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Takeshi Yoshitomi - One of the best experts on this subject based on the ideXlab platform.

  • remodeled structure and reduced contractile responsiveness of ocular Ciliary Artery in spontaneously hypertensive rats
    International Journal of Ophthalmology, 2019
    Co-Authors: Yaru Dong, Claire E Gustafson, Jun Wang, Ji-zhe Cui, Takeshi Yoshitomi
    Abstract:

    AIM To investigate the alterations in both structure and contractile responsiveness of ocular Ciliary Artery (OCA) in spontaneously hypertensive rat (SHR). METHODS In this experiment, 20-week-old male SHR and Wistar Kyoto rat (WKY) were studied. The heart rate (HR), the blood pressure (BP; the systolic BP and the diastolic BP) of rats with an electronic sphygmomanometer were measured. Vascular morphometry and isometric tension measurement were used to investigate the alterations in structure and contractility of OCA. RESULTS A general narrowing of OCAs was observed in SHR compared to the control WYK. In SHR, the media of OCAs were thicker, the luminal diameters were smaller, and the media-to-lumen ratios were higher when compared with WKY (P 0.05). Indomethacin (10 µmol/L) decreased the contractions induced by norepinephrine in OCAs from WKY (P 0.05). CONCLUSION Our results demonstrate that the structure and function of OCAs are altered in hypertension. OCAs from SHR are remodeled with decreased lumen diameter and increased media-to-lumen ratio. Moreover, the contractile responsiveness of OCAs from SHR is diminished due to the disruption of vasoconstrictive effect of prostaglandins.

  • Remodeled structure and reduced contractile responsiveness of ocular Ciliary Artery in spontaneously hypertensive rats
    Press of International Journal of Ophthalmology (IJO PRESS), 2019
    Co-Authors: Yaru Dong, Claire E Gustafson, Jun Wang, Ji-zhe Cui, Takeshi Yoshitomi
    Abstract:

    AIM: To investigate the alterations in both structure and contractile responsiveness of ocular Ciliary Artery (OCA) in spontaneously hypertensive rat (SHR). METHODS: In this experiment, 20-week-old male SHR and Wistar Kyoto rat (WKY) were studied. The heart rate (HR), the blood pressure (BP; the systolic BP and the diastolic BP) of rats with an electronic sphygmomanometer were measured. Vascular morphometry and isometric tension measurement were used to investigate the alterations in structure and contractility of OCA. RESULTS: A general narrowing of OCAs was observed in SHR compared to the control WYK. In SHR, the media of OCAs were thicker, the luminal diameters were smaller, and the media-to-lumen ratios were higher when compared with WKY (P

  • effects of ripasudil hydrochloride hydrate k 115 a rho kinase inhibitor on ocular blood flow and Ciliary Artery smooth muscle contraction in rabbits
    Japanese Journal of Ophthalmology, 2017
    Co-Authors: Yusuke Ohta, Sanae Takaseki, Takeshi Yoshitomi
    Abstract:

    Ripasudil, a Rho-associated coiled-coil-containing protein kinase (ROCK) inhibitor, is a novel drug for glaucoma in Japan. ROCK inhibition not only reduces intraocular pressure (IOP) but also increases ocular blood flow. We investigated the effects of ripasudil on optic disc blood flow (ODBF) in rabbit eyes and in isolated rabbit Ciliary arteries. We measured IOP by tonometry and ODBF by laser speckle flowgraphy (LSFG) in male Dutch rabbits. A single drop (20 μL) of 0.8% ripasudil was delivered to the ocular surface after topical application of phenylephrine hydrochloride to reduce the ODBF. The effects of ripasudil on isolated rabbit Ciliary Artery smooth muscle contractions were measured in vitro with a myograph. Ripasudil inhibited the reduction of ODBF induced by phenylephrine at 30 and 120 min after instillation (P < .05). The blood flow change was not significantly correlated with the IOP change. Ripasudil induced a concentration-dependent relaxation in isolated rabbit Ciliary arteries precontracted with a high-potassium solution. This relaxation was not mediated through the endothelium-dependent activities of nitric oxide synthase, prostacyclin, or the large-conductance calcium-activated K+ channel as shown by the inability of specific inhibitors of these pathways to block the ripasudil-induced relaxation. Taken together, our results showed that ripasudil not only decreased IOP but also increased ODBF in rabbits. However, the changes in IOP were not correlated with the changes in ODBF. Ripasudil also induced a concentration-dependent relaxation of isolated rabbit Ciliary arteries through a NO-independent mechanism. Further investigation of the effect of ripasudil on ODBF is needed.

