6-[4-(4′-吡啶)氨基苯]-4,5-二氢-3(2H)哒嗪酮对大鼠胸主动脉环收缩功能的影响

目的研究新型钙增敏强心剂6-4-(4′-吡啶)氨基苯]-4,5-二氢-3(2H)哒嗪酮(MCI-154)的扩血管作用机制。方法采用生物张力换能器及生理记录仪测定大鼠离体胸主动脉环和蜕膜胸主动脉环的收缩张力。结果MCI-154可浓度依赖性抑制1nmol.L-1~10μmol.L-1去甲肾上腺素(pD2′为4.21±0.23)和80mmol.L-1KCl(IC50为7μmol.L-1)引起的血管环收缩,提示其可通过抑制血管平滑肌细胞膜上受体操纵性和电压依赖性钙通道而减少胞外钙内流。在无Ca2+K-H液中,MCI-154预处理可浓度依赖性降低3μmol.L-1苯肾上腺素(IC50为5μmol.L-1)及20mmol.L-1咖啡因(IC50为16μmol.L-1)引起的血管环收缩张力,提示其可抑制血管平滑肌细胞胞内钙释放。在1μmol.L-1Ca2+溶液中,MCI-154可显著降低蜕膜血管环收缩张力(IC50为10μmol.L-1),提示其可降低血管平滑肌对Ca2+的敏感性。结论MCI-154可通过抑制血管平滑肌胞外钙内流、胞内钙释放和降低其对Ca2+敏感性来降低血管平滑肌收缩张力,体外具有扩血管效应。

Effects of 6-[4-(4′-pyridyl)amino-phenyl]-4,5-dihydro-3(2H)-pyridazinone on contraction of aorta in rats

AIM To explore the mechanism of vasodilation effect of 6-4-(4′-pyridyl) amino-phenyl]-4,5-dihydro-3(2H)-pyridazinone (MCI-154), a novel calcium sensitizer for cardiac contraction protein. METHODS Thoracic aorta rings isolated from rats and tension sensors were used for determining contractile tension in vitro. The skinned aortic rings were produced by α-toxin and used for Ca~ 2+ sensitivity examinaton. RESULTS In H-K solution, 0.01-10 μmol·L~ -1 MCI-154 concentration-dependently decreased contraction of aortic rings induced by 1 nmol·L~ -1 -10 μmol·L~ -1 norepinephrine (pD_2′ 4.21±0.23) and 80 mmol·L~ -1 KCl (IC_ 50 7 μmol·L~ -1 ), respectively, it suggested that MCI-154 decrease extracellular Ca~ 2+ influx by receptor-operate Ca~ 2+ channel and potential-dependent Ca~ 2+ channel. In Ca~ 2+ -free H-K solution, 0.01-10 μmol·L~ -1 MCI-154 significantly reduced contraction of aortic rings initiated by 3 μmol·L~ -1 phenylephrine (IC_ 50 5 μmol·L~ -1 ) and 20 mmol·L~ -1 caffeine (IC_ 50 16 μmol·L~ -1 ), it was revealed that MCI-154 inhibited intracellular Ca~ 2+ release from sarcoplasmic reticulum. In 1 μmol·L~ -1 Ca~ 2+ solution, 0.01-10 μmol·L~ -1 MCI-154 remarkably decreased the Ca~ 2+ -activated contraction developed in α-toxin-treated skinned aortic rings (IC_ 50 10 μmol·L~ -1 ), it was indicated that MCI-154 decreased sensitivity of VSM contractile elements by Ca~ 2+ . CONCLUSION MCI-154 inhibits vascular contraction by decreasing extracellular Ca~ 2+ influx, intracellular Ca~ 2+ release from sarcoplasmic reticulum and sensitivity of VSM contractile elements by Ca~ 2+ .