糖尿病網膜症の治療

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Effects of Habitual Cigarette Smoking on Retinal Circulation in Patients With Type 2 Diabetes

PURPOSE: To examine the long-term effects of cigarette smoking on retinal circulation in patients with type 2 diabetes. METHODS: Seventy-four patients with type 2 diabetes mellitus and minimal (no or mild nonproliferative) diabetic retinopathy (DR) were evaluated. These patients with type 2 diabetes were divided into three groups based on their smoking history: current smokers (n = 19), past smokers (n = 20), and never smoked (n = 35). The retinal circulatory parameters were measured with laser Doppler velocimetry and were compared among the groups. RESULTS: There were significant decreases in the retinal blood flow (RBF; 8.9 ± 2.9 vs. 11.6 ± 3.1 μL/min, P = 0.009) with decreased blood velocity (V; 29.6 ± 6.8 vs. 37.8 ± 9.0 mm/s, P = 0.003) but no difference in the vessel diameter (D; 112.0 ± 11.9 vs. 113.7 ± 8.6 μm, P = 0.57) in the current smokers compared with those who never smoked. There were no differences in the RBF, blood V, and vessel D in the past smokers compared with those who never smoked and current smokers. Multiple regression analysis showed that the creatinine level was correlated negatively with the RBF and that current smoking was significantly and independent correlated with decreased RBF. CONCLUSIONS: Our results indicated that the blood V and RBF in the retinal arterioles may decrease in patients with type 2 diabetes who are chronic smokers, suggesting that chronic smoking may be associated with decreased RBF, probably via lower blood V in the retinal arterioles in early-phase DR

Role of Ca2+ -dependent and Ca2+ -sensitive mechanisms in sphingosine 1-phosphate-induced constriction of isolated porcine retinal arterioles in vitro.

AuthorAlthough sphingosine 1-phosphate (S1P), a bioactive lipid derived from activated platelets, has a variety of physiologic effects on vessels, no reports have described the effect of S1P on the retinal circulation. We examined the effect and underlying mechanism of the vasomotor action of S1P on porcine retinal arterioles. The porcine retinal arterioles were isolated, cannulated, and pressurized without flow for in vitro study. S1P-induced diameter changes were recorded using videomicroscopic techniques. S1P elicited concentration-dependent (1 nM-10 μM) vasoconstriction of the retinal arterioles that was abolished by the S1P receptor 2 (S1PR2) antagonist JTE-013. S1P-induced vasoconstriction was abolished by the Rho kinase (ROCK) inhibitor H-1152 and was inhibited partly by the protein kinase C (PKC) inhibitor Gö-6983. The inhibition of phospholipase C by U73122 and L-type voltage-operated calcium channels (L-VOCCs) by nifedipine inhibited S1P-induced vasoconstriction; a combination of both inhibitors abolished S1P-induced vasoconstriction. Furthermore, inhibition of myosin light chain kinase (MLCK) by ML-9 significantly blocked S1P-induced vasoconstriction; further coadministration of ML-9 with H-1152 or Gö-6983 abolished S1P-induced vasoconstriction. The current data suggest that S1P elicits vasoconstriction of the retinal arterioles via S1PR2 in vascular smooth muscle cells and this vasoconstriction may be mediated by the Ca2+ -sensitive pathway via activation of PKC leading to activation of ROCK and the Ca2+ -dependent pathway via activation of L-VOCCs resulting in activation of MLCK

Retinal blood flow reduction after panretinal photocoagulation in Type 2 diabetes mellitus: Doppler optical coherence tomography flowmeter pilot study.

To use a Doppler optical coherence tomography (DOCT) flowmeter to investigate segmental retinal blood flow (RBF) and sum of the segmental RBFs (SRBF) changes after panretinal photocoagulation (PRP) was used to treat type 2 diabetes mellitus with severe diabetic retinopathy (DR). Data from five patients with proliferative DR (PDR) (mean age 51.9 ± 10.5 years) was analyzed. The vessel diameter (D), average velocity (V), and retinal blood flow (RBF) in veins were measured using a DOCT flowmeter before and four weeks after PRP. Segmental RBF from inferotemporal (IT), superotemporal (ST), inferonasal (IN), and superonasal (SN) veins were measured, and SRBF was defined as the sum of these measurements. All data were analyzed by Wilcoxson test. After PRP, there were statistically significant decreases in the every segmental D, V, RBF (P0.05). The DOCT flowmeter has the potential to be a clinically useful tool to noninvasively evaluate the changes in retinal circulation during PRP in patients with PDR

