title: The role of endothelium-derived hyperpolarizing factor and cyclooxygenase pathways in the inhibitory serotonergic response to the pressor effect elicited by sympathetic stimulation in chronic sarpogrelate treated rats.
abstract: We have demonstrated that the antagonism of 5-HT2 receptors produces an enhancement of serotonergic sympathoinhibitory effect by 5-HT1D and 5-HT7 activation. The aim of this work was to determine mechanisms involved in the 5-hydroxytriptaminergic inhibitory action on the pressor responses elicited by sympathostimulation in pithed rats treated with a 5-HT2 receptor blocker. The blockade of 5-HT2 receptors was induced by orally sarpogrelate treatment (30 mg/kg/day). Two weeks later, animals were anaesthetized and pithed. A bolus injection of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (10 µg/kg), a guanylyl cyclase inhibitor, or indomethacin (2mg/kg), a non-selective COX inhibitor, prior to the infusion of (2S)(+)-5-(1,3,5-trimethylpyrazol-4-yl)-2-(dimethylamino)tetralin, AS-19 (5 µg/kg/min) were not able to abolish its inhibitory action. However, i.v. administration of glibenclamide (20mg/kg), a blocker of ATP-sensitive K(+) channels, completely reversed AS-19 sympathoinhibitory action. The inhibitory effect of 2-[5-[3-(4-methylsulfonylamino)benzyl-1,2,4-oxadiazol-5-yl]-1H-indol-3-yl]ethanamine, L-694,247 (5 µg/kg/min) was abolished by indomethacin, whereas pretreatment with ODQ had no effect. Nimesulide (3mg/kg), a COX-2 inhibitor, completely reversed the inhibitory action of L-694,247, whereas 1-[[4,5-bis (4-methoxyphenyl)-2-thiazolyl]carbonyl]-4-methylpiperazine hydrochloride (FR122047) (3mg/kg), a COX-1 inhibitor, partially blocked this action. The sympathoinhibition by 5-HT (20 µg/kg/min) could not be elicited after i.v. treatment with indomethacin plus glibenclamide. In conclusion, these results suggest that in chronic sarpogrelate-treated rats, the inhibitory serotonergic effect of the pressor responses induced by electrical stimulation of the sympathetic outflow via 5-HT7 and 5-HT1D receptor activation is mediated by KATP channel-mediated smooth muscle hyperpolarization and the COX pathway, respectively.
authors.affiliation: Laboratorio de Farmacología, Departamento de Fisiología y Farmacología, Facultad de Farmacia, Universidad de Salamanca, 37007 Salamanca, Spain.
authors.forename: José Ángel
authors.initials: JÁ
authors.lastname: García-Pedraza
authors.affiliation: Laboratorio de Farmacología, Departamento de Fisiología y Farmacología, Facultad de Farmacia, Universidad de Salamanca, 37007 Salamanca, Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: García
authors.affiliation: Laboratorio de Farmacología, Departamento de Fisiología y Farmacología, Facultad de Farmacia, Universidad de Salamanca, 37007 Salamanca, Spain.
authors.forename: María Luisa
authors.initials: ML
authors.lastname: Martín
authors.affiliation: Laboratorio de Farmacología, Departamento de Fisiología y Farmacología, Facultad de Farmacia, Universidad de Salamanca, 37007 Salamanca, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: San Román
authors.affiliation: Laboratorio de Farmacología, Departamento de Fisiología y Farmacología, Facultad de Farmacia, Universidad de Salamanca, 37007 Salamanca, Spain. Electronic address: amoran@usal.es.
authors.forename: Asunción
authors.initials: A
authors.lastname: Morán
mesh_terms: D000818:Animals; D001685:Biological Factors / Q000378:metabolism*; D004558:Electric Stimulation; D005905:Glyburide / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D010069:Oxadiazoles / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044346:Receptor, Serotonin, 5-HT1D / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013386:Succinates / Q000494:pharmacology*; D013564:Sympathetic Nervous System / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D001685:Biological Factors; D010069:Oxadiazoles; D011810:Quinoxalines; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013386:Succinates; C067410:endothelium-dependent hyperpolarization factor; C104425:serotonin 7 receptor; C064294:sarpogrelate; D009569:Nitric Oxide; D012701:Serotonin; D011451:Prostaglandin-Endoperoxide Synthases; D005905:Glyburide; D007213:Indomethacin
keywords: 5-HT(1D); 5-HT(7) receptors; 5-hydroxytryptamine; COX; EDHF pathway; Sarpogrelate