Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1995 Apr;95(4):1747–1755. doi: 10.1172/JCI117852

Nitric oxide activity in the human coronary circulation. Impact of risk factors for coronary atherosclerosis.

A A Quyyumi 1, N Dakak 1, N P Andrews 1, S Husain 1, S Arora 1, D M Gilligan 1, J A Panza 1, R O Cannon 3rd 1
PMCID: PMC295695  PMID: 7706483

Abstract

The bioavailability of nitric oxide (NO) in the human coronary circulation at rest and after acetylcholine (ACH)-induced vasodilation was investigated in 32 patients with angiographically normal coronary arteries. The effects of intracoronary L-NG monomethyl arginine (L-NMMA) were investigated at rest and after ACH, sodium nitroprusside, and adenosine. L-NMMA (64 mumol/min) increased resting coronary vascular resistance by 22% (P < 0.001), reduced distal epicardial coronary artery diameter by 12.6% (P < 0.001), and inhibited ACH-induced coronary epicardial and microvascular vasodilation. These effects were reversed with intracoronary L-arginine. L-NMMA did not inhibit dilation in response to sodium nitroprusside and adenosine. 23 patients were exposed to one or more coronary risk factors. The vasoconstrictor effect of L-NMMA on the epicardial and microvessels was greater in patients free of risk factors: Coronary vascular resistance was 36% higher in patients without risks, compared to 17% higher in patients with risks (P < 0.05). Both epicardial and microvascular dilator effects of ACH were greater in patients without risk factors, and the inhibition of these effects by L-NMMA was also greater in patients without risk factors. Thus: (a) NO contributes importantly to resting epicardial and coronary microvascular tone, (b) coronary vascular dilation in response to ACH is predominantly due to increased production of NO, and (c) despite the absence of angiographic evidence of atherosclerosis, exposure to coronary risk factors is associated with reduced resting and stimulated bioavailability of NO from the human coronary circulation.

Full text

PDF
1750

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Amezcua J. L., Palmer R. M., de Souza B. M., Moncada S. Nitric oxide synthesized from L-arginine regulates vascular tone in the coronary circulation of the rabbit. Br J Pharmacol. 1989 Aug;97(4):1119–1124. doi: 10.1111/j.1476-5381.1989.tb12569.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Casino P. R., Kilcoyne C. M., Quyyumi A. A., Hoeg J. M., Panza J. A. The role of nitric oxide in endothelium-dependent vasodilation of hypercholesterolemic patients. Circulation. 1993 Dec;88(6):2541–2547. doi: 10.1161/01.cir.88.6.2541. [DOI] [PubMed] [Google Scholar]
  3. Cayatte A. J., Palacino J. J., Horten K., Cohen R. A. Chronic inhibition of nitric oxide production accelerates neointima formation and impairs endothelial function in hypercholesterolemic rabbits. Arterioscler Thromb. 1994 May;14(5):753–759. doi: 10.1161/01.atv.14.5.753. [DOI] [PubMed] [Google Scholar]
  4. Chilian W. M., Dellsperger K. C., Layne S. M., Eastham C. L., Armstrong M. A., Marcus M. L., Heistad D. D. Effects of atherosclerosis on the coronary microcirculation. Am J Physiol. 1990 Feb;258(2 Pt 2):H529–H539. doi: 10.1152/ajpheart.1990.258.2.H529. [DOI] [PubMed] [Google Scholar]
  5. Chilian W. M., Eastham C. L., Marcus M. L. Microvascular distribution of coronary vascular resistance in beating left ventricle. Am J Physiol. 1986 Oct;251(4 Pt 2):H779–H788. doi: 10.1152/ajpheart.1986.251.4.H779. [DOI] [PubMed] [Google Scholar]
  6. Chu A., Chambers D. E., Lin C. C., Kuehl W. D., Cobb F. R. Nitric oxide modulates epicardial coronary basal vasomotor tone in awake dogs. Am J Physiol. 1990 Apr;258(4 Pt 2):H1250–H1254. doi: 10.1152/ajpheart.1990.258.4.H1250. [DOI] [PubMed] [Google Scholar]