  • effects of prostaglandin f2α analogues on endothelin 1 induced impairment of rabbit ocular blood flow comparison among tafluprost travoprost and latanoprost
    Experimental Eye Research, 2010
    Co-Authors: Hiroaki Kurashima, Naruhiro Ishida, Hiroshi Watabe, Noriko Sato, Sanae Abe, Takeshi Yoshitomi
    Abstract:

    Abstract We investigated the effects of prostaglandin F 2α (PGF 2α ) analogues on the endothelin-1 (ET-1)-induced impairment of optic nerve head (ONH) blood flow and on ET-1-induced contraction in isolated Ciliary Artery segments. In male rabbits, one of four PGF 2α analogues [0.0015% tafluprost, 0.0015% 15-hydroxyl tafluprost (15-OH tafluprost), 0.005% latanoprost, or 0.004% travoprost] was topically administered at various pretreatment times before intravitreal ET-1 injection. ONH blood flow was estimated by the laser speckle method, which expresses blood velocity as a quantitative index, the squared blur rate (SBR). SBR was measured just before (baseline value) and at 30, 60, and 120 min after ET-1 injection. SBR was significantly decreased from 4.47 ± 0.20 to 3.50 ± 0.10 (78.6 ± 2.4% of baseline) at 120 min after intravitreal ET-1 injection (5 pmol/eye). The ET-1-induced decrease was almost completely prevented by tafluprost and significantly inhibited by the other three analogues. The inhibitory effect lasted longest with tafluprost, as indicated by the effective pretreatment times (tafluprost: 90, 120, or 240 min; 15-OH tafluprost: 90, but not 120 or 240 min; latanoprost and travoprost: 120, but not 240 min). In vitro, the effects of PGF 2α analogues on ET-1-induced contractions in male rabbit Ciliary arteries were evaluated using an isometric tension recording system. Tafluprost, latanoprost, travoprost, and 15-OH tafluprost concentration-dependently relaxed the 10 nM ET-1-induced Ciliary Artery contraction. Improvement of the ocular circulation may be superior with tafluprost than with the other PGF 2α analogues. The underlying mechanism may involve relaxation of ocular resistance vessels.

  • Relaxing effect and mechanism of tafluprost on isolated rabbit Ciliary arteries.
    Experimental eye research, 2008
    Co-Authors: Yaru Dong, Hitoshi Ishikawa, Hiroshi Watabe, Noriko Sato, Takeshi Yoshitomi
    Abstract:

    Abstract Our objective was to determine if tafluprost, a newly synthesized antiglaucoma drug, can relax precontracted rabbit Ciliary arteries, and if so, to elucidate the underlying mechanism. We used isometric tension recordings of smooth muscle contractions and fluorescence photometry to monitor the change of intracellular free calcium concentration ([Ca 2+ ] i ) in isolated rabbit Ciliary Artery segments. Tafluprost induced a concentration-dependent relaxation in rabbit Ciliary arteries precontracted with a high-K solution. The amplitude of relaxation induced by tafluprost was unchanged by 100 μM l -NAME, 10 μM indomethacin, denudation of vascular endothelium, 30 μM thapsigargin, or 100 μM ouabain. In Ca 2+ -free solution, 30 μM tafluprost did not decrease the amplitude of contraction induced by 1 μM histamine or the amplitude of the [Ca 2+ ] i increase induced by 10 μM histamine. The mechanism of tafluprost-induced relaxation was different from diltiazem, a voltage-dependent Ca 2+ channel blocker. However, in thapsigargin-pretreated preparations incubated in Ca 2+ -free solution, tafluprost attenuated the capacitative increase of [Ca 2+ ] i upon Ca 2+ reintroduction to the extracellular medium. Thus, we conclude that tafluprost relaxed isolated rabbit Ciliary Artery segments precontracted with a high-K solution. The relaxing mechanism was not dependent on endothelial-derived factors, and not affected by the intracellular Ca 2+ cycles or the Ca 2+ extrusion component of the extracellular Ca 2+ cycles. Relaxation of rabbit Ciliary Artery smooth muscle by tafluprost may be due, at least in part, to inhibition of capacitative Ca 2+ entry from the extracellular space.

Hitoshi Ishikawa - One of the best experts on this subject based on the ideXlab platform.

  • Relaxing effect and mechanism of tafluprost on isolated rabbit Ciliary arteries.
    Experimental eye research, 2008
    Co-Authors: Yaru Dong, Hitoshi Ishikawa, Hiroshi Watabe, Noriko Sato, Takeshi Yoshitomi
    Abstract:

    Abstract Our objective was to determine if tafluprost, a newly synthesized antiglaucoma drug, can relax precontracted rabbit Ciliary arteries, and if so, to elucidate the underlying mechanism. We used isometric tension recordings of smooth muscle contractions and fluorescence photometry to monitor the change of intracellular free calcium concentration ([Ca 2+ ] i ) in isolated rabbit Ciliary Artery segments. Tafluprost induced a concentration-dependent relaxation in rabbit Ciliary arteries precontracted with a high-K solution. The amplitude of relaxation induced by tafluprost was unchanged by 100 μM l -NAME, 10 μM indomethacin, denudation of vascular endothelium, 30 μM thapsigargin, or 100 μM ouabain. In Ca 2+ -free solution, 30 μM tafluprost did not decrease the amplitude of contraction induced by 1 μM histamine or the amplitude of the [Ca 2+ ] i increase induced by 10 μM histamine. The mechanism of tafluprost-induced relaxation was different from diltiazem, a voltage-dependent Ca 2+ channel blocker. However, in thapsigargin-pretreated preparations incubated in Ca 2+ -free solution, tafluprost attenuated the capacitative increase of [Ca 2+ ] i upon Ca 2+ reintroduction to the extracellular medium. Thus, we conclude that tafluprost relaxed isolated rabbit Ciliary Artery segments precontracted with a high-K solution. The relaxing mechanism was not dependent on endothelial-derived factors, and not affected by the intracellular Ca 2+ cycles or the Ca 2+ extrusion component of the extracellular Ca 2+ cycles. Relaxation of rabbit Ciliary Artery smooth muscle by tafluprost may be due, at least in part, to inhibition of capacitative Ca 2+ entry from the extracellular space.

