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首页> 外文期刊>American Journal of Physiology >cAMP modulates cGMP-mediated cerebral arteriolar relaxation in vivo.
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cAMP modulates cGMP-mediated cerebral arteriolar relaxation in vivo.

机译：cAMP在体内调节cGMP介导的脑小动脉松弛。

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摘要

No studies have specifically addressed whether cAMP can influence nitric oxide (NO)/cGMP-induced cerebral vasodilation. In this study, we examined whether cAMP can enhance or reduce NO-induced cerebral vasodilation in vivo via interfering with cGMP efflux or through potentiating phosphodiesterase 5 (PDE5)-mediated cGMP breakdown, respectively, in cerebral vascular smooth muscle cells (CVSMCs). To that end, we evaluated, in male rats, the effects of knockdown [via antisense oligodeoxynucleotide (ODN) applications] of the cGMP efflux protein multidrug resistance protein 5 (MRP5) and PDE5 inhibition on pial arteriolar NO donor [S-nitroso-N-acetyl penicillamine (SNAP)]-induced dilations in the absence and presence of cAMP elevations via forskolin. Pial arteriolar diameter changes were measured using well-established protocols in anesthetized rats. In control (missense ODN treated) rats, forskolin elicited a leftward shift in the SNAP dose-response curves (approximately 50% reduction in SNAP EC50). However,in MRP5 knockdown rats, cAMP increases were associated with a substantial reduction in SNAP-induced vasodilations (reflected as a significant 35-50% lower maximal response). In the presence of the PDE5 inhibitor MY-5445, the repression of the NO donor response accompanying forskolin was prevented. These findings suggest that cAMP has opposing effects on NO-stimulated cGMP increases. On the one hand, cAMP limits CVSMC cGMP loss by restricting cGMP efflux. On the other, cAMP appears to enhance PDE5-mediated cGMP breakdown. However, because increased endogenous cAMP seems to potentiate NO/cGMP-induced arteriolar relaxation when MRP5 expression is normal, the effect of cAMP to reduce cGMP efflux appears to predominate over cAMP stimulation of cGMP hydrolysis.
机译：尚无专门研究cAMP是否能影响一氧化氮（NO）/ cGMP诱导的脑血管舒张的研究。在这项研究中，我们分别检查了cAMP是否可以通过干扰cGMP外排或通过增强磷酸二酯酶5（PDE5）介导的cGMP分解来增强或减少NO诱导的体内脑血管舒张，其作用在脑血管平滑肌细胞（CVSMCs）中。为此，我们在雄性大鼠中评估了cGMP外排蛋白多药抗性蛋白5（MRP5）和PDE5抑制[通过反义寡聚脱氧核苷酸（ODN）应用]对小动脉小动脉NO供体[S-nitroso-N -乙酰青霉素胺（SNAP）]通过毛喉素诱导cAMP升高和不存在的扩张。使用公认的方案在麻醉的大鼠中测量小动脉直径的变化。在对照（未接受ODN处理的大鼠）大鼠中，福司可林引起SNAP剂量反应曲线向左移动（SNAP EC50降低约50％）。然而，在敲低MRP5的大鼠中，cAMP的增加与SNAP诱导的血管舒张的显着减少有关（反映为最大反应显着降低了35-50％）。在PDE5抑制剂MY-5445的存在下，防止了福司高林伴随的NO供体应答的抑制。这些发现表明，cAMP对NO刺激的cGMP升高具有相反的作用。一方面，cAMP通过限制cGMP外排来限制CVSMC cGMP损失。另一方面，cAMP似乎增强了PDE5介导的cGMP分解。但是，由于当MRP5表达正常时，内源性cAMP的增加似乎增强了NO / cGMP诱导的小动脉舒张，因此cAMP降低cGMP外排的作用似乎比cAMP刺激cGMP水解更为重要。

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