title: 5-HT2 receptor blockade exhibits 5-HT vasodilator effects via nitric oxide, prostacyclin and ATP-sensitive potassium channels in rat renal vasculature.
abstract: The aim of this study was to determine whether orally sarpogrelate (selective 5-HT2 antagonist) treatment (30 mg/kg/day; 14 days) could modify 5-HT renal vasoconstrictor responses, characterizing 5-HT receptors and mediator mechanisms involved in serotonergic responses in the in situ autoperfused rat kidney. Intra-arterial (i.a.) injections of 5-HT (0.00000125 to 0.1 μg/kg) decreased renal perfusion pressure (RPP) but did not affect the mean blood pressure (MBP). i.a. agonists 5-CT (5-HT1/7), CGS-12066B (5-HT1B), L-694,247 (5-HT1D) or AS-19 (5-HT7) mimicked renal 5-HT vasodilator effect. However, neither 8-OH-DPAT (5-HT1A) nor 1-phenylbiguanide (5-HT3) modified RPP. Moreover: (i) GR-55562 (5-HT1B antagonist) and L-NAME (nitric oxide synthase [NOS] inhibitor) blocked CGS-12066B-induced vasodilator response, (ii) LY310762 (5-HT1D antagonist) and indomethacin (non-selective cyclooxygenase inhibitor) blocked L-694,247-induced vasodilator response; (iii) SB-258719 (5-HT7 antagonist) and glibenclamide (ATP-sensitive K+ channel blocker) blocked AS-19-induced vasodilator response; and (iv) 5-HT- or 5-CT-elicited renal vasodilation was significantly blocked by the mixture of GR-55562 + LY310762 + SB-258719. Furthermore, eNOS and iNOS proteins and prostacyclin levels are overexpressed in sarpogrelate-treated rats. Our data suggest that 5-HT exerts renal vasodilator effect in the in situ autoperfused sarpogrelate-treated rat kidney, mediated by 5-HT1D, 5-HT1B and 5-HT7 receptors, involving cyclooxygenase-derived prostacyclin, nitric oxide synthesis/release and ATP-sensitive K+ channels, respectively.
authors.affiliation: Laboratorio de Farmacología, Departamento de Fisiología y Farmacología, Facultad de Farmacia, Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain.
authors.forename: J A
authors.initials: JA
authors.lastname: García-Pedraza
authors.affiliation: Laboratorio de Farmacología, Departamento de Fisiología y Farmacología, Facultad de Farmacia, Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain.
authors.forename: M
authors.initials: M
authors.lastname: García
authors.affiliation: Laboratorio de Farmacología, Departamento de Fisiología y Farmacología, Facultad de Farmacia, Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain.
authors.forename: M L
authors.initials: ML
authors.lastname: Martín
authors.affiliation: Unidad de Fisiopatología Renal y Cardiovascular, Departamento de Fisiología y Farmacología, Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Instituto Reina Sofía de Investigación Nefrológica, Fundación Iñigo Álvarez de Toledo, Universidad de Salamanca, 37007 Salamanca, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Rodríguez-Barbero
authors.affiliation: Laboratorio de Farmacología, Departamento de Fisiología y Farmacología, Facultad de Farmacia, Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain. Electronic address: amoran@usal.es.
authors.forename: A
authors.initials: A
authors.lastname: Morán
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D011464:Epoprostenol / Q000502:physiology*; D054086:KATP Channels / Q000502:physiology*; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D010069:Oxadiazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044348:Receptors, Serotonin, 5-HT2 / Q000502:physiology; D012701:Serotonin / Q000494:pharmacology / Q000502:physiology; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology*; D014363:Tryptamines / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D054086:KATP Channels; D010069:Oxadiazoles; D044348:Receptors, Serotonin, 5-HT2; D058825:Serotonin 5-HT1 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D014363:Tryptamines; D014665:Vasodilator Agents; C085632:L 694247; D009569:Nitric Oxide; D012701:Serotonin; D011464:Epoprostenol
keywords: 5-HT hydrochloride (Pubchem CID: 160436); 5-HT(2) receptor; 5-Hydroxytryptamine (5-HT); 5-carboxamidotryptamine maleate (Pubchem CID: 11709509); AS-19 (Pubchem CID: 16759607); Autoperfused rat kidney; CGS-12066B dimaleate (Pubchem CID: 56927914); L-694,247 (Pubchem CID: 132059); L-NAME hydrochloride (Pubchem CID: 135193); Renal vasodilation; Sarpogrelate; glibenclamide (Pubchem CID: 3488); indomethacin (Pubchem CID: 3715); sarpogrelate hydrochloride (Pubchem CID: 444005)