Endothelium-derived relaxing factor(s) and calcium antagonists

The presence of endothelium attenuates norepinephrine-induced vasoconstriction in the rat thoracic aorta by the spontaneous release of endothelium-derived relaxing factor. Calcium antagonists also inhibit catecholamine-induced vasoconstriction. Experiments were designed to determine the effect of calcium antagonists in the presence and absence of the endothelium on the responsiveness of the isolated rat aorta to norepinephrine. Rings of the thoracic aorta of Wistar Kyoto rats were suspended in organ chambers (in the presence of indomethacin) for isometric measurement of force. Mechanical removal of the endothelium shifted the concentration response curve to norepinephrine to the left and augmented the maximal response to the catecholamine. Diltiazem and verapamil shifted the concentration response curve to norepinephrine to the right only in rings without endothelium; they abolished the difference in sensitivities to norepinephrine caused by removal of the endothelium. Diltiazem, but not verapamil, also reduced the difference in the maximal response to norepinephrine. In the presence of oxyhemoglobin, diltiazem had similar effects on rings with and without endothelium. Sodium nitroprusside also abolished the hypersensitivity to norepinephrine caused by removal of the endothelium. These data suggest that calcium antagonists can prevent the hypersensitivity to norepinephrine in arteries in which the endothelium has been removed. They may explain some of the beneficial effects of calcium antagonists in conditions with endothelial dysfunction.