  • Effect and mechanism of betaxolol and timolol on vascular relaxation in isolated rabbit Ciliary Artery.
    Japanese Journal of Ophthalmology, 2006
    Co-Authors: Hitoshi Ishikawa, Kimiya Shimizu, Toshiaki Goseki, Takeshi Yoshitomi
    Abstract:

    In order to clarify the vasodilatory mechanism of betaxolol and timolol, we studied the effects of these drugs in isolated rabbit Ciliary arteries. Rabbit Ciliary Artery specimens were mounted in a double myograph system, and betaxolol, timolol, or another agent was introduced into the organ chamber. The mechanical response of the arteries was studied using an isometric tension recording method. The intracellular free calcium concentration [Ca2+]i was also measured using fluorescence photometry. Betaxolol and timolol induced dose-dependent relaxation in the rabbit Ciliary arteries precontracted by high-K+ Krebs solution. The minimum concentrations required to cause relaxation were 10 µM of betaxolol, and 30 µM of timolol. At the maximum concentration of 1 mM, betaxolol induced almost complete relaxation of the Ciliary arteries, whereas timolol induced approximately 70% relaxation. These actions were not inhibited by pretreatment with 100 µM NG-nitro-l-arginine methylester (L-NAME), a nitric oxide synthase inhibitor, or by denudation of the vascular endothelium. However, 300 µM of betaxolol or timolol decreased the [Ca2+]i of the vascular smooth muscle, an action similar to that of diltiazem, a typical L-type voltage calcium-channel blocker. Betaxolol, a selective β1-adrenoceptor antagonist, and timolol, a nonselective β-adrenoceptor antagonist, both frequently used in the medical management of glaucoma, decrease [Ca2+]i by acting as Ca2+ channel blockers, thus causing relaxation of isolated rabbit Ciliary Artery.

  • Pharmacological vascular reactivity in isolated diabetic rabbit Ciliary Artery.
    Experimental eye research, 2006
    Co-Authors: Toshiaki Goseki, Hitoshi Ishikawa, Takeshi Yoshitomi, Shigekazu Uga, Kimiyo Mashimo, Hisaharu Nishimoto, Kimiya Shimizu
    Abstract:

    Abstract Impairment of the ocular circulation induced by diabetes mellitus has not been fully defined, but is thought to be related to hemodynamic changes in the ocular circulation. The purpose of the present study is to investigate the functional and morphological changes occurring in the Ciliary Artery wall of rabbits with alloxan-induced diabetes mellitus. A single intravenous bolus injection of alloxan (100 mg/kg) was given to each of 26 10-week-old rabbits and 16 sham-injected control rabbits. Twenty weeks later, control rabbits and diabetic rabbits were sacrificed, and their Ciliary arteries were mounted in a myograph system. The responses of these arteries to high K+ solution (K-Krebs solution), phenylephrine and carbachol were investigated using isometric tension recording. L-NAME (NG-nitro- l -arginine methyl ester; 100 μM) and indomethacin (1 μM) were also used to test the mechanism causing the carbachol induced relaxation. The arteries were also examined morphologically. The maximum tensions induced by K-Krebs solution in this tissue were not significantly different: 17.2 ± 0.8 mN (n = 16) in the control rabbits and 17.6 ± 0.8 mN (n = 23) in the diabetic rabbits (P = 0.36). Phenylephrine caused dose-dependent contraction with EC50 values of 1.3 ± 0.4 μM (n = 6) in the control and 5.1 ± 2.3 μM (n = 6) in the diabetic rabbits, but there was no significant difference between the two (P = 0.36). Carbachol induced dose-dependent relaxations in segments precontracted with K-Krebs solution. These relaxations were significantly reduced in the diabetic rabbits. The maximum relaxation induced by carbachol was 77.0 ± 2.4% (10 μM) and 66.4 ± 2.5% (100 μM) in the control and diabetic rabbits, respectively. These values were significantly different (P = 0.0076). The IC50 value for carbachol was 396.3 ± 58.4 nM (n = 16) in the control, and 443.6 ± 141.1 nM (n = 23) in the diabetic rabbit (P = 0.87). Application of a 100 μM nitric oxide synthase inhibitor, L-NAME, significantly inhibited the amplitude of relaxations evoked by carbachol (P = 0.0066). However, these relaxations were not inhibited by pretreatment with 1 μM indomethacin (P = 0.60). Histologically, the frequency of invaginations was less in the diabetic arterioles with a flattening of the lamina in the diabetic rabbits than in the controls. The cytoplasm of endothelial cells contained large vacuoles, indicating weak adhesion to the lamina. Some endothelial cells even showed vacuolar degeneration due to breakdown of the cell membranes. However, the smooth muscle cells were well preserved in the diabetic rabbit. These results suggest that the mechanism of impairment of ocular circulation induced by diabetes mellitus is mainly the reduction of NO synthase due to endothelial cell dysfunction. Furthermore, the characteristics of rabbits with alloxan-induced diabetes mellitus probably make them a useful model for investigating ocular complications induced by diabetic mellitus.

