Leukotriene D4-induced vasoconstriction of coronary arteries in anaesthetized dogs

Abstract

We examined in pentobarbital-anaesthetized dogs, the effects of intracoronary leukotriene D4 (LTD4) on large vessel (circumflex artery) flow and diameter and on calculations of late diastolic and total coronary resistance. Heart rate, systolic and end-diastolic ventricular pressures and the dP/dt were the haemodynamic variables studied. The peripheral ECG was obtained in lead II. LTD4 (0.1-10 micrograms kg-1) reduced coronary diameter up to 12 +/- 3% (mean +/- s.e.m.). Coronary flow decreased in dose-dependent fashion up to 100%. Blood flow returned to control values within 3-15 min of LTD4 administration. Blood pressure, heart rate and ventricular pressure did not change while LV dP/dtmax fell and filling pressure increased. The sum of ST segments and R wave voltages of the ECG increased indicating transient myocardial ischaemia during LTD4-induced coronary blood flow cessation. Small vessel and total coronary resistance rose in a dose-dependent manner between 33-232% and 50-500%, respectively. Inhibition of cyclo-oxygenase enzyme (indomethacin, 5 mg kg-1, i.v.) and lipoxygenase enzymes (nafazatrom, 10 mg kg-1, i.d.) had no effect on LTD4-caused alterations in coronary flow, resistance and arterial diameter. Thus, in canine experiments the intracoronary administration of LTD4 can constrict coronary arteries--presumably large conductive vessels. This is independent of the cyclooxygenase and additional lipoxygenase metabolites of the arachidonic acid pathway other than LTD4. Therefore, the agent may contribute to cardiac dysfunction in coronary artery disease and spasm.

International Union of Pharmacology XXXVII. Nomenclature for Leukotriene and Lipoxin Receptors

“…Subsequent to the early investigations , which reported that partially purified SRS markedly reduced coronary blood flow, a number of other investigators have explored the cardiovascular effects of the cys-LTs in a variety of different animal models. The early studies have shown that the cys-LTs are potent vasoconstrictors of the coronary vasculature in both isolated perfused hearts (Woodman and Dusting, 1982; and in a number of species in vivo (Michelassi et al, 1982;Panzenbeck and Kaley, 1983;Fiedler et al, 1984Leffler et al, 1984;Kopia et al, 1987;Michelassi et al, 1987) including human (Marone et al, 1988). In sheep and pigs, cys-LTs induced not only coronary vasoconstriction but also ischemia and impaired left ventriclar function (Michelassi et al, 1982;Ezra et al, 1983;Fiedler et al, 1985).…”

Comparison of cardiac and hemodynamic effects of plateletactivating factor-acether and leukotriene D4 in anesthetized dogs

“…Since indomethacin cannot block these negative inotropic actions of both reagents, the cardiodepressant PAF effects are not mediated by cyclooxygenase products, e.g., TxA2. A negative inotropic effect has also been shown for leukotrienes (17,18,24,38,39), and was related to an inhibition of transsarcolemmal calcium influx (39).…”

“…Besides others (16), we have recently shown (17)(18)(19) that LTD4 can increase coronary arterial tone and resistance and diminishes the external diameter of canine epicardial coronary arteries (17).…”

“…Small vessel coronary resistance was less affected than total coronary resistance, probably indicative of stronger effects of i.c. PAF (just as LTD4) on large conductive coronary arteries (17,23,41). This may be deleterious to coronary stenosis (26) when changes in large vessel tone or diameter could be critical in the regulation of flow to jeopardized muscle regions.…”

Vascular responses to leukotriene B4, C4 and D4 following FPL 55712, indomethacin, saralasin, phentolamine and verapamil in the conscious rat

“…Some recent observations have suggested that calcium ion fluxes might be important in mediating the effects of leukotrienes in non-vascular (Findlay et al, 1982;Weichmann et al, 1983;Kohrogi et al, 1985) and in coronary vascular smooth muscle in vitro (Roth & Lefer, 1983;Fiedler et al, 1984). The capacity of (b) Figure 4.…”