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, α- and β₁-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 α₁/α₂, β₁ and 5-HT_2A receptor-blocking activities. The order of pA₂ values in isolated tissues of WKY was 5-HT_2A > α₁/α₂ > β₁. However, the order of pA₂ values in isolated tissues of SHR was α₁/α₂ >5-HT_2A > β₁. 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-HT_1B and 5-HT_2A receptors. In radioligand binding experiments, eugenosedin-A had significant binding affinities on α₁/α₂, β₁, 5-HT_1B and 5-HT_2A receptors. Finally, we suggest that the hypotensive effects of eugenosedin-A can be attributed to its multiple actions on the blockade of 5-HT_1B, 5-HT_2A, α and β₁ receptors in both WKY and SHR strains.

Structure–activity relationships of isoeugenol‐based chlorophenylpiperazine derivatives on serotonergic/adrenergic receptor, platelet aggregation, and lipid peroxidation

“…, 10 À7 M) also Shen et al [2004Shen et al [ , 2008. , 10 À7 M) produced the concentration-dependent curves of 5-nonyloxytryptamine or 5-HT to shift rightward.…”

“…Experiments were performed as previously described [Shen et al, 2008]. Briefly, Wistar rats weighing 250-300 g were anesthetized with pentobarbital sodium (50 mg/kg, ip).…”

“…Experiments were performed as previously described [Shen et al, 2008]. Rat thoracic aorta was quickly removed, cleaned of adhering fat and connective tissue, and cut into 3-4-mm-wide transverse rings.…”

“…Rat brain homogenates (1 ml) were incubated at 371C for 5 min with 10 ml of test compound or vehicle. Lipid peroxidation was initiated by the addition of 0.1 ml of 0.25 mM FeCl 2 and 1 mM ascorbic acid [Shen et al, 2008]. After 30 min of incubation, the reaction was stopped by adding 0.1 ml of 0.2% BHT.…”

“…In previous reports, we have demonstrated that eugenosedin-A (Eu-A) and eugenosedin-B (Eu-B) containing o-CPP-and m-CPP-based moieties have serotonergic and adrenergic receptor antagonist activities [Shen et al, 2004[Shen et al, , 2005[Shen et al, , 2007[Shen et al, , 2008. Recently, Eu-A was found to activate large-conductance Ca 21 -activated K 1 channels via cyclic nucleotide-dependent protein kinases in rat basilar artery .…”