Influence of atherosclerosis on the vascular reactivity of isolated human epicardial coronary arteries to leukotriene C4.
Leukotrienes, lipid mediators derived from arachidonic acid by the 5-lipoxygenase pathway, have been implicated in a variety of myocardial ischemic events including myocardial infarction and coronary spasm. We have examined the comparative effects of leukotriene C4 in isolated human non-atherosclerotic and atherosclerotic coronary arteries to gain an insight into the role of leukotrienes in coronary heart disease. Human coronary arteries, obtained from recipient hearts at the time of cardiac transplantation, were cut into rings and examined in an isolated organ bath. In atherosclerotic arteries leukotriene C4 (1nM-100nM) produced a maximal contractile response of 54.9 +/- 7.98% KCI (n = 7) and the mean EC50 value was 11.1nM (95% confidence interval: 9.4-13.0). The leukotriene receptor antagonist ICI-198,615 (3 x 10(-8)M) produced an approximate 50-fold rightward shift of the leukotriene C4 dose-response curve (n = 5). In contrast, non-atherosclerotic arteries were either non-responsive (n = 5) or only weakly responsive (n = 2) to leukotriene C4 (1nM-100nM), producing an average maximum response of 3.65 +/- 3.05% KCI (n = 7; p < 0.01 atherosclerotic vs non-atherosclerotic). In the presence of indomethacin and in vessels denuded of endothelium, non-atherosclerotic arteries remained unresponsive to leukotriene C4 (n = 3). In addition, leukotriene C4 did not relax preconstricted vessels (n = 7). In vitro autoradiography showed specific [3H]-leukotriene C4 binding to smooth muscle in both non-atherosclerotic and atherosclerotic arteries, with no evidence of endothelium-dependent binding.(ABSTRACT TRUNCATED AT 250 WORDS)
Allen
S P
SP
National Heart and Lung Institute, Harefield Hospital, U.K.
Dashwood
M R
MR
Chester
A H
AH
Tadjkarimi
S
S
Collins
M
M
Piper
P J
PJ
Yacoub
M H
MH
D000293:Adolescent; D000328:Adult; D001161:Arteriosclerosis / Q000209:etiology / Q000503:physiopathology*; D002648:Child; D002675:Child, Preschool; D003331:Coronary Vessels / Q000187:drug effects* / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D007191:Indazoles / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007962:Leukocytes / Q000502:physiology; D008875:Middle Aged; D013189:SRS-A / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology
D007191:Indazoles; D013189:SRS-A; C054217:ICI 198615; D007213:Indomethacin