Mechanisms responsible for MaxiK_<Ca> channel-mediated vascular relaxation

本文研究了前列腺素I2b(PGI2b，IP)激动剂贝拉前列素(Beraprost)对血管松弛作用的细胞内通路(S)的影响。在高钾收缩的组织中，贝拉前列素引起的豚鼠主动脉松弛几乎消失，表明K~+电导在血管反应中起主要作用。选择性的Maxik；lt；Ca&gt；通道阻滞剂伊比利亚毒素(Iberiooxin，10^；lt；-7；gt；M)也几乎完全消除了贝拉前列斯特引起的松弛。其他K~+通道阻断剂格列本脲和钙离子通道阻滞剂格列本脲对贝拉前列素的松弛作用无明显影响，但可被4-氨基吡啶轻度减弱。Beraprost增加细胞内cANP水平，提示cAMP依赖通路的作用。RO-20-1724是cAMP特异性磷酸二酯酶的选择性抑制剂，显著增强贝拉前列素引起的血管松弛。伊比利亚毒素完全抵消了这种增强作用。此外，由于福司可林或8-溴环腺苷引起的张力降低可被毒素c…彻底恢复。更多地确认了cAMP依赖机制的作用。腺苷环化酶抑制剂SQ 22,536几乎完全抑制了维拉帕米引起的cAMP含量升高，但对维拉帕米诱导的血管松弛无明显影响，提示存在环磷酸腺苷非依赖性机制。此外，霍乱毒素是腺酰环化酶(Gs)刺激性G蛋白的激活剂，在没有和存在SQ22,536的情况下，都能显著抑制PGF2α引起的收缩。伊比利亚毒素也能恢复霍乱毒素引起的松弛。这些结果表明，Maxik；lt；Ca&gt；通道在介导贝拉前列素刺激IP受体后的豚鼠主动脉平滑肌松弛中起中心作用。在这个血管组织中，环状AMP依赖和非独立途径都参与了IP受体刺激后的Maxik_&lt；Ca&gt；通道介导的松弛。Gs对Maxik&lt；Ca&Gt；通道的直接调节是环状AMP非依赖性松弛机制的部分原因。较少

The intracellular pathway(s) controlling vascular relaxation/induced by a prostaglandin I_2 (PGI_2b, IP) agonist beraprost was investigated. Beraprost-induced relaxation of guinea-pig aorta was almost abolished in high-KCl-contracted tissue, indicating a major role of K^+ conductances in the vascular reponse. Beraprost-induced relaxation was also practically abolished by a selective MaxiK_<Ca> channel blocker, Iberiotoxin (10^<-7> M). The relaxation induced by beraprost was not significantly affected by other K^+ channel blockers glibenclamide or Ba^<2+>, but was slightly attenuated by 4-aminopyridine. Beraprost increased intracellular cANP levels, suggesting a role for cAMP-dependent pathways. RO-20-1724, a selective inhibitor of cAMP-specific phosphodiesterase, significantly potentiated beraprost-induced vascular relaxation. Iberiotoxin completely counteracted this potentiation. Moreover, tension decrement due to forskolin or 8-bromo-cyclic AMP was thoroughly restored by the toxin, c … More onfirming a role for a cAMP-dependent mechanism. However, SQ 22,536, an adenylyl cyclase inhibitor, did not affect beraprost-induced vascular relaxation though it almost totally inhibited the elevation of cAMP contents induced by beraprost, which suggests the existence of cyclic AMP-independent mechanism. Moreover, cholera toxin, an activator of the stimulatory G protein of adenylyl cyclase (Gs), significantly inhibited PGF_<2α>-induced contraction both in the absence and presence of SQ 22,536. Iberiotoxin was also capable of restoring the relaxation induced by cholera toxin. These findings suggest that MaxiK_<Ca> channel plays a central role in mediating smooth muscle relaxation following stimulation of IP receptor with beraprost in guinea-pig aorta. Both cyclic AMP-dependent and -independent pathways contribute to the MaxiK_<Ca> channel-mediated relaxation following IP receptor stimulation in this vascular tissue. Direct regulation of MaxiK_<Ca> channels by Gs partly accounts for the cyclic AMP-independent relaxant mechanism. Less