Hypotensive effects of eugenosedin-A with serotonin, alpha- and beta-adrenoceptor antagonistic activities in spontaneously hypertensive and normotensive rats.
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.
Shen
Kuo-Pyng
KP
Department of Pharmacology, College of Medicine, Kaohsiung Medical University, Taiwan.
Chiu
Chaw-Chi
CC
Chen
Sheue-Jiun
SJ
Chen
Ing-Jun
IJ
Wu
Bin-Nan
BN
D000317:Adrenergic alpha-Antagonists / Q000378:metabolism* / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000378:metabolism* / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D001919:Bradycardia / Q000139:chemically induced / Q000150:complications; D003000:Clonidine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004423:Ear / Q000098:blood supply / Q000473:pathology; D004558:Electric Stimulation; D006325:Heart Atria / Q000166:cytology / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D007022:Hypotension / Q000139:chemically induced* / Q000150:complications; D007275:Injections, Intravenous; D007545:Isoproterenol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009200:Myocardial Contraction / Q000187:drug effects; D009638:Norepinephrine / Q000494:pharmacology; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D011918:Rats, Inbred SHR / Q000502:physiology*; D011921:Rats, Inbred WKY; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects / Q000378:metabolism; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects / Q000502:physiology; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects / Q000502:physiology; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects / Q000502:physiology; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000378:metabolism* / Q000494:pharmacology*; D013045:Species Specificity; D014316:Tritium; D014363:Tryptamines / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects
D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D010879:Piperazines; D044402:Receptor, Serotonin, 5-HT2A; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; D018342:Receptors, Adrenergic, beta-1; D012702:Serotonin Antagonists; D014363:Tryptamines; C496985:eugenosedin-A; D014316:Tritium; D012701:Serotonin; C030820:tryptamine; D007545:Isoproterenol; D003000:Clonidine; D009638:Norepinephrine