Laboratory Investigation Coronary Artery Disease

Effects of leukotriene (LT) C4 and LTD4 on coronary artery spasm in atherosclerotic miniature pigs were examined angiographically. Endothelial balloon denudation of the left circumflex coronary artery was performed in 15 Gottingen miniature pigs; 11 were fed a 2% cholesterol diet and four were fed a regular diet for 3 months. Three months after this denudation, the area of the coronary artery was reduced by 94 ± 2% and 43 + 5% (p<.01) in the denuded and nondenuded areas by the intracoronary administration of 10 ,g/kg histamine after pretreatment with 60 mg/kg iv cimetidine. The effects of LTC4 and LTD4 on coronary diameter and the preventive effects of FPL-557 12, a LTC4 and LTD4-receptor blocker, or diphenhydramine, a histamine HI-receptor blocker, on histamineinduced coronary spasm were then examined angiographically. Administration of LTC4 or LTD4 in doses of 1 and 10 ,ug into the left coronary artery, or selectively into the left circumflex and left anterior descending coronary arteries in a dose of 5 ,ug, led to the elevations in the ST segment on the electrocardiogram and there was delayed filling of the contrast medium in the peripheral coronary artery. However, these LTs provoked no augmented constrictions at any site on the epicardial coronary arteries (n = 15). Diphenhydramine, 1 mg/kg (n = 6), abolished the histamine-induced coronary spasm. FPL-55712, 0.1 mg/kg, with which the LT-induced myocardial ischemia was abolished, did not prevent the histamine-induced coronary artery spasm. Hence, in a swine preparation of coronary artery spasm, LTC4 and LTD4 constricted the coronary arteries at the level of small vessels and rendered the perfused myocardium ischemic. These compounds do not seem to play a primary role in the provocation of epicardial coronary artery spasm induced by histamine in this atherosclerotic swine preparation. Circulation 76, No. 2, 480-487, 1987. LEUKOTRIENES (LTs), which are 5-lipoxygenase metabolites of arachidonic acid, are released from leukocytes, macrophages, and other cells in response to inflammatory reactions after tissue injury. 1.2 LTC4 and LTD4, major active components of the slow-reacting substance (SRS)-A,1 have a potent constrictive effect on vascular smooth muscle.3`6 Accordingly, these LTs are assumed to be one of the causative factors linked to spasm of the coronary artery.4 8 In anesthetized, From Research Institute of Angiocardiology and Cardiovascular Clinic, Faculty of Medicine, Kyushu University, Higashi-ku, Fukuoka 812, Japan. Supported in part by Grants-in-Aid for Scientific Research (61440042, 60570396), a grant for Development Scientific Research (No. 61870037) from the Ministry of Education, Science, and Culture, Japan, and a grant from the Taisha-Ijo Foundation. Address for correspondence: Hitonobu Tomoike, M.D., Research Institute of Angiocardiology, and Cardiovascular Clinic, Faculty of Medicine, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812, Japan. Received June 4, 1986; revision accepted April 9, 1987. 480 open-chest intact pigs, dogs, and sheep, intracoronary administration of LTC4 and LTD4 reduced coronary blood flow followed by electrocardiographic changes associated with transient ischemia.5 13 Although the LT-induced vasoconstriction led to a marked reduction in coronary blood flow, it has not been clarified whether the LT-induced myocardial ischemia was caused by spasm of the large epicardial vessels or that of the small resistence vessels of the coronary artery. We designed a miniature swine preparation of coronary artery spasm in which spasm was repeatedly provoked along the atherosclerotic portion of the large epicardial coronary artery in the presence of histamine."1'6 Using this preparation, the goal of the present study was (1) to examine whether LTC4 and LTD4 provoke myocardial ischemia with or without coronary artery spasm, and (2) to determine whether LT receptors play any role in evolution of histamine-induced CIRCULATION by gest on July 5, 2017 http://ciajournals.org/ D ow nladed from LABORATORY INVESTIGATION-CORONARY ARTERY DISEASE coronary artery spasm. To these ends, we used FPL55712, an antagonist of LTC4 and LTD4.3' 4 12, 17,18