| Vasorelaxing effect of BAY 41-2272 in rat basilar artery: involvement of cGMP-dependent and independent mechanisms. | |
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MedLine Citation:
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PMID: 16391173 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Cleber E Teixeira; Fernanda B M Priviero; Joseph Todd; R Clinton Webb |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2006-01-03 |
Journal Detail:
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Title: Hypertension Volume: 47 ISSN: 1524-4563 ISO Abbreviation: Hypertension Publication Date: 2006 Mar |
Date Detail:
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Created Date: 2006-02-17 Completed Date: 2006-03-17 Revised Date: 2007-11-15 |
Medline Journal Info:
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Nlm Unique ID: 7906255 Medline TA: Hypertension Country: United States |
Other Details:
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Languages: eng Pagination: 596-602 Citation Subset: IM |
Affiliation:
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Department of Physiology, Medical College of Georgia, Augusta, GA 30912-3000, USA. cteixeira@mail.mcg.edu |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Basilar Artery / drug effects*, physiology* Brain Stem / drug effects, metabolism Calcium Chloride / pharmacology Cyclic AMP / metabolism Cyclic GMP / metabolism, physiology* Endothelium, Vascular / physiology Enzyme Inhibitors / pharmacology Guanylate Cyclase / metabolism Male NG-Nitroarginine Methyl Ester / pharmacology Ouabain / pharmacology Oxadiazoles / pharmacology Phosphodiesterase Inhibitors / pharmacology Piperazines / pharmacology Potassium Channel Blockers / pharmacology Purines Pyrazoles / pharmacology* Pyridines / pharmacology* Quinoxalines / pharmacology Rats Rats, Sprague-Dawley Serotonin / pharmacology Sulfones Vasoconstriction Vasoconstrictor Agents / pharmacology Vasodilation / physiology* Vasodilator Agents / pharmacology* |
| Grant Support | |
ID/Acronym/Agency:
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HL-71138/HL/NHLBI NIH HHS; HL-74167/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; 0/3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; 0/Enzyme Inhibitors; 0/Oxadiazoles; 0/Phosphodiesterase Inhibitors; 0/Piperazines; 0/Potassium Channel Blockers; 0/Purines; 0/Pyrazoles; 0/Pyridines; 0/Quinoxalines; 0/Sulfones; 0/Vasoconstrictor Agents; 0/Vasodilator Agents; 10043-52-4/Calcium Chloride; 139755-83-2/sildenafil; 50-67-9/Serotonin; 50903-99-6/NG-Nitroarginine Methyl Ester; 60-92-4/Cyclic AMP; 630-60-4/Ouabain; 7665-99-8/Cyclic GMP; EC 4.6.1.2/Guanylate Cyclase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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