  7. Chu A., Chambers D. E., Lin C. C., Kuehl W. D., Palmer R. M., Moncada S., Cobb F. R. Effects of inhibition of nitric oxide formation on basal vasomotion and endothelium-dependent responses of the coronary arteries in awake dogs. J Clin Invest. 1991 Jun;87(6):1964–1968. doi: 10.1172/JCI115223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cocks T. M., Angus J. A. Endothelium-dependent relaxation of coronary arteries by noradrenaline and serotonin. Nature. 1983 Oct 13;305(5935):627–630. doi: 10.1038/305627a0. [DOI] [PubMed] [Google Scholar]
  9. Cox D. A., Vita J. A., Treasure C. B., Fish R. D., Alexander R. W., Ganz P., Selwyn A. P. Atherosclerosis impairs flow-mediated dilation of coronary arteries in humans. Circulation. 1989 Sep;80(3):458–465. doi: 10.1161/01.cir.80.3.458. [DOI] [PubMed] [Google Scholar]
  10. Creager M. A., Gallagher S. J., Girerd X. J., Coleman S. M., Dzau V. J., Cooke J. P. L-arginine improves endothelium-dependent vasodilation in hypercholesterolemic humans. J Clin Invest. 1992 Oct;90(4):1248–1253. doi: 10.1172/JCI115987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. De Mey J. G., Claeys M., Vanhoutte P. M. Endothelium-dependent inhibitory effects of acetylcholine, adenosine triphosphate, thrombin and arachidonic acid in the canine femoral artery. J Pharmacol Exp Ther. 1982 Jul;222(1):166–173. [PubMed] [Google Scholar]
  12. Doucette J. W., Corl P. D., Payne H. M., Flynn A. E., Goto M., Nassi M., Segal J. Validation of a Doppler guide wire for intravascular measurement of coronary artery flow velocity. Circulation. 1992 May;85(5):1899–1911. doi: 10.1161/01.cir.85.5.1899. [DOI] [PubMed] [Google Scholar]
  13. Drexler H., Zeiher A. M., Meinzer K., Just H. Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolaemic patients by L-arginine. Lancet. 1991 Dec 21;338(8782-8783):1546–1550. doi: 10.1016/0140-6736(91)92372-9. [DOI] [PubMed] [Google Scholar]
  14. Drexler H., Zeiher A. M., Wollschläger H., Meinertz T., Just H., Bonzel T. Flow-dependent coronary artery dilatation in humans. Circulation. 1989 Sep;80(3):466–474. doi: 10.1161/01.cir.80.3.466. [DOI] [PubMed] [Google Scholar]
  15. Egashira K., Inou T., Hirooka Y., Kai H., Sugimachi M., Suzuki S., Kuga T., Urabe Y., Takeshita A. Effects of age on endothelium-dependent vasodilation of resistance coronary artery by acetylcholine in humans. Circulation. 1993 Jul;88(1):77–81. doi: 10.1161/01.cir.88.1.77. [DOI] [PubMed] [Google Scholar]
  16. Egashira K., Inou T., Hirooka Y., Yamada A., Maruoka Y., Kai H., Sugimachi M., Suzuki S., Takeshita A. Impaired coronary blood flow response to acetylcholine in patients with coronary risk factors and proximal atherosclerotic lesions. J Clin Invest. 1993 Jan;91(1):29–37. doi: 10.1172/JCI116183. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Egashira K., Inou T., Hirooka Y., Yamada A., Urabe Y., Takeshita A. Evidence of impaired endothelium-dependent coronary vasodilatation in patients with angina pectoris and normal coronary angiograms. N Engl J Med. 1993 Jun 10;328(23):1659–1664. doi: 10.1056/NEJM199306103282302. [DOI] [PubMed] [Google Scholar]
  18. Feletou M., Vanhoutte P. M. Endothelium-dependent hyperpolarization of canine coronary smooth muscle. Br J Pharmacol. 1988 Mar;93(3):515–524. doi: 10.1111/j.1476-5381.1988.tb10306.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Flavahan N. A. Atherosclerosis or lipoprotein-induced endothelial dysfunction. Potential mechanisms underlying reduction in EDRF/nitric oxide activity. Circulation. 1992 May;85(5):1927–1938. doi: 10.1161/01.cir.85.5.1927. [DOI] [PubMed] [Google Scholar]
