title: Pharmacological actions of the slow release hydrogen sulfide donor GYY4137 on phenylephrine-induced tone in isolated bovine ciliary artery.
abstract: Hydrogen sulfide (H2S), a colorless gas characterized by its pungent odor of rotten eggs has been reported to elicit relaxation effects on basal and pre-contracted non-ocular smooth muscles of several mammalian species. In the present study, we investigated the pharmacological actions of a H2S donor, GYY4137 on isolated bovine posterior ciliary artery after contraction with the adrenergic receptor agonist, phenylephrine. Furthermore, we studied the underlying mechanism of inhibitory action of GYY4137 on the posterior ciliary arteries. Isolated bovine posterior ciliary arteries were mounted in oxygenated organ baths and changes in isometric tension were measured with a Grass FT03 transducer connected to a recorder using a Grass Polyview Software. The relaxant actions of GYY4137 on phenylephrine pre-contracted arteries were observed in the absence and presence of an inhibitor of cyclo-oxygenase, flurbiprofen. Furthermore, the inhibitory effects of GYY4137 were studied in the absence or presence of inhibitors/activators of biosynthetic enzymes for H2S and nitric oxide production, as well as specific ion channel blockers. In the concentration range, 100 nM to 100 μM, GYY4137 elicited a concentration-dependant relaxation of phenylephrine-induced tone in isolated posterior ciliary arteries, with IC50 value of 13.4 ± 1.9 μM (n = 6). The cyclo-oxygenase inhibitor, flurbiprofen, significantly (p < 0.01) enhanced the relaxation induced by GYY4137 yielding IC50 value of 0.13 ± 0.08 μM (n = 6). Both the inhibitors of cystathionine β-synthase (aminooxyacetic acid, AOAA, 30 μM) and cystathionine γ-lyase (propargylglycine, PAG, 1 mM) caused significant (p < 0.05) rightward shifts in the concentration-response curve to GYY4137. Furthermore, the KATP channel antagonist, glibenclamide (100 μM) significantly (p < 0.01) attenuated the relaxant action induced by GYY4137 on bovine ciliary artery. Conversely, the activator of cystathionine β-synthase, SAM (100 μM) and an inhibitor of nitric oxide synthase, L-NAME (100 μM) had no significant effect on relaxations induced by GYY4137. We conclude that the inhibitory action of GYY4137 on isolated bovine ciliary artery is dependent upon the endogenous production of both prostanoids and H2S. Furthermore, the observed vascular smooth muscle relaxation induced by GYY4137 is mediated, at least in part, by KATP channels.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX 77004, USA.
authors.forename: Madhura Kulkarni
authors.initials: MK
authors.lastname: Chitnis
authors.forename: Ya Fatou
authors.initials: YF
authors.lastname: Njie-Mbye
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Opere
authors.forename: Mark E
authors.initials: ME
authors.lastname: Wood
authors.forename: Matthew
authors.initials: M
authors.lastname: Whiteman
authors.forename: Sunny E
authors.initials: SE
authors.lastname: Ohia
mesh_terms: D000818:Animals; D002417:Cattle; D019842:Ciliary Arteries / Q000187:drug effects / Q000502:physiology*; D003692:Delayed-Action Preparations; D006862:Hydrogen Sulfide / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology*; D009946:Organothiophosphorus Compounds / Q000494:pharmacology*; D010656:Phenylephrine / Q000494:pharmacology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D003692:Delayed-Action Preparations; C529376:GYY 4137; D009025:Morpholines; D009946:Organothiophosphorus Compounds; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; D006862:Hydrogen Sulfide
keywords: AOAA; CBS; COX; CSE; GYY4137; H(2)S; NaSH; PAG; PCA; S-adenosyl-l-methionine; SAM; aminooxyacetic acid; bovine posterior ciliary artery; cyclo-oxygenase; cystathionine β-synthase; cystathionine γ-lyase; hydrogen sulfide; l-NAME; l-nitroarginine methyl ester; posterior ciliary arteries; propargylglycine; prostanoids; sodium hydrosulfide