Vasorelaxing effect of BAY 41-2272 in rat basilar artery: involvement of cGMP-dependent and independent mechanisms.
Decreases in intrinsic NO cause cerebral vasospasms because of the dysregulation of cGMP formation by NO-mediated pathways. Because 5-cyclopropyl-2-{1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl}pyrimidin-4-ylamine (BAY 41-2272) is a potent soluble guanylyl cyclase (sGC) stimulator in an NO-independent manner, this study aimed to investigate the mechanisms underlying the relaxant effects of BAY 41-2272 in the rat basilar artery. BAY 41-2272 (0.0001 to 1 micromol/L) induced relaxations in a concentration-dependent manner, with pEC50 values of 8.13+/-0.03 and 7.63+/-0.05 in intact and denuded rings, respectively. The sGC inhibitor 1H-[1,2,4] oxadiazolo [4,3,-a]quinoxalin-1-one (ODQ) markedly displaced the curve for BAY 41-2272 to the right in intact or denuded rings (&10-fold). The NO synthesis inhibitor NG-nitro-L-arginine methyl ester caused a rightward shift in the curve for BAY 41-2272 (4-fold), whereas the phosphodiesterase type 5 inhibitor sildenafil enhanced BAY 41-2272-induced relaxations (3- to 4-fold). The Na+-K+-ATPase inhibitor ouabain caused 3-fold rightward shifts in the curves for BAY 41-2272. Ca2+-induced contractions in K+ depolarized rings were significantly attenuated by BAY 41-2272 in an ODQ-insensitive manner. The NO donor glyceryl trinitrate and BAY 41-2272 caused rightward shifts in the contractile responses to serotonin. Their coincubation caused a synergistic inhibition of serotonin-induced contractions. BAY 41-2272 and glyceryl trinitrate increased cGMP levels (but not cAMP) by 10-fold and 4-fold above baseline, respectively, in an ODQ-sensitive manner. cGMP levels increased by 50-fold after coincubation. BAY 41-2272 potently relaxes the rat basilar artery in a synergistic fashion with NO. Targeting the sGC with selective activators, such as BAY 41-2272, may represent a new therapy to treat cerebrovascular disease.
Teixeira
Cleber E
CE
Department of Physiology, Medical College of Georgia, Augusta, GA 30912-3000, USA. cteixeira@mail.mcg.edu
Priviero
Fernanda B M
FB
Todd
Joseph
J
Webb
R Clinton
RC
D000818:Animals; D001488:Basilar Artery / Q000187:drug effects* / Q000502:physiology*; D001933:Brain Stem / Q000187:drug effects / Q000378:metabolism; D002122:Calcium Chloride / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism / Q000502:physiology*; D004730:Endothelium, Vascular / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000378:metabolism; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D010042:Ouabain / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011687:Purines; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000494:pharmacology; D000068677:Sildenafil Citrate; D013450:Sulfones; D014661:Vasoconstriction; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology*
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D026902:Potassium Channel Blockers; D011687:Purines; D011720:Pyrazoles; D011725:Pyridines; D011810:Quinoxalines; D013450:Sulfones; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D012701:Serotonin; D010042:Ouabain; D000068677:Sildenafil Citrate; D000242:Cyclic AMP; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D002122:Calcium Chloride; D019331:NG-Nitroarginine Methyl Ester