Simvastatin elicits dilation of isolated porcine retinal arterioles: role of nitric oxide and mevalonate-rho kinase pathways.
OBJECTIVE
Results in a prior study have demonstrated that systemic administration of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor simvastatin to healthy subjects reduces intraocular pressure and increases retinal blood flow. However, it remains unclear whether simvastatin can directly elicit dilation of retinal microvessels. In the current study, the direct effect and the underlying mechanism of the vasomotor action of simvastatin in retinal arterioles was studied.


METHODS
Porcine retinal arterioles ( approximately 75 mum internal diameter) were isolated, cannulated, and pressurized (55 cmH(2)O) without flow for in vitro study. Diameter changes in response to simvastatin were recorded using videomicroscopic techniques.


RESULTS
Retinal arterioles dilated dose dependently to simvastatin (1 nM to 10 muM). This vasodilation was significantly reduced after removal of the endothelium. The nitric oxide (NO) synthase inhibitor l-NAME (N(G)-nitro-l-arginine methyl ester) markedly inhibited the vasodilation, and combined administration of l-NAME with cyclooxygenase inhibitor indomethacin mimicked the effect of denudation. Blockade of soluble guanylyl cyclase by ODQ (1H-[1,2,4] oxadiazolo[4,3,-a]quinoxalin-1-one) produced a similar inhibitory effect as that by l-NAME. In contrast, the dilation was unaffected by cytochrome-P450 epoxygenase inhibitor sulfaphenazole. Intraluminal incubation of vessels with mevalonate, an immediate metabolite of HMG-CoA reductase, partially inhibited vasodilation to simvastatin. The Rho kinase inhibitor Y-27632 abolished the antagonistic effect of mevalonate.


CONCLUSIONS
Simvastatin elicits mainly an endothelium-dependent, NO-mediated dilation of retinal arterioles via activation of guanylyl cyclase; cyclooxygenase plays a relatively minor role. It appears that inhibition of the mevalonate-Rho kinase pathway in endothelial cells contributes in part to the simvastatin-induced vasodilation. A better understanding of the action of statins on retinal vasculature may help shed light on its therapeutic potential in retinal vascular disease.
Nagaoka
Taiji
T
Department of Ophthalmology, Scott and White Eye Institute, Temple, Texas 76504, USA. tnagaoka@medicine.tamhsc.edu
Hein
Travis W
TW
Yoshida
Akitoshi
A
Kuo
Lih
L
D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004730:Endothelium, Vascular / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D008798:Mevalonic Acid / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012161:Retinal Artery / Q000187:drug effects* / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology*; D013552:Swine; D014664:Vasodilation / Q000502:physiology*; D014666:Vasomotor System / Q000187:drug effects; D054460:rho-Associated Kinases
D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D009569:Nitric Oxide; D019821:Simvastatin; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D006162:Guanylate Cyclase; D008798:Mevalonic Acid; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin