereux RB, Chien S, Alderman MH, Atlas SA, Laragh JH (1990) Relation of blood viscosity to demographic and physiologic variables and to cardiovascular risk factors in apparently normal adults. Circulation 81:107–117

    PubMed  Google Scholar 

  28. Nakamura Y, Moss AJ, Brown MW, Kinoshita M, Kawai C (1999) Long-term nitrate use may be deleterious in ischemic heart disease: A study using the databases from two large-scale postinfarction studies. Am Heart J 138:577–585

    Article  PubMed  CAS  Google Scholar 

  29. Moss AJ, Goldstein RE, Hall WJ, Bigger JT Jr., Fleiss JL, Greenberg H, Bodenheimer M, Krone RJ, Marcus FI, Wackers FJ, Benhorin J, Brown MW, Case R, Coromilas J, Dwyer EM Jr., Gillespie JA, Gregory JJ, Kleiger R, Lichstein E, Parker JO, Raubertas RF, Stern S, Tzivoni D, Voorhees LV, for the Multicenter Myocardial Ischemia Group (1993) Detection and significance of myocardial ischemia in stable patients after recovery from an acute coronary event. Multicenter Myocardial Ischemia Research Group. JAMA 269:2379–2385

    Article  PubMed  CAS  Google Scholar 

  30. The Multicenter Diltiazem Post-infarction Trial Group (1988) The effect of diltiazem on mortality and reinfarction after myocardial infraction. N Engl J Med 319:385–392

    Google Scholar 

  31. Caramori PR, Adelman AG, Azevedo ER, Newton GE, Parker AB, Parker JD (1998) Therapy with nitroglycerin increases coronary vasoconstriction in response to acetylcholine. J Am Coll Cardiol 32(7):1969–1974

    Article  PubMed  CAS  Google Scholar 

  32. Parker JD, Gori T (2001) Tolerance to the organic nitrates: new ideas, new mechanisms, continued mystery. Circulation 104(19):2263–2265

    PubMed  CAS  Google Scholar 

  33. Mangione NJ, Glasser SP (1994) Phenomenon of nitrate tolerance. Am Heart J 128:137–146

    Article  PubMed  CAS  Google Scholar 

  34. Dupuis J, Lalonde G, Lemieux R, Rouleau JL (1990) Tolerance to intravenous nitroglycerin in patients with congestive heart failure: role of increased intravascular volume, neurohumoral activation and lack of prevention with N-Acetylcysteine. J Am Coll Cardiol 16:923–931

    Article  PubMed  CAS  Google Scholar 

  35. Keller LH, Hulley SB, Cohen JD, Neaton J (1986) Unexpected effects of treating hypertension in men with electrocardiographic abnormalities: a critical analysis. Circulation 73:114–123

    Google Scholar 

  36. Topper JN, Cai J, Falb D, Gimbrone MAJ (1996) Identification of vascular endothelial genes differentially responsive to fluid mechanical stimuli: cyclooxygenase-2, manganese superoxide dismutase, and endothelial cell nitric oxide synthase are selectively up-regulated by steady laminar shear stress. Proc Natl Acad Sci USA 93:10417–10422

    Article  PubMed  CAS  Google Scholar 

  37. Feron O, Dessy C, Moniotte S, Desager JP, Balligand JL (1999) Hypercholesterolemia decreases nitric oxide production by promoting the interaction of caveolin and endothelial nitric oxide synthase. J Clin Invest 103:897–905

    Article  PubMed  CAS  Google Scholar 

  38. Chou TC, Yen MH, Li CY, Ding YA (1998) Alterations of nitric oxide synthase expression with aging and hypertension in rats. Hypertension 31:643–648

    PubMed  CAS  Google Scholar 

  39. Kawano H, Motoyama T, Hirashima O, Hirai N, Miyao Y, Sakamoto T, Kugiyama K, Ogawa H, Yasue H (1999) Hyperglycemia rapidly suppresses flow-mediated endothelium-dependent vasodilation of brachial artery. J Am Coll Cardiol 34:146–154