  20. Furchgott R. F., Zawadzki J. V. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980 Nov 27;288(5789):373–376. doi: 10.1038/288373a0. [DOI] [PubMed] [Google Scholar]
  21. Förstermann U., Mügge A., Alheid U., Haverich A., Frölich J. C. Selective attenuation of endothelium-mediated vasodilation in atherosclerotic human coronary arteries. Circ Res. 1988 Feb;62(2):185–190. doi: 10.1161/01.res.62.2.185. [DOI] [PubMed] [Google Scholar]
  22. Gardiner S. M., Compton A. M., Bennett T., Palmer R. M., Moncada S. Control of regional blood flow by endothelium-derived nitric oxide. Hypertension. 1990 May;15(5):486–492. doi: 10.1161/01.hyp.15.5.486. [DOI] [PubMed] [Google Scholar]
  23. Garg U. C., Hassid A. Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest. 1989 May;83(5):1774–1777. doi: 10.1172/JCI114081. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Gilligan D. M., Panza J. A., Kilcoyne C. M., Waclawiw M. A., Casino P. R., Quyyumi A. A. Contribution of endothelium-derived nitric oxide to exercise-induced vasodilation. Circulation. 1994 Dec;90(6):2853–2858. doi: 10.1161/01.cir.90.6.2853. [DOI] [PubMed] [Google Scholar]
  25. Gordon J. B., Ganz P., Nabel E. G., Fish R. D., Zebede J., Mudge G. H., Alexander R. W., Selwyn A. P. Atherosclerosis influences the vasomotor response of epicardial coronary arteries to exercise. J Clin Invest. 1989 Jun;83(6):1946–1952. doi: 10.1172/JCI114103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Hodgson J. M., Marshall J. J. Direct vasoconstriction and endothelium-dependent vasodilation. Mechanisms of acetylcholine effects on coronary flow and arterial diameter in patients with nonstenotic coronary arteries. Circulation. 1989 May;79(5):1043–1051. doi: 10.1161/01.cir.79.5.1043. [DOI] [PubMed] [Google Scholar]
  27. Holtz J., Förstermann U., Pohl U., Giesler M., Bassenge E. Flow-dependent, endothelium-mediated dilation of epicardial coronary arteries in conscious dogs: effects of cyclooxygenase inhibition. J Cardiovasc Pharmacol. 1984 Nov-Dec;6(6):1161–1169. [PubMed] [Google Scholar]
  28. Ignarro L. J., Byrns R. E., Buga G. M., Wood K. S. Endothelium-derived relaxing factor from pulmonary artery and vein possesses pharmacologic and chemical properties identical to those of nitric oxide radical. Circ Res. 1987 Dec;61(6):866–879. doi: 10.1161/01.res.61.6.866. [DOI] [PubMed] [Google Scholar]
  29. Ishizaka H., Okumura K., Yamabe H., Tsuchiya T., Yasue H. Endothelium-derived nitric oxide as a mediator of acetylcholine-induced coronary vasodilation in dogs. J Cardiovasc Pharmacol. 1991 Nov;18(5):665–669. doi: 10.1097/00005344-199111000-00003. [DOI] [PubMed] [Google Scholar]
  30. Komaru T., Lamping K. G., Eastham C. L., Harrison D. G., Marcus M. L., Dellsperger K. C. Effect of an arginine analogue on acetylcholine-induced coronary microvascular dilatation in dogs. Am J Physiol. 1991 Dec;261(6 Pt 2):H2001–H2007. doi: 10.1152/ajpheart.1991.261.6.H2001. [DOI] [PubMed] [Google Scholar]
  31. Lefroy D. C., Crake T., Uren N. G., Davies G. J., Maseri A. Effect of inhibition of nitric oxide synthesis on epicardial coronary artery caliber and coronary blood flow in humans. Circulation. 1993 Jul;88(1):43–54. doi: 10.1161/01.cir.88.1.43. [DOI] [PubMed] [Google Scholar]
  32. Leipert B., Becker B. F., Gerlach E. Different endothelial mechanisms involved in coronary responses to known vasodilators. Am J Physiol. 1992 Jun;262(6 Pt 2):H1676–H1683. doi: 10.1152/ajpheart.1992.262.6.H1676. [DOI] [PubMed] [Google Scholar]
