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

研究了前列腺素I_2（PGI_2b，IP）激动剂贝前列素（Berprost）控制血管舒张的细胞内途径。贝前列素诱导的豚鼠主动脉舒张在高KCl收缩的组织中几乎被消除，表明K^+电导在血管反应中起主要作用。贝前列素诱导的舒张也几乎被选择性MaxiK_<Ca>通道阻断剂伊比利亚毒素（Iberiotoxin）（10 μ <-7>M）消除。贝前列素诱导的舒张作用不受其他K^+通道阻断剂格列本脲或Ba^&lt;2+&gt;的显著影响，但可被4-氨基吡啶轻微减弱。贝前列素增加细胞内cANP水平，表明cAMP依赖性途径的作用。RO-20-1724是cAMP特异性磷酸二酯酶的选择性抑制剂，可显著增强贝前列素诱导的血管舒张。伊比利亚毒素完全抵消了这种增强作用。此外，由于毛喉素或8-溴-环AMP引起的张力降低被毒素完全恢复，c ...更多信息 证实了cAMP依赖性机制的作用。腺苷酸环化酶抑制剂SQ 22，536几乎完全抑制贝前列素引起的cAMP含量升高，但不影响贝前列素引起的血管舒张，提示存在环腺苷酸非依赖性机制。此外，霍乱毒素（一种腺苷酸环化酶（Gs）刺激性G蛋白的激活剂）在SQ 22，536存在和不存在的情况下均显著抑制PGF &lt;2α&gt;诱导的收缩。伊比利亚毒素还能够恢复霍乱毒素引起的松弛。提示<Ca>贝前列素刺激IP受体后，MaxiK_2通道在介导平滑肌舒张中起重要作用。在该血管组织中，环AMP依赖性和非依赖性途径都有助于<Ca>IP受体刺激后MaxiK_通道介导的舒张。Gs对MaxiK_1通道的直接调节<Ca>部分解释了环AMP非依赖性舒张机制。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