5-HT2-Receptor Blockade Restores Vasodilations to 5-HT in Atherosclerotic Rabbit Hearts

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Abstract
Summary: In the control rabbit coronary circulation serotonin [5-hydroxytryptamine (5-HT)] causes vasodilation, whereas in atherosclerotic hearts, 5-HT causes vasoconstriction. The present study was designed to test the effect of 5-HT2-receptor blockade and the role of the coronary endothelium on the 5-HT-induced responses in control and atherosclerotic rabbit hearts. Male rabbits were fed either a control or a cholesterol-rich (0.5%) diet for 18 weeks. Hearts were isolated and perfused at constant flow according to the Langendorff technique. Changes in vascular resistance were recorded as changes in perfusion pressure. The perfusion fluid contained indomethacin (10 μM) and propranolol (1 μM). In control hearts, 5-HT (0.2-200 nmol) evoked rapid reversible dilations; in hearts of hypercholesterolemic rabbits, either biphasic responses (dilations followed by constrictions) or vasoconstrictions were obtained with 5-HT. Ritanserin (0.1 to 10 nM) did not alter the control dilations to 5-HT; in the atherosclerotic hearts, the drug not only blocked the vasoconstrictions to 5-HT but restored the dilator responses to the amine. The endothelium-derived relaxing factor (EDRF) inhibitor N-monomethyl-l-arginine (l-NMMA, 10-30 μM) augmented basal tone and reduced the dilations to acetylcholine in both the control and the atherosclerotic hearts but the inhibitor did not significantly affect the dilator responses to 5-HT; the augmentation of basal tone was less important in the atherosclerotic hearts. l-arginine (100 μM) reversed the effects of l-NMMA. Our data confirm the vasoconstrictor nature of 5-HT in the atherosclerotic rabbit coronary circulation, where 5-HT2-receptor blockade can restore the normal vasodilator response to the amine. Both in the control and the atherosclerotic hearts, the EDRF inhibitor (l-NMMA failed to block the dilator responses to 5-HT, suggesting that an EDRF-nitric oxide (NO)-independent mechanism may be involved. The results with l-NMMA demonstrate a basal release of EDRF-NO (less important in atherosclerosis) and an acetylcholine-stimulated release of EDRF-NO in the rabbit coronary circulation.

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