  33. Ludmer P. L., Selwyn A. P., Shook T. L., Wayne R. R., Mudge G. H., Alexander R. W., Ganz P. Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. N Engl J Med. 1986 Oct 23;315(17):1046–1051. doi: 10.1056/NEJM198610233151702. [DOI] [PubMed] [Google Scholar]
  34. Minor R. L., Jr, Myers P. R., Guerra R., Jr, Bates J. N., Harrison D. G. Diet-induced atherosclerosis increases the release of nitrogen oxides from rabbit aorta. J Clin Invest. 1990 Dec;86(6):2109–2116. doi: 10.1172/JCI114949. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Nabel E. G., Selwyn A. P., Ganz P. Paradoxical narrowing of atherosclerotic coronary arteries induced by increases in heart rate. Circulation. 1990 Mar;81(3):850–859. doi: 10.1161/01.cir.81.3.850. [DOI] [PubMed] [Google Scholar]
  36. Naruse K., Shimizu K., Muramatsu M., Toki Y., Miyazaki Y., Okumura K., Hashimoto H., Ito T. Long-term inhibition of NO synthesis promotes atherosclerosis in the hypercholesterolemic rabbit thoracic aorta. PGH2 does not contribute to impaired endothelium-dependent relaxation. Arterioscler Thromb. 1994 May;14(5):746–752. doi: 10.1161/01.atv.14.5.746. [DOI] [PubMed] [Google Scholar]
  37. Newman C. M., Maseri A., Hackett D. R., el-Tamimi H. M., Davies G. J. Response of angiographically normal and atherosclerotic left anterior descending coronary arteries to acetylcholine. Am J Cardiol. 1990 Nov 1;66(15):1070–1076. doi: 10.1016/0002-9149(90)90507-w. [DOI] [PubMed] [Google Scholar]
  38. Ofili E., Kern M. J., Tatineni S., Deligonul U., Aguirre F., Serota H., Labovitz A. J. Detection of coronary collateral flow by a Doppler-tipped guide wire during coronary angioplasty. Am Heart J. 1991 Jul;122(1 Pt 1):221–225. doi: 10.1016/0002-8703(91)90780-l. [DOI] [PubMed] [Google Scholar]
  39. Osborne J. A., Siegman M. J., Sedar A. W., Mooers S. U., Lefer A. M. Lack of endothelium-dependent relaxation in coronary resistance arteries of cholesterol-fed rabbits. Am J Physiol. 1989 Mar;256(3 Pt 1):C591–C597. doi: 10.1152/ajpcell.1989.256.3.C591. [DOI] [PubMed] [Google Scholar]
  40. Palmer R. M., Ashton D. S., Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature. 1988 Jun 16;333(6174):664–666. doi: 10.1038/333664a0. [DOI] [PubMed] [Google Scholar]
  41. Palmer R. M., Ferrige A. G., Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987 Jun 11;327(6122):524–526. doi: 10.1038/327524a0. [DOI] [PubMed] [Google Scholar]
  42. Panza J. A., Casino P. R., Kilcoyne C. M., Quyyumi A. A. Role of endothelium-derived nitric oxide in the abnormal endothelium-dependent vascular relaxation of patients with essential hypertension. Circulation. 1993 May;87(5):1468–1474. doi: 10.1161/01.cir.87.5.1468. [DOI] [PubMed] [Google Scholar]
  43. Parent R., Paré R., Lavallée M. Contribution of nitric oxide to dilation of resistance coronary vessels in conscious dogs. Am J Physiol. 1992 Jan;262(1 Pt 2):H10–H16. doi: 10.1152/ajpheart.1992.262.1.H10. [DOI] [PubMed] [Google Scholar]
  44. Quyyumi A. A., Cannon R. O., 3rd, Panza J. A., Diodati J. G., Epstein S. E. Endothelial dysfunction in patients with chest pain and normal coronary arteries. Circulation. 1992 Dec;86(6):1864–1871. doi: 10.1161/01.cir.86.6.1864. [DOI] [PubMed] [Google Scholar]
  45. Rees D. D., Palmer R. M., Hodson H. F., Moncada S. A specific inhibitor of nitric oxide formation from L-arginine attenuates endothelium-dependent relaxation. Br J Pharmacol. 1989 Feb;96(2):418–424. doi: 10.1111/j.1476-5381.1989.tb11833.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Sellke F. W., Armstrong M. L., Harrison D. G. Endothelium-dependent vascular relaxation is abnormal in the coronary microcirculation of atherosclerotic primates. Circulation. 1990 May;81(5):1586–1593. doi: 10.1161/01.cir.81.5.1586. [DOI] [PubMed] [Google Scholar]
