cAMP modulates cGMP-mediated cerebral arteriolar relaxation in vivo.
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
Hao-Liang
HL
Neuroanesthesia Research Laboratory, Dept. of Anesthesiology, Univ. of Illinois, 900 S. Ashland Ave., Molecular Biology Research Bldg., Rm. 4314, M/C513, Chicago, IL 60607, USA.
Wolde
Hailemariam M
HM
Gavrilyuk
Vitaliy
V
Baughman
Verna L
VL
Pelligrino
Dale A
DA
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000818:Animals; D001160:Arterioles / Q000502:physiology; D002560:Cerebrovascular Circulation / Q000502:physiology*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism*; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D020536:Enzyme Activators / Q000494:pharmacology; D006868:Hydrolysis; D007191:Indazoles / Q000494:pharmacology; D008297:Male; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D005576:Colforsin; D000242:Cyclic AMP; D006152:Cyclic GMP; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D020536:Enzyme Activators; D007191:Indazoles; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009569:Nitric Oxide; D020030:Nitric Oxide Donors; D010727:Phosphoric Diester Hydrolases; C492375:Abcc5 protein, rat; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; C517384:Pde5a protein, rat