A Major Role for Prostacyclin in Nitric Oxide–Induced Ocular Vasorelaxation in the Piglet

From the Centre de Recherche de l'Hôpital Sainte-Justine, Department of Pediatrics and Pharmacology, Université de Montréal (P.H., D.A., X.H., I.L., K.G.P., P.A., S.C.), and the Department of Pharmacology and Therapeutics, McGill University (D.R.V., S.C.), Montréal, Québec, Canada.

Correspondence to Sylvain Chemtob, MD, PhD, Research Center, Hôpital Sainte-Justine, Departments of Pediatrics, Ophthalmology, and Pharmacology, 3175 Côte Sainte-Catherine, Montréal, Québec, Canada H3T 1C5. E-mail chemtobs{at}ere.umontreal.ca

Abstract—We studied the mechanisms of retinal and choroidal vasorelaxation elicited by nitric oxide (NO) using piglet eyes. The NO donors sodium nitroprusside (SNP) and diethylamine-NONOate caused comparable concentration–dependent relaxation that was partially (40%) attenuated by the guanylate cyclase inhibitors methylene blue and LY83583 and reduced to a lesser extent (25%) by the inhibitor of cGMP–dependent kinase, KT 5823. In contrast, NO-induced dilatation (by NO donors and endogenous NO after stimulation with bradykinin) was substantially (70%) diminished by the K_Ca channel blockers tetraethylammonium (TEA), charybdotoxin, and iberiotoxin; by the cyclooxygenase inhibitors indomethacin and ibuprofen; by the prostaglandin I (PGI₂) synthase inhibitor trans-2-phenyl cyclopropylamine (TPC); and by the removal of endothelium; whereas relaxation of endothelium-denuded vasculature to SNP was unaltered by indomethacin, TPC, and charybdotoxin but was nearly nullified by methylene blue and the K_v channel blocker 4-aminopyridine. NO donors significantly increased PGI₂ synthesis and the putative PGI₂ receptor–coupled second messenger cAMP, from ocular vasculature (retinal microvessels and choroidal perfusate), and this increase in PGI₂ formation was markedly reduced by TPC, tetraethylammonium, charybdotoxin, and/or the removal of endothelium, but it was only slightly reduced by methylene blue and LY83583. Also, SNP and K_Ca channel openers NS1619 and NS004 caused an increase in PGI₂ synthesis in cultured endothelial cells, which was virtually abolished by K_Ca blockers. Finally, vasorelaxation to a cGMP analogue, 8-bromo cGMP, and protein kinase G stimulant ß-phenyl-1,N²-etheno-8-bromoguanosine 3':5'-cyclic monophosphate was mostly K_v dependent and, in contrast to NO, largely unrelated to PGI₂ formation. In conclusion, data indicate that NO-induced ocular vasorelaxation is partly mediated by cGMP through its action on smooth muscle, and more importantly, by stimulating PGI₂ formation of endothelial origin via a mechanism mostly independent of guanylate cyclase, which involves the opening of a K_Ca channel.

Key Words: nitric oxide • sodium nitroprusside • prostacyclin • cGMP • K⁺ channel

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