Thrombin-Induced Responses via Protease-Activated Receptor 1 Blocked by the Endothelium on Isolated Porcine Retinal Arterioles

<p><i><b>Purpose</b></i>: Thrombin, a serine protease, causes organ-specific responses to vessels. However, the mechanism by which thrombin affects the retinal microcirculation remains unclear. We examined the effects of thrombin on the retinal microvasculature and signaling mechanisms.</p> <p><i><b>Methods</b></i>: Porcine retinal arterioles were isolated, cannulated, and pressurized (55 cmH₂O) without flow in this in vitro study. Videomicroscopy techniques recorded changes in diameter in the retinal arterioles in response to thrombin at concentrations ranging from 0.001 to 20 mU/ml.</p> <p><i><b>Results</b></i>: Extraluminal administration of thrombin induced concentration-dependent vascular responses, that is, vasoconstriction at low concentrations less than 5 mU/ml and vasorelaxation with high concentrations greater than 5 mU/ml. However, intraluminal administration of thrombin (5 mU/m) did not constrict the retinal arterioles; in denuded vessels, intraluminal administration constricted the retinal arterioles. Thrombin-induced vasoconstriction was significantly (<i>p</i> < 0.01) suppressed by pretreatment with a protein kinase C (PKC) inhibitor and a protease-activated receptor (PAR)-1 inhibitor but not by PAR-2 and PAR-4 inhibitors or denudation. A rho kinase (ROCK) inhibitor also suppressed thrombin-induced vasoconstriction (5 mU/ml) compared with sodium nitroprusside. Endothelial denudation and pretreatment with an endothelial nitric oxide (NO) synthase inhibitor suppressed vasorelaxation caused by a high concentration of thrombin.</p> <p><i><b>Conclusions</b></i>: A low concentration of thrombin causes vasoconstriction of smooth muscles via PAR-1, PKC, and ROCK, and a high concentration of thrombin possibly causes vasorelaxation of the retinal arterioles via nitric oxide synthase activation in the endothelium. The vascular endothelium might block signaling of thrombin-induced vasoconstriction in the retinal arterioles when administered intraluminally.</p

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

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

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

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.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 μM) 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 (NG-nitro-L-arginine methyl ester, L-NAME), or Ca2+ -activated K+ (KCa) 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 KCa channel activation, in addition to the endothelial release of NO and prostanoids

Optical Coherence Tomography Angiography in Diabetic Retinopathy: A Prospective Pilot Study.

PURPOSE: To evaluate how optical coherence tomography (OCT) angiography depicts clinical fundus findings in patients with diabetic retinopathy (DR). DESIGN: Prospective study evaluating imaging technology. METHODS: Forty-seven eyes of 25 patients with DR were scanned using a high-speed 840-nm-wavelength spectral-domain optical coherence tomography instrument (RTVue XR Avanti; Optovue, Inc, Fremont, California, USA). Blood flow was detected using the split-spectrum amplitude-decorrelation angiography algorithm. Fluorescein angiography (FA) images were also obtained in all eyes and the ability to visualize microaneurysms, retinal nonperfused areas, and neovascularization was compared with that of the en face OCT angiograms. RESULTS: In 42 eyes, microaneurysms detected by FA near the macula appeared as focally dilated saccular or fusiform capillaries on OCT angiograms of the superficial and/or deep capillary plexus. Retinal nonperfused areas visualized by FA appeared as lesions with no or sparse capillaries on OCT angiograms. Area measurement of retinal nonperfusion near the macula in 7 eyes revealed a difference between the extent of nonperfused areas in superficial and deep plexuses. In 4 eyes, the vascular structures of neovascularization at the optic disc were clearly visualized on OCT angiograms. Decreases and re-increases of flow in new vessels were quantified in an eye treated with anti-vascular endothelial growth factor. CONCLUSIONS: OCT angiography can clearly visualize microaneurysms and retinal nonperfused areas and enables closer observation of each layer of the retinal capillaries. Quantitative information on new vessels can also be obtained. OCT angiography may be clinically useful to evaluate the microvascular status and therapeutic effect of treatments for DR