  • Vasodilatory mechanism of unoprostone isopropyl on isolated rabbit Ciliary Artery.
    Current eye research, 2004
    Co-Authors: Takeshi Yoshitomi, Hitoshi Ishikawa, Kazutsuna Yamaji, Yoshitaka Ohnishi
    Abstract:

    Purpose. To clarify the vasodilatory mechanism of unoprostone isopropyl (unoprostone), a PG F2a related compound used for treatment of glaucoma, we have investigated the effect of this drug and its metabolites on isolated rabbit Ciliary Artery in vitro. Methods. Under the dissecting microscope, Ciliary arteries were prepared from albino rabbit eyes and mounted in a myograph system. The effects of unoprostone isopropyl and other agents were investigated using isometric tension recording methods. Results. Unoprostone induced a dose-dependent relaxation in Ciliary arteries that were pre-contracted with high-K solution, 10µM histamine or 10µM PG F2a. Neither unoprostone metabolite M1 or M2 had a relaxant effect on the precontracted vessels. Relaxation was unaffected by inhibition of adenylyl cyclase with SQ 22536, guanylyl cyclase with ODQ, or maxi-K channels with iberiotoxin. Pretreatment with unoprostone did not affect histamine-induced transient contractions in Ca 2+ -free solution. However, SKF96365, a ge...

  • Pharmacological vascular reactivity in isolated hypercholesterolemic rabbit Ciliary Artery
    Experimental eye research, 2004
    Co-Authors: Hitoshi Ishikawa, Takeshi Yoshitomi, Shigekazu Uga, Kimiyo Mashimo, Masahiko Kusanagi, Kimiya Shimizu
    Abstract:

    Abstract We have investigated functional and morphological changes occurring in the wall of the hypercholesterolemic rabbit Ciliary Artery. A mutant rabbit with hypercholesterolemia and atherosclerosis was created by serial breeding. Ciliary arteries from hypercholesterolemic, age-matched control and young control rabbits' eyes were mounted in a myograph system. The effects of phenylephrine (PE), carbachol and electrical field stimulation on this Artery were investigated using isometric tension recording methods. The arteries were also examined morphologically. PE caused dose-dependent contraction in young control, age-matched control and hypercholesterolemic rabbits. The EC 50 values were 1·0 μ m (0·2–2·1, n =6), 1·4 μ m (0·4–2·4, n =6) and 4·7 μ m (1·8–7·7, n =8) in the young, age-matched controls and in the Kurosawa and Kusanagi-hypercholesterolemic (KHC) rabbits, respectively. The EC 50 values of the KHC rabbit were significantly different from those of control. Electrical field stimulation evoked contraction only in the control rabbits. On the other hand, electrical field stimulation evoked relaxation when the Ciliary Artery was pre-contracted by 10 μ m histamine in each type of rabbit equally. Carbachol also induced approximately equal dose-dependent relaxation after pre-contraction. The morphological findings of KHC rabbit Ciliary Artery revealed irregular contours on the internal elastic lamina and deformation of the shape of the medial smooth muscle cells with irregularity in size and widening of the intercellular spaces. However, the endothelial cells were well preserved. Compared with the Ciliary Artery, typical atherosclerotic changes existed in the intima, not the media, in the KHC rabbit aorta. In the hypercholesterolemic rabbit Ciliary Artery, the vasoconstricting function was reduced but vasodilatation was well preserved. Morphological findings supported this. The pharmacological vascular reactivity in the hypercholesterolemic rabbit Ciliary Artery is quite different from that of the large arteries.

Kimiya Shimizu - One of the best experts on this subject based on the ideXlab platform.

  • Effect and mechanism of betaxolol and timolol on vascular relaxation in isolated rabbit Ciliary Artery.
    Japanese Journal of Ophthalmology, 2006
    Co-Authors: Hitoshi Ishikawa, Kimiya Shimizu, Toshiaki Goseki, Takeshi Yoshitomi
    Abstract:

    In order to clarify the vasodilatory mechanism of betaxolol and timolol, we studied the effects of these drugs in isolated rabbit Ciliary arteries. Rabbit Ciliary Artery specimens were mounted in a double myograph system, and betaxolol, timolol, or another agent was introduced into the organ chamber. The mechanical response of the arteries was studied using an isometric tension recording method. The intracellular free calcium concentration [Ca2+]i was also measured using fluorescence photometry. Betaxolol and timolol induced dose-dependent relaxation in the rabbit Ciliary arteries precontracted by high-K+ Krebs solution. The minimum concentrations required to cause relaxation were 10 µM of betaxolol, and 30 µM of timolol. At the maximum concentration of 1 mM, betaxolol induced almost complete relaxation of the Ciliary arteries, whereas timolol induced approximately 70% relaxation. These actions were not inhibited by pretreatment with 100 µM NG-nitro-l-arginine methylester (L-NAME), a nitric oxide synthase inhibitor, or by denudation of the vascular endothelium. However, 300 µM of betaxolol or timolol decreased the [Ca2+]i of the vascular smooth muscle, an action similar to that of diltiazem, a typical L-type voltage calcium-channel blocker. Betaxolol, a selective β1-adrenoceptor antagonist, and timolol, a nonselective β-adrenoceptor antagonist, both frequently used in the medical management of glaucoma, decrease [Ca2+]i by acting as Ca2+ channel blockers, thus causing relaxation of isolated rabbit Ciliary Artery.

  • Pharmacological vascular reactivity in isolated diabetic rabbit Ciliary Artery.
    Experimental eye research, 2006
    Co-Authors: Toshiaki Goseki, Hitoshi Ishikawa, Takeshi Yoshitomi, Shigekazu Uga, Kimiyo Mashimo, Hisaharu Nishimoto, Kimiya Shimizu
    Abstract:

    Abstract Impairment of the ocular circulation induced by diabetes mellitus has not been fully defined, but is thought to be related to hemodynamic changes in the ocular circulation. The purpose of the present study is to investigate the functional and morphological changes occurring in the Ciliary Artery wall of rabbits with alloxan-induced diabetes mellitus. A single intravenous bolus injection of alloxan (100 mg/kg) was given to each of 26 10-week-old rabbits and 16 sham-injected control rabbits. Twenty weeks later, control rabbits and diabetic rabbits were sacrificed, and their Ciliary arteries were mounted in a myograph system. The responses of these arteries to high K+ solution (K-Krebs solution), phenylephrine and carbachol were investigated using isometric tension recording. L-NAME (NG-nitro- l -arginine methyl ester; 100 μM) and indomethacin (1 μM) were also used to test the mechanism causing the carbachol induced relaxation. The arteries were also examined morphologically. The maximum tensions induced by K-Krebs solution in this tissue were not significantly different: 17.2 ± 0.8 mN (n = 16) in the control rabbits and 17.6 ± 0.8 mN (n = 23) in the diabetic rabbits (P = 0.36). Phenylephrine caused dose-dependent contraction with EC50 values of 1.3 ± 0.4 μM (n = 6) in the control and 5.1 ± 2.3 μM (n = 6) in the diabetic rabbits, but there was no significant difference between the two (P = 0.36). Carbachol induced dose-dependent relaxations in segments precontracted with K-Krebs solution. These relaxations were significantly reduced in the diabetic rabbits. The maximum relaxation induced by carbachol was 77.0 ± 2.4% (10 μM) and 66.4 ± 2.5% (100 μM) in the control and diabetic rabbits, respectively. These values were significantly different (P = 0.0076). The IC50 value for carbachol was 396.3 ± 58.4 nM (n = 16) in the control, and 443.6 ± 141.1 nM (n = 23) in the diabetic rabbit (P = 0.87). Application of a 100 μM nitric oxide synthase inhibitor, L-NAME, significantly inhibited the amplitude of relaxations evoked by carbachol (P = 0.0066). However, these relaxations were not inhibited by pretreatment with 1 μM indomethacin (P = 0.60). Histologically, the frequency of invaginations was less in the diabetic arterioles with a flattening of the lamina in the diabetic rabbits than in the controls. The cytoplasm of endothelial cells contained large vacuoles, indicating weak adhesion to the lamina. Some endothelial cells even showed vacuolar degeneration due to breakdown of the cell membranes. However, the smooth muscle cells were well preserved in the diabetic rabbit. These results suggest that the mechanism of impairment of ocular circulation induced by diabetes mellitus is mainly the reduction of NO synthase due to endothelial cell dysfunction. Furthermore, the characteristics of rabbits with alloxan-induced diabetes mellitus probably make them a useful model for investigating ocular complications induced by diabetic mellitus.

  • Pharmacological vascular reactivity in isolated hypercholesterolemic rabbit Ciliary Artery
    Experimental eye research, 2004
    Co-Authors: Hitoshi Ishikawa, Takeshi Yoshitomi, Shigekazu Uga, Kimiyo Mashimo, Masahiko Kusanagi, Kimiya Shimizu
    Abstract:

