Hypotensive effects of eugenosedin-A with serotonin, alpha- and beta-adrenoceptor antagonistic activities in spontaneously hypertensive and normotensive rats

Abstract

Eugenosedin-A is a newly synthesized compound with special serotonergic, alpha- and beta1-adrenergic blocking actions. Intravenous injection of eugenosedin-A significantly caused dose-dependent decreases in the mean arterial blood pressure and heart rate in normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). The effects of eugenosedin-A-decreased blood pressure and heart rate in SHR were more potent than in WKY. In in vitro experiments, eugenosedin-A competitively antagonized the serotonin-, norepinephrine- and clonidine-induced vasocontraction in a concentration-dependent manner in isolated thoracic aorta of WKY and SHR. We also observed that eugenosedin-A competitively antagonized the isoproterenol-induced positive inotropic effects in a concentration-dependent manner in the isolated left atrium of WKY and SHR. These findings clearly suggested that eugenosedin-A possesses alpha1/alpha2, beta1 and 5-HT2A receptor-blocking activities. The order of pA2 values in isolated tissues of WKY was 5-HT2A > alpha1/alpha2 > beta1. However, the order of pA2 values in isolated tissues of SHR was alpha1/alpha2 > 5-HT2A > beta1. Similarly, we found that the in vitro functional activity of eugenosedin-A is quite different between WKY and SHR. On the other hand, in the isolated rabbit ear artery sensitized with 16 mmol/l K+, eugenosedin-A antagonized 5-nonyloxytryptamine- and serotonin-induced vasocontractions, indicating that it also blocked 5-HT1B and 5-HT2A receptors. In radioligand binding experiments, eugenosedin-A had significant binding affinities on alpha1/alpha2, beta1, 5-HT1B and 5-HT2A receptors. Finally, we suggest that the hypotensive effects of eugenosedin-A can be attributed to its multiple actions on the blockade of 5-HT1B, 5-HT2A, alpha and beta1 receptors in both WKY and SHR strains.