  47. Tschudi M., Richard V., Bühler F. R., Lüscher T. F. Importance of endothelium-derived nitric oxide in porcine coronary resistance arteries. Am J Physiol. 1991 Jan;260(1 Pt 2):H13–H20. doi: 10.1152/ajpheart.1991.260.1.H13. [DOI] [PubMed] [Google Scholar]
  48. Vallance P., Collier J., Moncada S. Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. Lancet. 1989 Oct 28;2(8670):997–1000. doi: 10.1016/s0140-6736(89)91013-1. [DOI] [PubMed] [Google Scholar]
  49. Vanhoutte P. M. The endothelium--modulator of vascular smooth-muscle tone. N Engl J Med. 1988 Aug 25;319(8):512–513. doi: 10.1056/NEJM198808253190809. [DOI] [PubMed] [Google Scholar]
  50. Vita J. A., Treasure C. B., Nabel E. G., McLenachan J. M., Fish R. D., Yeung A. C., Vekshtein V. I., Selwyn A. P., Ganz P. Coronary vasomotor response to acetylcholine relates to risk factors for coronary artery disease. Circulation. 1990 Feb;81(2):491–497. doi: 10.1161/01.cir.81.2.491. [DOI] [PubMed] [Google Scholar]
  51. Woodman O. L., Dusting G. J. N-nitro L-arginine causes coronary vasoconstriction and inhibits endothelium-dependent vasodilatation in anaesthetized greyhounds. Br J Pharmacol. 1991 Jun;103(2):1407–1410. doi: 10.1111/j.1476-5381.1991.tb09802.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Yamamoto H., Bossaller C., Cartwright J., Jr, Henry P. D. Videomicroscopic demonstration of defective cholinergic arteriolar vasodilation in atherosclerotic rabbit. J Clin Invest. 1988 Jun;81(6):1752–1758. doi: 10.1172/JCI113516. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Yao S. K., Ober J. C., Krishnaswami A., Ferguson J. J., Anderson H. V., Golino P., Buja L. M., Willerson J. T. Endogenous nitric oxide protects against platelet aggregation and cyclic flow variations in stenosed and endothelium-injured arteries. Circulation. 1992 Oct;86(4):1302–1309. doi: 10.1161/01.cir.86.4.1302. [DOI] [PubMed] [Google Scholar]
  54. Yasue H., Matsuyama K., Matsuyama K., Okumura K., Morikami Y., Ogawa H. Responses of angiographically normal human coronary arteries to intracoronary injection of acetylcholine by age and segment. Possible role of early coronary atherosclerosis. Circulation. 1990 Feb;81(2):482–490. doi: 10.1161/01.cir.81.2.482. [DOI] [PubMed] [Google Scholar]
  55. Yeung A. C., Vekshtein V. I., Krantz D. S., Vita J. A., Ryan T. J., Jr, Ganz P., Selwyn A. P. The effect of atherosclerosis on the vasomotor response of coronary arteries to mental stress. N Engl J Med. 1991 Nov 28;325(22):1551–1556. doi: 10.1056/NEJM199111283252205. [DOI] [PubMed] [Google Scholar]
  56. Zeiher A. M., Drexler H., Wollschläger H., Just H. Endothelial dysfunction of the coronary microvasculature is associated with coronary blood flow regulation in patients with early atherosclerosis. Circulation. 1991 Nov;84(5):1984–1992. doi: 10.1161/01.cir.84.5.1984. [DOI] [PubMed] [Google Scholar]
  57. Zeiher A. M., Drexler H., Wollschläger H., Just H. Modulation of coronary vasomotor tone in humans. Progressive endothelial dysfunction with different early stages of coronary atherosclerosis. Circulation. 1991 Feb;83(2):391–401. doi: 10.1161/01.cir.83.2.391. [DOI] [PubMed] [Google Scholar]
  58. Zeiher A. M., Schächlinger V., Hohnloser S. H., Saurbier B., Just H. Coronary atherosclerotic wall thickening and vascular reactivity in humans. Elevated high-density lipoprotein levels ameliorate abnormal vasoconstriction in early atherosclerosis. Circulation. 1994 Jun;89(6):2525–2532. doi: 10.1161/01.cir.89.6.2525. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES