Pioglitazone, a Peroxisome Proliferator–Activated Receptor-γ Agonist, Induces Dilation of Isolated Porcine Retinal Arterioles: Role of Nitric Oxide and Potassium Channels

Omae, Tsuneaki; Nagaoka, Taiji; Tanano, Ichiro; Yoshida, Akitoshi

doi:10.1167/iovs.10-6826

Cited by 34 publications

(30 citation statements)

References 43 publications

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“…8,9,11,21,22,35,36 The current data showed that the BK Ca channel blocker, iberiotoxin, inhibited cilostazol-induced vasodilation (Fig. 3) in the same manner as the nonselective K channel blocker, TEA, whereas this vasodilation was unaffected by glibenclamide, suggesting that the BK Ca channel, which can produce membrane hyperpolarization that results in relaxation of smooth muscle, 37 may be involved primarily in cilostazol-induced vasodilation of the retinal arterioles.…”

Section: Figurementioning

confidence: 63%

“…11 Briefly, the vessel was perfused intraluminally with a nonionic detergent, CHAPS (0.4%), for 1 to 2 minutes to remove the endothelial cells, 10,13 which we confirmed previously by immunohistochemical staining. 11 …”

Section: Endothelial Denudationmentioning

confidence: 84%

“…[8][9][10][11] Briefly, the isolated retinal arterioles (90-130 lm in situ) were cannulated with a pair of glass micropipettes and pressurized to 55 cm H 2 O (~40 mm Hg) intraluminal pressure without flow using two independent pressure reservoir systems. 12 The vasomotor activity of the isolated vessels was recorded continuously using video microscopic techniques 8 throughout the experiments.…”

Section: Isolation and Cannulation Of Microvesselsmentioning

confidence: 99%

“…To study the involvement of the K channels, we examined these pathways by treating the vessels with various K channel inhibitors: the nonselective K channel blocker, tetraethylammonium (TEA, 10 mM) 21 ; the large-conductance Ca 2þ -activated K channel (BK Ca channel) blocker, iberiotoxin (0.1 lM) 11,[22][23][24] ; and the adenosine triphosphatesensitive K channel blocker, glibenclamide (5 lM). 9 Role of PKA and AMPK To examine the direct contribution of PKA to the retinal arterioles, we studied the vasodilatory effect of the PKA agonist, forskolin (0.1 lM), 19 before and after incubation with Rp-8-Br-cAMPS, L-NAME, iberiotoxin, or endothelial denudation.…”

Section: Roles Of Potassium Channels In Cilostazol-induced Dilationmentioning

confidence: 99%

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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

Tanano¹,

Nagaoka²,

Omae³

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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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 lM) 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 cilostazolinduced vasodilation than blockade of PKA. The largeconductance Ca 2þ -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. (Invest Ophthalmol Vis

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Section: Figurementioning

confidence: 63%

Section: Endothelial Denudationmentioning

confidence: 84%

Section: Isolation and Cannulation Of Microvesselsmentioning

confidence: 99%

Section: Roles Of Potassium Channels In Cilostazol-induced Dilationmentioning

confidence: 99%

See 2 more Smart Citations

Dilation of Porcine Retinal Arterioles to Cilostazol: Roles of eNOS Phosphorylation via cAMP/Protein Kinase A and AMP-Activated Protein Kinase and Potassium Channels

Tanano¹,

Nagaoka²,

Omae³

et al. 2013

Invest. Ophthalmol. Vis. Sci.

Self Cite

View full text Add to dashboard Cite

show abstract

“…[27][28][29][30] Briefly, the isolated retinal arterioles (90-110 lm in situ) were cannulated with a pair of glass micropipettes and pressurized to 55 cm H 2 O intraluminal pressure without flow by using two independent pressure reservoir systems. 31 The internal diameter of the isolated vessels was recorded continuously by using videomicroscopic techniques throughout the experiments.…”

Section: Isolation and Cannulation Of Microvesselsmentioning

confidence: 99%

Histamine-Induced Dilation of Isolated Porcine Retinal Arterioles: Role of Endothelium-Derived Hyperpolarizing Factor

Otani

Nagaoka

Omae

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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Citation: Otani S, Nagaoka T, Omae T, et al. Histamine-induced dilation of isolated porcine retinal arterioles: role of endothelium-derived hyperpolarizing factor. Invest Ophthalmol Vis Sci. 2016;57:4791-4798. DOI:10.1167/iovs.15-19038 PURPOSE. Although endothelium-dependent nitric oxide (NO)-mediated dilation of retinal arterioles has been well described, the role of endothelium-derived hyperpolarizing factor (EDHF) in the retinal arteriolar response remains unclear. In the current study, we examined the contribution of EDHF to the retinal arteriolar dilation to the inflammatory agent histamine and investigated the signaling mechanisms underlying this vasomotor activity.METHODS. Porcine retinal arterioles were isolated, cannulated, and pressurized without flow for functional study by using video microscopic techniques. The immunohistochemical staining was performed to determine histamine receptor subtypes.RESULTS. Histamine (0.1-30 lM) produced concentration-dependent dilation of retinal arterioles in a manner sensitive to H1-and H2-receptor antagonists chlorpheniramine and famotidine, respectively. Histamine-induced vasodilation was almost abolished after endothelial removal. In the intact vessels, vasodilation to histamine was partially inhibited by the inhibitors of cyclooxygenase (indomethacin), NO synthase (N G -nitro-L-arginine methyl ester, L-NAME), or Ca 2þ -activated K þ (K Ca ) channels (apamin plus charybdotoxin). Combination of the above inhibitors abolished histamine-induced vasodilation. Residual vasodilation in the presence of indomethacin and L-NAME was further reduced by the cytochrome P450 enzyme inhibitor sulfaphenazole but not by the gap junction inhibitor carbenoxolone or the hydrogen peroxide scavenger catalase. Immunohistochemical signals for H1-and H2-receptor expression were found only in the endothelium. CONCLUSIONS.The endothelium plays an essential role in the dilation of porcine retinal arterioles to histamine via H1-and H2-receptor activation. The EDHF derived from cytochrome P450 contributed in part to this vasodilation via K Ca channel activation, in addition to the endothelial release of NO and prostanoids.

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Relaxation of human pulmonary arteries by PPARγ agonists

Kozłowska

Baranowska-Kuczko

Schlicker

et al. 2013

Naunyn-Schmiedeberg's Arch Pharmacol

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It has been suggested that activation of nuclear peroxisome proliferator-activated receptors γ (PPARγ) may represent a new strategy for the treatment of pulmonary arterial hypertension. It has been demonstrated that PPARγ activation relaxed the isolated mouse pulmonary artery. The aims of the present study were to examine whether and to which extent the two PPARγ agonists rosiglitazone and pioglitazone relax the isolated human pulmonary artery and to investigate the underlying mechanism(s). Isolated human pulmonary arteries were obtained from patients without clinical evidence of pulmonary hypertension during resection of lung carcinoma. Vasodilatory effects of PPARγ agonists were examined on endothelium-intact or endothelium-denuded vessels preconstricted with the thromboxane prostanoid receptor agonist U-46619. Rosiglitazone and pioglitazone (0.01–100 μM) caused a concentration- and/or time-dependent full relaxation of U-46619-preconstricted vessels. The rosiglitazone-induced relaxation was attenuated by the PPARγ antagonist GW9662 1 μM, endothelium denudation, the nitric oxide synthase inhibitor L-NAME 300 μM, the cyclooxygenase inhibitor indomethacin 10 μM, and the KATP channel blocker glibenclamide 10 μM. The prostacyclin IP receptor antagonist RO1138452 1 μM shifted the concentration–response curve for rosiglitazone to the right. The PPARγ agonists pioglitazone and rosiglitazone relax human pulmonary arteries. The rosiglitazone-induced vasorelaxation is partially endothelium-dependent and involves PPARγ receptors, arachidonic acid degradation products, nitric oxide, and KATP channels. Thus, the relaxant effect of PPARγ agonists in human pulmonary arteries may represent a new therapeutic target in pulmonary arterial hypertension.

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Pioglitazone, a Peroxisome Proliferator–Activated Receptor-γ Agonist, Induces Dilation of Isolated Porcine Retinal Arterioles: Role of Nitric Oxide and Potassium Channels

Cited by 34 publications

References 43 publications

Dilation of Porcine Retinal Arterioles to Cilostazol: Roles of eNOS Phosphorylation via cAMP/Protein Kinase A and AMP-Activated Protein Kinase and Potassium Channels

Dilation of Porcine Retinal Arterioles to Cilostazol: Roles of eNOS Phosphorylation via cAMP/Protein Kinase A and AMP-Activated Protein Kinase and Potassium Channels

Histamine-Induced Dilation of Isolated Porcine Retinal Arterioles: Role of Endothelium-Derived Hyperpolarizing Factor

Relaxation of human pulmonary arteries by PPARγ agonists

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