    Abstract We have investigated functional and morphological changes occurring in the wall of the hypercholesterolemic rabbit Ciliary Artery. A mutant rabbit with hypercholesterolemia and atherosclerosis was created by serial breeding. Ciliary arteries from hypercholesterolemic, age-matched control and young control rabbits' eyes were mounted in a myograph system. The effects of phenylephrine (PE), carbachol and electrical field stimulation on this Artery were investigated using isometric tension recording methods. The arteries were also examined morphologically. PE caused dose-dependent contraction in young control, age-matched control and hypercholesterolemic rabbits. The EC 50 values were 1·0 μ m (0·2–2·1, n =6), 1·4 μ m (0·4–2·4, n =6) and 4·7 μ m (1·8–7·7, n =8) in the young, age-matched controls and in the Kurosawa and Kusanagi-hypercholesterolemic (KHC) rabbits, respectively. The EC 50 values of the KHC rabbit were significantly different from those of control. Electrical field stimulation evoked contraction only in the control rabbits. On the other hand, electrical field stimulation evoked relaxation when the Ciliary Artery was pre-contracted by 10 μ m histamine in each type of rabbit equally. Carbachol also induced approximately equal dose-dependent relaxation after pre-contraction. The morphological findings of KHC rabbit Ciliary Artery revealed irregular contours on the internal elastic lamina and deformation of the shape of the medial smooth muscle cells with irregularity in size and widening of the intercellular spaces. However, the endothelial cells were well preserved. Compared with the Ciliary Artery, typical atherosclerotic changes existed in the intima, not the media, in the KHC rabbit aorta. In the hypercholesterolemic rabbit Ciliary Artery, the vasoconstricting function was reduced but vasodilatation was well preserved. Morphological findings supported this. The pharmacological vascular reactivity in the hypercholesterolemic rabbit Ciliary Artery is quite different from that of the large arteries.

  • pharmacological effects of latanoprost prostaglandin e2 and f2α on isolated rabbit Ciliary Artery
    Graefes Archive for Clinical and Experimental Ophthalmology, 2002
    Co-Authors: Hitoshi Ishikawa, Takeshi Yoshitomi, Kimiyo Mashimo, Motoi Nakanishi, Kimiya Shimizu
    Abstract:

    Background: Latanoprost is a prostaglandin (PG)F2 α analogue widely recognized in the treatment of glaucoma. To investigate the action of this drug on the ocular circulation, we have studied its effects on isolated rabbit Ciliary Artery. The data obtained on this drug are compared with the data from PGE2 and PGF2 α. Methods: Under the microscope, Ciliary Artery specimens were prepared from rabbit eyes and mounted in a myograph system. The effects of latanoprost, PGE2, and PGF2 α on the isolated rabbit Ciliary Artery were investigated in vitro using isometric tension recording methods. Results: Exogenously applied PGF2 α, but not latanoprost, evoked contraction in the rabbit Ciliary Artery. After precontraction with excess-[K]0 solution, latanoprost evoked relaxation dose-dependently. Latanoprost at a concentration of 100µM induced maximum relaxation, which was not blocked by 10 µM L-nitro-L-arginine methylester (L-NAME), 1 µM 8-37 calcitonin gene-related peptide (CGRP) or 10 µM indomethacin. Moreover, latanoprost induced relaxation even in preparations without endothelium. The maximum relaxation obtained with PGE2 was somewhat less than 50% of that with latanoprost. Conclusions: These results indicate that latanoprost and PGE2 relaxed rabbit Ciliary Artery to different degrees. The relaxation provoked by latanoprost was not dependent on endothelium and was not caused by intrinsic PG, CGRP or nitric oxide. The mechanism of this relaxation is not yet clear.

  • Effects of isopropyl unoprostone on rabbit Ciliary Artery.
    Japanese journal of ophthalmology, 2000
    Co-Authors: Eri Hayashi, Hitoshi Ishikawa, Takeshi Yoshitomi, Ryoko Hayashi, Kimiya Shimizu
    Abstract:

    Abstract Purpose: Isopropyl unoprostone (unoprostone), a prostaglandin F2α (PG F2α)-related compound, is widely used for treatment of glaucoma in Japan and is reported to have effects on ocular circulation. To investigate the action of this drug, we have studied the effect of unoprostone on the isolated rabbit Ciliary Artery. Methods: Under microscopic observation, Ciliary arteries were prepared from rabbit eyes and mounted in a myograph system. The effects of unoprostone on the isolated rabbit Ciliary Artery were investigated in vitro using isometric tension recordings. Results: Exogenously applied PG F2α but not unoprostone evoked contraction in the rabbit Ciliary Artery. After precontraction with excess-[K]o solution, unoprostone evoked dose-dependent relaxation. The relaxation was not blocked by 10 μM/L NG-nitro-L-arginine methylester (L-NAME), 1 μM/L 8-37 calcitonin gene-related peptide (8-37 CGRP) or 10 μM/L indomethacin. Moreover, unoprostone could induce relaxation even in preparations without endothelium. The relaxation induced by diltiazem was greater in muscle precontracted in excess-[K]o solution than that precontracted by 10 μM/L histamine. On the other hand, unoprostone induced a similar amplitude of relaxation in muscles precontracted by either drug. Conclusions: These results indicate that unoprostone acts directly to relax rabbit Ciliary Artery. The relaxation was not dependent on the endothelium and was not caused by intrinsic prostoglandins CGRP, or nitric oxide. Moreover, the relaxation was different from that caused by a Ca2+ antagonist. The mechanism for this relaxation is not yet determined.

