García-Pedraza José Ángel, García Mónica, Martín María Luisa, San Román Luis, Morán Asunción
Laboratorio de Farmacología, Departamento de Fisiología y Farmacología, Facultad de Farmacia, Universidad de Salamanca, 37007 Salamanca, Spain.
Laboratorio de Farmacología, Departamento de Fisiología y Farmacología, Facultad de Farmacia, Universidad de Salamanca, 37007 Salamanca, Spain.
Eur J Pharmacol. 2014 May 15;731:80-7. doi: 10.1016/j.ejphar.2014.02.043. Epub 2014 Mar 24.
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.
我们已经证明，5-HT2受体的拮抗作用通过5-HT1D和5-HT7激活增强了5-羟色胺能的交感神经抑制作用。本研究的目的是确定在用5-HT2受体阻滞剂治疗的去大脑大鼠中，5-羟色胺能对交感神经刺激引起的升压反应的抑制作用所涉及的机制。通过口服沙格雷酯治疗（30mg/kg/天）诱导5-HT2受体的阻断。两周后，将动物麻醉并去大脑。在输注（2S）（+）-5-（1,3,5-三甲基吡唑-4-基）-2-（二甲基氨基）四氢萘，AS-19（5μg/kg/分钟）之前，静脉注射1H-[1,2,4]恶二唑并[4,3-a]喹喔啉-1-酮（ODQ）（10μg/kg），一种鸟苷酸环化酶抑制剂，或吲哚美辛（2mg/kg），一种非选择性COX抑制剂，不能消除其抑制作用。然而，静脉注射格列本脲（20mg/kg），一种ATP敏感性钾（K+）通道阻滞剂，完全逆转了AS-19的交感神经抑制作用。吲哚美辛消除了2-[5-[3-（4-甲基磺酰氨基）苄基-1,2,4-恶二唑-5-基]-1H-吲哚-3-基]乙胺，L-694,247（5μg/kg/分钟）的抑制作用，而用ODQ预处理则没有效果。COX-2抑制剂尼美舒利（3mg/kg）完全逆转了L-694,247的抑制作用，而COX-1抑制剂1-[[4,5-双（4-甲氧基苯基）-2-噻唑基]羰基]-4-甲基哌嗪盐酸盐（FR122047）（3mg/kg）部分阻断了这种作用。静脉注射吲哚美辛加格列本脲后，5-HT（20μg/kg/分钟）不能引起交感神经抑制。总之，这些结果表明，在慢性沙格雷酯治疗的大鼠中，通过5-HT7和5-HT1D受体激活，由交感神经传出电刺激诱导的升压反应的抑制性5-羟色胺能作用分别由KATP通道介导的平滑肌超极化和COX途径介导。
