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.
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.
Hao-Liang
HL
Xu
Hailemariam M
HM
Wolde
Vitaliy
V
Gavrilyuk
Verna L
VL
Baughman
Dale A
DA
Pelligrino
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