Ivan O Haefliger - One of the best experts on this subject based on the ideXlab platform.

  • Effect of palmitoleic acid on bradykinin-induced endothelium-dependent relaxation in isolated pig Ciliary Artery.
    Klinische Monatsblatter Fur Augenheilkunde, 2002
    Co-Authors: Thomas Morf, Jean-louis Bény, Josef Flammer, Ivan O Haefliger
    Abstract:

    BACKGROUND: Endothelial-dependent relaxation has been reported to be impaired in some normal tension glaucoma patients. The present study investigates whether the gap junction uncoupling agent palmitoleic acid (PA) affects bradykinin-induced endothelium-dependent relaxation in isolated pig Ciliary Artery. MATERIAL AND METHODS: In a myograph system (isometric force measurement), vessels precontracted with the thromboxane A2 agonist U 46619 ( approximately 0.1 micrometer) were relaxed by increasing concentrations (cumulative) of bradykinin (0.003 - 3 micrometer). Experiments were repeated in the presence of 100 micrometer L-NAME (inhibitor of nitric oxide formation) and/or 100 micrometer PA. Some experiments were conducted in vessels with a non-functional endothelium (intentionally and mechanically damaged). All experiments were conducted in the presence of 10 microM indomethacin (cyclooxygenase inhibitor). RESULTS: In a concentration-dependent manner, bradykinin evoked a relaxation (101 +/- 2 %) that was abolished in vessels with a non-functional endothelium (maximal relaxation: 7 +/- 1 %, p < 0.001). In the presence of L-NAME, relaxations induced by bradykinin were almost completely inhibited (maximal relaxation: 25 +/- 5 %, p < 0.001). Relaxations evoked by bradykinin were not significantly affected by PA (either in the presence or in the absence of L-NAME). CONCLUSIONS: The bradykinin-induced relaxation, known to be associated in porcine Ciliary arteries with an electrical coupling between endothelial and smooth muscle cells, appears to be unaffected by the gap junction uncoupling agent palmitoleic acid. Further investigations are needed to understand the physiology of the endothelium-dependent ocular blood flow modulation that is considered to be dysregulated in some glaucoma patients.

  • Effect of Ox-LDL on endothelium-dependent response in pig Ciliary Artery: prevention by an ET(A) antagonist.
    Investigative ophthalmology & visual science, 1999
    Co-Authors: Peili Zhu, Josef Flammer, Thomas F Luscher, Eike S. Dettmann, T. J. Resink, Ivan O Haefliger
    Abstract:

    PURPOSE To investigate whether oxidized low-density lipoprotein (Ox-LDL) affects endothelium-dependent responses in isolated porcine Ciliary arteries. METHODS In a myograph system for isometric force measurements, quiescent vessels were incubated with 50 microg/ml, 100 microg/ml, or 200 microg/ml Ox-LDL; 100 microg/ml native LDL (n-LDL); 1 microM of the ET(A)- endothelin receptor antagonist BQ 123; 100 microg/ml Ox-LDL coadministered with 1 microM BQ 123; or 100 microg/ml Ox-LDL coadministered with 50 microM of the protein synthesis inhibitor cycloheximide. Vessels with nonfunctional endothelium (intentionally and mechanically damaged) were also exposed to 100 microg/ml Ox-LDL. Two hours later, vessels were washed, precontracted with the thromboxane A2 analog U 46619 (approximately 0.1 microM), and exposed to bradykinin (0.1 nM to 3 microM), an endothelium-dependent relaxing agent. RESULTS In quiescent vessels, Ox-LDL evoked delayed contractions. In contrast, no contractions were observed after exposure to n-LDL, BQ 123, Ox-LDL with BQ 123, or Ox-LDL with cycloheximide. In vessels with nonfunctional endothelium, Ox-LDL did not evoke contraction. Bradykinin-induced relaxations were inhibited in a dose-dependent manner by Ox-LDL, but not by n-LDL, BQ 123 alone, Ox-LDL with BQ 123, or Ox-LDL with cycloheximide. CONCLUSIONS In porcine Ciliary arteries, Ox-LDL affects endothelium-dependent responses through the activation of ET(A)- endothelin receptors. As Ox-LDL can accumulate in atherosclerotic plaques, such a mechanism might be involved in the occlusion of the ophthalmic circulation observed in patients with hypercholesterolemia and atherosclerosis.

