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

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 (PGI 2 ) 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 PGI 2 synthesis and the putative PGI 2 receptor–coupled second messenger cAMP, from ocular vasculature (retinal microvessels and choroidal perfusate), and this increase in PGI 2 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 PGI 2 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 β-phenyl-1, N 2 -etheno-8-bromoguanosine 3′:5′-cyclic monophosphate was mostly K v dependent and, in contrast to NO, largely unrelated to PGI 2 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 PGI 2 formation of endothelial origin via a mechanism mostly independent of guanylate cyclase, which involves the opening of a K Ca channel.

Eicosapentaenoic Acid (EPA) Reduces Cardiovascular Events: Relationship with the EPA/Arachidonic Acid Ratio

“…At the same time, PGI2 regulates the endothelial function via crosstalk with endothelial nitric oxide synthase (eNOS) 57) . This indicates that NO activates PGI2 synthase and increases PGI2 production 58) . It is believed that EPA-derived PGI3 is also involved in NO production.…”

Retinal expression, regulation, and functional bioactivity of prostacyclin-stimulating factor

“…Prostacyclin is a vasoactive prostaglandin produced by vascular cells that induce vasodilation in vivo at physiologic concentrations (19,20). PGI2 is also reported to increase vascular permeability (21,22), promote pericyte relaxation (20), and mediate nitric oxideinduced (NO-induced) ocular vasorelaxation (19).…”

“…PGI2 is also reported to increase vascular permeability (21,22), promote pericyte relaxation (20), and mediate nitric oxideinduced (NO-induced) ocular vasorelaxation (19). Elevated glucose concentrations stimulate PGI2 secretion in human retinal pericytes (RPCs) (23), and acutely elevated blood glucose increases retinal blood flow (1).…”

Intravenously Administered Vasodilatory Prostaglandins Increase Retinal and Choroidal Blood Flow in Rats

“…These results suggest that both NO and PGs appear to be important in the regulatory mechanisms of retinal / choroidal hemodynamics. However, the vasorelaxant effects of NO on retinal / choroidal vasculature may be explained by PGI 2 released from endothelial cells (9,10). In preliminary studies, we also found that, NO-mediated vasodilation of retinal arterioles was largely attenuated by indomethacin, an inhibitor of cyclooxygenase, in rats (11,12).…”