Abstract
Several previous studies have suggested decreased bioactivity of nitric oxide (NO) in coronary artery diseases using NO synthase inhibitors. Nitrite is delivered as bioactive NO in the forearm circulation. However, the role(s) of NO metabolites in the systemic and coronary circulation are still unknown. The aim of this study was to investigate the role(s) of systemic NO metabolites for human coronary circulation in patients with and without coronary spastic angina (CSA). Twenty-nine patients with chest symptoms were enrolled to perform the acetylcholine (Ach) provocative test. Blood was sampled from the aorta at baseline, and from the great cardiac vein at baseline and after Ach to measure plasma levels of nitrate and nitrite (NOx). The epicardial left anterior descending artery was examined by quantitative angiography. The patients were divided into the two groups according to the Ach provocative test. In the non-CSA group, the NOx uptake across the coronary circulation correlated with the endothelium-dependent vasoresponse to Ach (r = −0.61, p < 0.05) and NOx levels of the aorta also correlated (r = −0.72, p < 0.005), which suggested the compensatory increase of systemic NOx levels for impaired endothelial function. In the CSA group, the NOx uptake across the coronary circulation did not correlate with the vasoresponse to Ach (r = 0.29, p = 0.28). However, NOx levels of the aorta correlated with vasosensitivity to Ach (r = 0.61, p < 0.005). The higher systemic NOx levels correlated well with the vasodilator responsiveness to Ach. These results suggest that systemic NOx is delivered into the coronary circulation as bioactive NO to preserve endothelial function in the non-CSA patients, and to attenuate Ach-induced vasoconstriction in the CSA patients. There is a possibility that systemic NOx plays a complementary role on impaired coronary vasoregulation.
Similar content being viewed by others
References
Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980;288:373–376.
Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci USA 1987;84:9265–9269.
Palmer RM, Ashton DS, Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature 1988;16:333:664–666.
Egashira K, Katsuda Y, Mohri M, et al. Basal release of endothelium-derived nitric oxide at site of spasm in patients with variant angina. J Am Coll Cardiol 1996;27:1444–1449.
Kugiyama K, Yasue H, Okumura K, et al. Nitric oxide activity is deficient in spastic arteries of patients with coronary spastic angina. Circulation 1996;94:266–272.
Gladwin MT, Shelhamer JH, Schechter AN, et al. Role of circulating nitrite and S-nitrosohemoglobin in the regulation of regional blood flow in humans. Proc Natl Acad Sci USA 2000;97:11482–11487.
Cockcroft DW, Gault MH. Prediction of creatinine clearance of creatinine. Am J Med 1975;32:65–68.
Okumura K, Yasue H, Matsuyama K, et al. Sensitivity and specificity of intracoronary injection of acetylcholine for the induction of coronary artery spasm. J Am Coll Cardiol 1988;12:883–888.
Marletta MA, Yoon PS, Iyengar R, Leaf CD, Wishnok JS. Macrophage oxidation of L-arginine to nitrite and nitrate: Nitric oxide is an intermediate. Biochemistry 1988;27:8706–8711.
Kitakaze M, Node K, Minamino T, et al. Role of nitric oxide in regulation of coronary blood flow during myocardial ischemia in dogs. J Am Coll Cardiol 1996;27:1804–1812.
Okumura K, Yasue H, Matsuyama K, et al. A study on coronary hemodynamics during acetylcholine-induced coronary spasm in patients with variant angina: Endothelium-dependent dilation in the resistance vessels. J Am Coll Cardiol 1992;19:1426–1434.
Oemar BS, Tschudi MR, Godoy N, Brovkovich V, Malinski T, Luscher TF. Reduced endothelial nitric oxide synthase expression and production in human atherosclerosis. Circulation 1998;97:2494–2498.
Ohara Y, Peterson TE, Harrison DG. Hypercholesterolemia increases endothelial superoxide anion production. J Clin Invest 1993;91:2546–255111.
Harrison DG, Ohara Y. Physiologic consequences of increased vascular oxidant stresses in hypercholesterolemia and atherosclerosis: Implications for impaired vasomotion. Am J Cardiol 1995;75:75B–81B.
Antman E, Muller J, Goldberg S, et al. Nifedipine therapy for coronary-artery spasm. Experience in 127 patients. N Engl J Med 1980;5;302:1269–1273.
Kitakaze M, Node K, Minamino T, Asanuma H, Kuzuya T, Hori M. A Ca channel blocker, benidipine, increases coronary blood flow and attenuates the severity of myocardial ischemia via NO-dependent mechanisms in dogs. J Am Coll Cardiol. 1999;33:242–249.
Yamashita T, Kawashima S, Ozaki M, et al. A calcium channel blocker, benidipine, inhibits intimal thickening in the carotid artery of mice by increasing nitric oxide production. J Hypertens 2001;19:451–458.
Taddei S, Virdis A, Ghiadoni L, et al. Restoration of nitric oxide availability after calcium antagonist treatment in essential hypertension. Hypertension 2001;37:943–948.
Benidipine improves endothelial function in renal resistance arteries of hypertensive rats. Hypertension 1996;28:58–63.
Minamino T, Kitakaze M, Matsumura Y, et al. Impact of coronary risk factors on contribution of nitric oxide and adenosine to metabolic coronary vasodilation in humans. J Am Coll Cardiol 1998;31:1274–1279.
Kugiyama K, Yasue H, Ohgushi M, et al. Deficiency in nitric oxide bioactivity in epicardial coronary arteries of cigarette smokers. J Am Coll Cardiol 1996;28:1161–1167.
Kawano H, Motoyama T, Hirai N, Kugiyama K, Ogawa H, Yasue H. Estradiol supplementation suppresses hyperventilation-induced attacks in postmenopausal women with variant angina. J Am Coll Cardiol 2001;37:735–740.
Marinella R, Bruno I, Paul JK, Edwin KJ, Raghvendra KD. Circulating nitric oxide (Nitrite/Nitrate) levels in postmenopausal women substituted with 17β-estradiol and norethisterone acetate: A two-year follow-up study. Hypertension 1995;25:848–853.
Kugiyama K, Ohgushi M, Sugiyama S, et al. Supersensitive dilator response to nitroglycerin but not to atrial natriuretic peptide in spastic coronary arteries in coronary spastic angina. Am J Cardiol 1997;79:606–610.
Fukai T, Egashira K, Hata H, et al. Serotonin-induced coronary spasm in a swine model. A minor role of defective endothelium-derived relaxing factor. Circulation 1993;88:1922–1930.
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;81:482–490.
Beltrame JF, Sasayama S, Maseri A. Racial heterogeneity in coronary artery vasomotor reactivity: Differences between Japanese and Caucasian patients. J Am Coll Cardiol 1999;33:1442–1452.
Lefroy DC, Crake T, Uren NG, Davies GJ, Maseri A. Effect of inhibition of nitric oxide synthesis on epicardial coronary artery caliber and coronary blood flow in humans. Circulation 1993;88:43–54.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Kato, Y., Kijima, Y., Kitakaze, M. et al. Roles of Systemic Nitric Oxide Metabolites for Human Coronary Circulation. Cardiovasc Drugs Ther 18, 189–195 (2004). https://doi.org/10.1023/B:CARD.0000033639.17638.32
Issue Date:
DOI: https://doi.org/10.1023/B:CARD.0000033639.17638.32