Permissive contributions of NO and prostacyclin in CO-induced cerebrovascular dilation in piglets.
Permissive contributions of NO and prostacyclin in CO-induced cerebrovascular dilation in piglets.
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NO 和前列环素在 CO 诱导仔猪脑血管扩张中的许可作用。
DOI：
10.1152/ajpheart.01195.2004
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
Jaggar,JonathanH
中科院分区：
文献类型：
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作者：
Leffler,CharlesW;Fedinec,AlexanderL;Parfenova,Helena;Jaggar,JonathanH
内源性一氧化碳是新生儿脑血管循环的重要扩张剂。CO通过激活Ca 2+激活的K+通道扩张脑小动脉，但其他效应物和第二信使输入的调节作用尚不清楚。具体而言，前列环素和NO的强制性许可作用背后的机制是不确定的。因此，本研究使用急性植入的新生猪闭合颅窗进行，以解决NO和前列环素在响应CO的脑血管扩张中的许可作用涉及共同机制的假设。NO供体硝普钠在用前列腺素环氧合酶抑制剂吲哚美辛抑制扩张后恢复了对CO的反应。稳定的前列环素类似物伊洛前列素恢复了由NO合酶抑制剂N ω-硝基-L-精氨酸阻断的CO诱导的扩张。cGMP依赖性磷酸二酯酶抑制剂扎普司特可恢复对CO的扩张反应，鸟苷酸环化酶抑制剂1H-[1，2，4]恶二唑-[4，3-a]喹喔啉-1-酮（ODQ）可阻断CO扩张反应，表明cGMP/PKG通路参与其中。ODQ给药后，伊洛前列素或cAMP依赖性扩张剂异丙肾上腺素恢复了对CO的扩张反应。然而，一氧化碳诱导的扩张被cGMP依赖性PKG抑制剂RP-8-[（4-氯苯基）硫代]-cGMPS三乙胺阻断，不能被硝普钠、伊洛前列素或异丙肾上腺素逆转。相反，PKA抑制并没有阻止扩张响应CO。总体而言，数据表明，PKG的激活是主要的机制的许可行动的NO和前列环素CO诱导的软脑膜小动脉扩张。
Endogenously produced CO is an important dilator in newborn cerebrovascular circulation. CO dilates cerebral arterioles by activating Ca2+-activated K+channels, but modulatory actions of other effectors and second messenger inputs are unclear. Specifically, the mechanisms behind the obligatory permissive roles of prostacyclin and NO are uncertain. Therefore, the present study was performed using acutely implanted, closed cranial windows in newborn pigs to address the hypothesis that the permissive roles of NO and prostacyclin in cerebrovascular dilation in response to CO involve a common mechanism. The NO donor sodium nitroprusside restored dilation in response to CO after inhibition of that dilation with the prostaglandin cyclooxygenase inhibitor indomethacin. The stable prostacyclin analog iloprost restored CO-induced dilation blocked by the NO synthase inhibitorNω-nitro-l-arginine. Restoration of dilation in response to CO by the cGMP-dependent phosphodiesterase inhibitor zaprinast and blockade of CO dilation by the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazole-[4,3-a]quinoxalin-1-one (ODQ) suggests involvement of the cGMP/PKG pathway. Iloprost or the cAMP-dependent dilator isoproterenol restored dilation in response to CO after ODQ administration. However, CO-induced dilation blocked by the cGMP-dependent PKG inhibitor Rp-8-[(4-chlorophenyl)thio]-cGMPS triethylamine could not be reversed by administration of sodium nitroprusside, iloprost, or isoproterenol. Conversely, PKA inhibition did not block dilation in response to CO. Overall, data indicate that activation of PKG is the predominant mechanism of the permissive actions of NO and prostacyclin for CO-induced pial arteriolar dilation.