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Enhanced inhibition by melatonin of α‐adrenoceptor‐ induced aortic contraction and inositol phosphate production in vascular smooth muscle cells from spontaneously hypertensive rats

Objective To test the hypothesis that the enhanced inhibition by melatonin of the norepinephrine-induced vasoconstriction and formation of inositol phosphate in spontaneously hypertensive rats are mediated by its antioxidant effect. Methods Aortic rings from spontaneously hypertensive rats and age-matched Wistar-Kyoto rats were used for measuring vascular contraction forces. Cultured aortic smooth muscle cells were prelabelled with myo-[2-3H]inositol for evaluation of formation of inositol phosphate after exposure to agonist or antagonist. Basal or forskolin-induced formation of cyclic AMP was evaluated using a [3H]-cyclic AMP assay system. Oxygen-derived free radicals were generated with a hypoxanthine and xanthine oxidase system. Results The inhibition of the norepinephrine-induced aortic contraction by melatonin was more potent in spontaneously hypertensive than it was in Wistar-Kyoto rats. The inhibition of the norepinephrine-induced formation of inositol phosphate by 0.3–300 μmol/l melatonin was also greater in smooth muscle cells from spontaneously hypertensive rats than it was in those cells from Wistar-Kyoto rats. In contrast, the inhibition of the norepinephrine-induced formation of inositol phosphate in smooth muscle cells from spontaneously hypertensive and Wistar-Kyoto rats by 2-iodomelatonin, an agonist of melatonin receptors, was not different. Prazosin, but not yohimbine, eliminated or partially inhibited the norepinephrine-induced formation of inositol phosphate in smooth muscle cells from Wistar-Kyoto rats or from spontaneously hypertensive rats, respectively. In the presence both of prazosin and of melatonin, the norepinephrine-induced production of inositol phosphate was abolished in smooth muscle cells from spontaneously hypertensive rats. Furthermore, superoxide dismutase significantly inhibited the norepinephrine-induced aortic contraction and formation of inositol phosphate in smooth muscle cells from spontaneously hypertensive rats, but not in those cells from Wistar-Kyoto rats. In contrast, catalase had no effect on the norepinephrine-induced formation of inositol phosphate and vascular contraction either in cells from spontaneously hypertensive rats or in cells from Wistar-Kyoto rats. Hypoxanthine-xanthine oxidase induced formation of more inositol phosphate in smooth muscle cells from spontaneously hypertensive rats than it did in those from Wistar-Kyoto rats. Melatonin and superoxide dismutase similarly inhibited the hypoxanthine-xanthine oxidase-induced formation of inositol phosphate more in cells from spontaneously hypertensive rats than it did in those from Wistar-Kyoto rats. However, melatonin had no effect either on basal or on the forskolin-induced formation of cyclic AMP in smooth muscle cells from rats of both strains. Conclusion The enhanced inhibitory effect of melatonin on the norepinephrine-induced cellular production of inositol phosphate in spontaneously hypertensive rats was not mediated by melatonin receptors or a-adrenoceptors. Rather, the antioxidant effect of melatonin could become important in spontaneously hypertensive rats, which are suspected to have a lower cellular content of antioxidants or a greater sensitivity to superoxide anions, or both, of the vascular tissue. J Hypertens 16:339–347 © 1998 Rapid Science Ltd.