Preferential Dilation of Large Coronary Microvessels by the Mononitrates SPM-4744 and SPM-5185

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Abstract
A novel aspect of the pharmacodynamic action of nitroglycerin is that it is a potent dilator of larger coronary arteries, yet it dilates smaller coronary microvessels submaximally and only in high concentrations. We sought to determine whether this property was shared by other organic nitrates. The effects of two mononitrates. SPM-4744 and SPM-5185 (the latter of which possesses a thioester in its structure), on coronary microvessels of different sizes were studied. Large (200-microns diameter) and small ( < 100-microns diameter) porcine coronary microvessels were studied in vitro while pressurized in a no-flow state. After constriction with the thromboxane analogue U46619, maximal dilations (as a percent of preconstricted tone at the highest applied concentration, 10 microM) of small coronary microvessels were 18 +/- 3 and 16 = 2% in response to SPM-4744 and SPM-5185, respectively. The dilations of larger coronary microvessels to SPM-4744 and SPM-5185 were 55 +/- 5 and 43 +/- 6%, respectively (both p < 0.001 vs. the small vessel responses). This pattern of differential vasodilatation of large and small coronary microvessels was similar to that produced by nitroglycerin. In contrast, sodium nitroprusside produced equivalent degrees of vasodilation of small and large coronary microvessels. Additional experiments demonstrated that both SPM compounds produced dilation of the coronary microcirculation in isolated rat heart and relaxed isolated segments of rat aortic rings only in high ( > or = 1 microM) concentrations. These data demonstrate that the organic mononitrates are similar to nitroglycerin in their selectivity for larger coronary microvessels and produce only minimal dilation of coronary microvessels < 100 microM in diameter.