Inhibition by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) of responses to nitric oxide-donors in rat pulmonary artery: influence of the mechanism of nitric oxide generation
| Autor: | Steven A. Fiore, Kerry L. Homer, Janet C. Wanstall |
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| Rok vydání: | 1999 |
| Předmět: |
Male
Pharmaceutical Science Pharmacology In Vitro Techniques Pulmonary Artery Nitric Oxide Nitric oxide chemistry.chemical_compound Quinoxalines medicine Extracellular Animals Nitric Oxide Donors Enzyme Inhibitors Rats Wistar Phenylephrine Oxadiazoles biology Dose-Response Relationship Drug Linsidomine Nitro Compounds Rats Vasodilation Dose–response relationship Hydrazines chemistry Mechanism of action Biochemistry Enzyme inhibitor Guanylate Cyclase Molsidomine biology.protein Nitrogen Oxides Spermine medicine.symptom Isosorbide dinitrate medicine.drug |
| Zdroj: | The Journal of pharmacy and pharmacology. 51(2) |
| ISSN: | 0022-3573 |
| Popis: | ODQ, (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, an inhibitor of soluble guanylate cyclase) inhibits vasorelaxant responses to nitric oxide (NO)-donor drugs, but the extent of the inhibition varies depending on the NO donor studied. The purpose of this study was to test the hypothesis that these variations in the effects of ODQ reflect differences in the mechanisms whereby each NO donor generates NO. On pulmonary artery preparations pre-contracted submaximally with phenylephrine, ODQ (3 μM) almost abolished the relaxant responses to glyceryl trinitrate, isosorbide dinitrate and nitroprusside; each of these drugs requires activation in the tissue (by enzymes or reducing agents) to generate NO. In contrast, ODQ (3 μM) caused a parallel shift in the concentration-relaxation curves to linsidomine (SIN-1), FK409, MAHMA NONOate and spermine NONOate (1.63 to 2.54 log units) with no depression in maximum response; each of these NO donors generates NO in the physiological bathing solution without requiring tissue activation. For the four drugs in this group, the effects of 10 μM ODQ were not significantly greater than the effects of 3 μM ODQ; thus there was an ODQ-resistant component to the response suggesting that part of the response involved a mechanism that was independent of soluble guanylate cyclase. NO donors that require tissue activation probably generate NO within the smooth-muscle cell, whereas those that do not require tissue activation generate NO outside the cell. Hence it is concluded that the site of NO generation (intra- or extracellular) might determine whether or not there is an ODQ-resistant component in the relaxation response. |
| Databáze: | OpenAIRE |
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