Vasodilatory activity of etozoline in rat and guinea-pig isolated aorta: study of the mechanism of action.
In isolated rings of guinea-pig aorta not responding to acetylcholine, the diuretic etozoline did not influence basal vascular tone but inhibited noradrenaline- and histamine-induced contractions. The inhibition was evident at concentrations of the diuretic (10 microM-1 mM) suitable to inhibit, in a competitive manner, the contractions evoked by a K+ channel blocker, tetraethylammonium, in the same preparation (Dorigo et al., 1989, 1990). In isolated rings of guinea-pig aorta, etozoline, at very low concentrations (1 nM-0.1 microM), inhibited also serotinin-induced contractions. The contractile effect of serotonin was abolished by nifedipine associated with 2-nitro-4-carboxyphenyl N,N-diphenyl-carbamate (an inhibitor of phospholipase C) or with etozoline, thus suggesting that the diuretic, besides inhibiting extracellular Ca++ uptake, also prevents intracellular Ca++ mobilization mediated by inositol triphosphate. In isolated rings of rat aorta responding to acetylcholine, etozoline did not influence basal vascular tone either in the absence or in the presence of superoxide-dismutase. In the same preparation, the diuretic inhibited vascular contractions induced by the three spasmogenic agents used, i.e. noradrenaline, histamine and serotonin. This inhibition occurred at concentrations of etozoline ranging from 10 microM to 1 mM and was uninfluenced by indomethacin (10 microMs). In isolated rings of rat aorta, the contractile effect of noradrenaline was not influenced by the addition of either 100 microM pyrogallol, or 10 microM methylene blue or 100 U/ml superoxide-dismutase, while the contractile responses to histamine and to serotonin were potentiated by pyrogallol and by methylene blue and reduced by superoxide-dismutase. This indicates that, in rat aorta, noradrenaline evokes only a direct contractile response, whereas both serotonin and histamine have a double effect: direct contraction of vascular smooth muscle and release of a relaxing factor from the endothelium. The inhibitory activity of etozoline towards serotonin- and histamine-induced contractions was reduced by pyrogallol and by methylene blue, whereas it was potentiated by superoxide-dismutase. The ability of etozoline to reverse the noradrenaline-induced contraction was unaffected by pyrogallol, methylene blue or superoxide-dismutase. These results emphasize the spasmolytic activity of etozoline, which seems to involve only the muscular component of rat and guinea-pig aorta.