Increased endogenous cAMP potentiates NO/cGMP-induced arteriolar relaxation when MRP5 expression is normal, as the reduction of cGMP efflux predominates over cAMP stimulation of cGMP hydrolysis.
In vivo, cAMP potentiates NO/cGMP-induced cerebral arteriolar relaxation primarily by reducing cGMP efflux via MRP5, which predominates over its opposing effect of stimulating cGMP hydrolysis via PDE5.
Estimación del efecto: 35-50% lower maximal response in MRP5 knockdown
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.
Xu et al. (Fri,) conducted a other in Cerebral vasodilation. cAMP elevation via forskolin, MRP5 knockdown, and PDE5 inhibition vs. Control (missense ODN treated) rats was evaluated on Pial arteriolar diameter changes (SNAP-induced dilations) (35-50% lower maximal response in MRP5 knockdown). Increased endogenous cAMP potentiates NO/cGMP-induced arteriolar relaxation when MRP5 expression is normal, as the reduction of cGMP efflux predominates over cAMP stimulation of cGMP hydrolysis.