Modulation of coronary flow rate and cardiac contractility by the divalent cation ionophore A23187 and inhibitors of the cyclooxygenase and 5-lipoxygenase pathways: development of heterogeneous patterns of myocardial ischemia.

Abstract

In the present studies, we demonstrate in buffer-perfused isolated working guinea pig hearts that indometacin reduces coronary flow rate in a dose-dependent manner (max 56.7 +/- 5.5%, SEM, n = 6, of control at 5 x 10(-6) mol/l of indometacin, P less than 0.01), and that this leads to a development of heterogeneous patterns of myocardial ischemia (elevated myocardial levels of reduced pyridine nucleotide, NADH) and depressed cardiac work (64.7 +/- 11.7%, SEM, of control at 5 x 10(-6) mol/l of indometacin, P less than 0.05). The effect of indometacin on coronary flow rate and consequently on myocardial tissue oxygenation was completely prevented by the preferential 5-lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA) (1 x 10(-6) mol/l), or the sulfidopeptide leukotriene receptor antagonist FPL 55712 (2 x 10(-5) mol/l), indicating that the isolated working guinea pig heart, even when deprived of blood, is able to produce vasoactive sulfidopeptide leukotrienes at significant levels. At higher concentrations of indometacin (5 x 10(-5) mol/l, 1 x 10(-4) mol/l), coronary flow rate returned to initial levels while cardiac work became further depressed despite normoxic levels of NADH. These data support that indometacin also has a direct suppressive effect on the myocardium independent of its coronary vascular effect. This conclusion is supported by the observation that addition of sodium arachidonate (6 x 10(-5) mol/l) completely inhibited the vascular effect of indometacin, but not the depressive effect on the myocardium. The divalent cation ionophore A23187 (6 x 10(-6) mol/l) had a strong positive chronotropic effect on the heart and a biphasic effect on coronary flow rate. After a brief period of increased coronary flow rate, presumably due to coronary vasodilatation, the ionophore caused a sustained reduction in coronary flow, and this was accompanied by high myocardial levels of NADH fluorescence of characteristically heterogeneous pattern. This is presumably caused by vasoconstrictory effects of elevated levels of intracellular Ca2+ of vascular smooth muscle, independent of stimulation of 5-lipoxygenase or cyclooxygenase pathways, since neither indometacin nor nordihydroguaiaretic acid modified the effect of A23187.