title: Dorzolamide-induced relaxation of porcine retinal arterioles in vitro depends on nitric oxide but not on acidosis in vascular smooth muscle cells.
abstract: The carbonic anhydrase inhibitor dorzolamide can induce relaxation of retinal arterioles with a consequent increase in blood flow and oxygenation of the retina. It has been shown that the mechanisms underlying this relaxation are independent of extracellular acidosis and CO2. The purpose of the present study was to investigate the possible involvement of nitric oxide (NO) and intracellular acidosis in dorzolamide-induced relaxation of retinal arterioles. Porcine retinal arterioles were mounted in a wire myograph and dorzolamide induced relaxation was studied after 1) the addition of the NO synthase inhibitor l-NAME (3 × 10(-4) M) or the guanylyl cyclase inhibitor ODQ (3 × 10(-6) M), and 2) after loading the smooth muscle cells with the pH sensitive fluorophore SNARF-1-AM and studying changes in vascular tone and intracellular fluorescence after the induction of hypoxia, addition of lactate (10(-2) M), and extracellular acidification (pH = 7.0) alone and in the presence of dorzolamide (10(-3) M). Dorzolamide significantly relaxed retinal arterioles (p < 0.03), and the effect was significantly higher in the presence of perivascular tissue than in isolated vessels at the highest concentration (p < 0.01). In the presence of perivascular tissue dorzolamide-induced relaxation could be reduced by NO inhibition (p < 0.02). Dorzolamide increased intracellular acidification (p < 0.02) during extracellular acidosis, but there was no relation between relaxation and intracellular acidosis. In conclusion, dorzolamide-induced vasorelaxation depends on NO and the perivascular retinal tissue, but is independent of acidification in the extracellular and the intracellular space of retinal vascular smooth muscle cells. Other factors than NO and acidification are involved in dorzolamide-induced relaxation of retinal arterioles.
authors.affiliation: Department of Ophthalmology, Aarhus University Hospital, 8000 Aarhus C, Denmark. Electronic address: galaly@me.com.
authors.forename: A
authors.initials: A
authors.lastname: El-Galaly
authors.affiliation: Institute of Biomedicine (Physiology), Aarhus University, 8000 Aarhus C, Denmark.
authors.forename: C
authors.initials: C
authors.lastname: Aalkjaer
authors.affiliation: Department of Ophthalmology, Aarhus University Hospital, 8000 Aarhus C, Denmark.
authors.forename: S K
authors.initials: SK
authors.lastname: Kringelholt
authors.affiliation: Department of Ophthalmology, Aarhus University Hospital, 8000 Aarhus C, Denmark.
authors.forename: M W
authors.initials: MW
authors.lastname: Misfeldt
authors.affiliation: Department of Ophthalmology, Aarhus University Hospital, 8000 Aarhus C, Denmark.
authors.forename: T
authors.initials: T
authors.lastname: Bek
mesh_terms: D000138:Acidosis / Q000378:metabolism*; D000818:Animals; D001160:Arterioles / Q000187:drug effects; D001578:Benzopyrans / Q000378:metabolism; D001920:Bradykinin / Q000494:pharmacology; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005456:Fluorescent Dyes / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007773:Lactates / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D009213:Myography; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D010069:Oxadiazoles / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D012161:Retinal Artery / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology*; D013552:Swine; D013876:Thiophenes / Q000494:pharmacology*; D014664:Vasodilation / Q000502:physiology*
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D001578:Benzopyrans; D002257:Carbonic Anhydrase Inhibitors; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D007773:Lactates; D010069:Oxadiazoles; D011810:Quinoxalines; C063917:SNARF dye; D013449:Sulfonamides; D013876:Thiophenes; D009569:Nitric Oxide; C062765:dorzolamide; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester
keywords: Carbonic anhydrase inhibitors; Dorzolamide; Intracellular acidosis; Nitric oxide; Relaxation; Retina