    Article  PubMed  CAS  Google Scholar 

  40. Oemar BS, Tschudi MR, Godoy N, Brovkovich V, Malinski T, Luscher TF (1998) Reduced endothelial nitric oxide synthase expression and production in human atherosclerosis. Circulation 97:2494–2498

    PubMed  CAS  Google Scholar 

  41. Davies PF (1995) Flow-mediated endothelial mechanotransduction. Physiol Rev 75:519–560

    PubMed  CAS  Google Scholar 

  42. Gimbrone MA Jr, Topper JN, Nagel T, Anderson KR, Garcia-Cardena G (2000) Endothelial dysfunction, hemodynamic forces, and atherogenesis. Ann N Y Acad Sci 902:230–239

    PubMed  CAS  Google Scholar 

  43. Gotlieb AI, Langille BL (1996) The role of rheology in atherosclerotic coronary artery disease. In: Fuster V, Ross R, Topol EJ (eds) Atherosclerosis and coronary artery disease. Lippincott-Raven, Philadelphia, pp 595–606

    Google Scholar 

  44. Ben Drias A, Benessiano J, Poitevin P, Levy BI, Michel JB (1997) Arterial expansive remodeling induced by high flow rates. Am J Physiol 272:H851–858

    Google Scholar 

  45. Fukaya Y, Ohhashi T (1996) Acetylcholine-and flow-induced production and release of nitric oxide in arterial and venous endothelial cells. Am J Physiol 270:H99–106

    PubMed  CAS  Google Scholar 

  46. Griscavage JM, Fukuto JM, Komori Y, Ignarro LJ (1994) Nitric oxide inhibits neuronal nitric oxide synthase by interacting with the heme prosthetic group. Role of tetrahydrobiopterin in modulating the inhibitory action of nitric oxide. J Biol Chem 269:21644–21649

    PubMed  CAS  Google Scholar 

  47. Suwaidi J AL, Hamasaki S, Higano ST, Nishimura RA, Holmes DR Jr, Lerman A (2000) Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation 101:948–954

    PubMed  CAS  Google Scholar 

  48. Schachinger V, Britten MB, Zeiher AM (2000) Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation 101:1899–1906

    PubMed  CAS  Google Scholar 

  49. Zeiher AM, Drexeler H, Wollschlyger H, Just H (1991) Modulation of coronary vascular tone in humans: progressive endothelial dysfunction with different early stages of coronary atherosclerosis. Circulation 83:391–401

    PubMed  CAS  Google Scholar 

  50. De Caterina R, Libby P, Peng HB, Thannickal VJ, Rajavashisth TB, Gimbrone MA Jr, Shin WS, Liao JK (1995) Nitric oxide decreases cytokine-induced endothelial activation: nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest 96:60–68

    Article  PubMed  Google Scholar 

  51. van der Wal AC, Becker AE, van der Loos CM, Das PK (1994) Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaque is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation 89:36–44

    PubMed  Google Scholar 

  52. Zeiher AM, Krause T, Schachinger V, Minners J, Moser E (1995) Impaired endothelium-dependent vasodilation of coronary resistance vessels is associated with exercise-induced myocardial ischemia. Circulation 91:2345–2352

    PubMed  CAS  Google Scholar 

  53. Beltrame JF, Sasayama S, Maseri A (1999) Racial heterogeneity in coronary artery vasomotor reactivity: differences between Japanese and Caucasian patients. J Am Coll Cardiol 33:1442–1452

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Shuichi Hamasaki.

Additional information

These authors contributed equally to this study.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ninomiya, Y., Hamasaki, S., Saihara, K. et al. Comparison of effect between nitrates and calcium channel antagonist on vascular function in patients with normal or mildly diseased coronary arteries. Heart Vessels 23, 83–90 (2008). https://doi.org/10.1007/s00380-007-1019-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00380-007-1019-4

Key words

Navigation