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Dilation of porcine retinal arterioles to cilostazol: roles of eNOS phosphorylation via cAMP/protein kinase A and AMP-activated protein kinase and potassium channels.

Abstract：

PURPOSE:Cilostazol, a selective inhibitor of phosphodiesterase 3, has antiplatelet aggregation and peripheral vasodilation effects. We examined the effects of cilostazol on the retinal microvascular diameter to determine its dependence on the endothelium and/or smooth muscle to reveal the signaling mechanisms involved in this vasomotor activity. METHODS:Porcine retinal arterioles were isolated, cannulated, and pressurized without flow in vitro. Video microscopic techniques recorded the diametric responses to cilostazol. RESULTS:The retinal arterioles dilated in response to cilostazol in a dose-dependent (100 pM-10 μM) manner; the dilation decreased by 60% after endothelial removal. The nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), inhibited cilostazol-induced vasodilation comparable to denudation. Inhibition of soluble guanylyl cyclase and blockade of protein kinase A (PKA) were comparable to L-NAME. Compound C, an AMP-activated protein kinase (AMPK) inhibitor, partially inhibited cilostazol-induced vasodilation, which exhibited a weaker inhibitory effect on cilostazol-induced vasodilation than blockade of PKA. The large-conductance Ca²⁺-activated K channel (BK(Ca) channel) blocker, iberiotoxin, also inhibited cilostazol-induced vasodilation. The residual vasodilation decreased further with co-administration of L-NAME and iberiotoxin. CONCLUSIONS:Cilostazol elicits endothelium-dependent and -independent dilation of the retinal arterioles mediated by NO release and BK(Ca) channel activation, respectively. Endothelial nitric oxide synthase (eNOS) phosphorylation via the cAMP/PKA and AMPK pathways and consequent activation of the soluble guanylyl cyclase/cyclic guanosine monophosphate pathway might play an important role in cilostazol-induced vasodilation of the retinal arterioles.

journal_name

Invest Ophthalmol Vis Sci

journal_title

Investigative ophthalmology & visual science

authors

Tanano I,Nagaoka T,Omae T,Ishibazawa A,Kamiya T,Ono S,Yoshida A

doi

10.1167/iovs.12-10115

subject

Has Abstract

pub_date

2013-02-19 00:00:00

pages

1443-9

issue

eissn

0146-0404

issn

1552-5783

pii

iovs.12-10115

journal_volume

pub_type

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Dilation of porcine retinal arterioles to cilostazol: roles of eNOS phosphorylation via cAMP/protein kinase A and AMP-activated protein kinase and potassium channels.