  • relaxation by bradykinin in porcine Ciliary Artery role of nitric oxide and k channels
    Investigative Ophthalmology & Visual Science, 1997
    Co-Authors: Peili Zhu, Jean-louis Bény, Josef Flammer, Thomas F Luscher, Ivan O Haefliger
    Abstract:

    PURPOSE To assess the effects of K(+)-channel blockers on bradykinin-induced relaxations in porcine Ciliary Artery. METHODS Vascular isometric forces were measured with a myograph system. Ciliary vascular rings were precontracted with thromboxane A2 analog (U 46619, 10(-7) M) to assess dose-dependent (10(-10)-3 x 10(-6) M) bradykinin-induced relaxation after addition of one of the following: the nitric oxide (NO) synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME, 10(-4) M) or inactive enantiomer (D-NAME, 10(-4) M); the nonspecific K(+)-channel blocker tetra-ethylammonium (TEA, 10(-2) M); or the ATP-sensitive K(+)-channel blocker glibenclamide (10(-5) M). The effect of TEA on relaxations to the NO donor, sodium nitroprusside (SNP, 10(-10)-10(-4) M) was investigated. The membrane potential of vascular smooth muscle cells (VSMC) was recorded after exposure to bradykinin (2.5 x 10(-7) M). RESULTS Endothelium-dependent relaxations to bradykinin (maximal [max], 99% +/- 3%) were strongly inhibited by L-NAME (max, 39% +/- 4%, P < 0.01) and partially by TEA (max, 62% +/- 3%, P < 0.01) or glibenclamide (max, 77% +/- 4%, P < 0.01). Administration of glibenclamide plus L-NAME further suppressed bradykinin-induced relaxation (max, 23% +/- 6%; P < 0.01), whereas TEA and L-NAME (max, 6% +/- 2%; P < 0.01) abolished the relaxation. SNP relaxations were unaffected by TEA. Bradykinin had no effect on the membrane potential of VSMC. CONCLUSIONS In porcine Ciliary Artery, the endothelium-dependent relaxations to bradykinin are primarily mediated by NO and involve K(+)-channels. As only relaxations to bradykinin, but not those mediated by SNP, were inhibited by TEA, this implies that K(+)-channel blockers most likely affect the bradykinin-evoked NO production or release by the endothelium.

  • Lack of bradykinin-induced smooth muscle cell hyperpolarization despite heterocellular dye coupling and endothelial cell hyperpolarization in porcine Ciliary Artery.
    Journal of vascular research, 1997
    Co-Authors: Jean-louis Bény, Peili Zhu, Ivan O Haefliger
    Abstract:

    In porcine coronary Artery, bradykinin-induced endothelium-dependent vasodilatations are associated with simultaneous endothelium as well as endothelium-dependent smooth muscle cell (SMC) hyperpolarizations. In contrast, in porcine Ciliary Artery bradykinin evokes endothelium-dependent relaxations, but no change in SMC membrane potential. This study addresses the question of whether the lack of bradykinin-induced SMC hyperpolarization is also associated with an absence of endothelial hyperpolarization in porcine Ciliary Artery. With a microelectrode to impale cells in arterial strips, a 12-mV transient bradykinin-induced hyperpolarization was measured in endothelial cells. Bradykinin evoked no SMC hyperpolarization deep in the media. Only occasionally, a slight 4-mV hyperpolarization could be recorded in some SMC next to the endothelium. The endothelial intracellular injection (through the recording electrode) of the fluorescent tracers, lucifer yellow or ethidium bromide, showed the existence of a heterocellular dye coupling between endothelial cells and SMC. These observations in porcine Ciliary Artery demonstrate that the lack of bradykinin-induced endothelium-dependent SMC hyperpolarization is not due to an absence of endothelial cell hyperpolarization, but most likely to an insufficient electrotonic propagation space constant from endothelial cells to SMC, despite the presence of a dye coupling between these cells.

Mark A. Yorek - One of the best experts on this subject based on the ideXlab platform.

  • early loss of innervation of cornea epithelium in streptozotocin induced type 1 diabetic rats improvement with ilepatril treatment
    Investigative Ophthalmology & Visual Science, 2012
    Co-Authors: Eric P Davidson, Lawrence J Coppey, Mark A. Yorek
    Abstract:

    PURPOSE. Cornea confocal microscopy is emerging as a clinical tool to evaluate the development and progression of diabetic neuropathy. The purpose of these studies was to characterize the early changes in corneal sensitivity and innervation in a rat model of type 1 diabetes in relation to standard peripheral neuropathy endpoints and to assess the effect of Ilepatril, a vasopeptidase inhibitor which blocks angiotensin converting enzyme and neutral endopeptidase, on these endpoints. METHODS. Streptozotocin-diabetic rats 8 weeks duration were treated with or without Ilepatril for the last 6 weeks of the experimental period. Afterwards, standard diabetic neuropathy endpoints, subbasal corneal nerves and innervation of the epithelium, corneal sensitivity using a Cochet-Bonnet esthesiometer, and vascular reactivity of the posterior Ciliary Artery were examined. RESULTS. Diabetes caused a decrease in nerve conduction velocity, thermal hypoalgesia, and a reduction in intraepidermal nerve fiber profiles. In the cornea there was a decrease in corneal nerve fibers innervating the epithelium and corneal sensitivity, but subbasal corneal nerve fibers was not changed. Vascular relaxation in response to acetylcholine was decreased in the posterior Ciliary Artery. These defects were partially to completely prevented by Ilepatril treatment. CONCLUSIONS. These studies suggest that in type 1 diabetic rats decreased innervation of the cornea epithelium occurs early in diabetes and prior to a detectable decrease in subbasal corneal nerves and that these and other diabetic neuropathy-related defects can be partially to completely prevented by a vasopeptidase inhibitor. (Invest Ophthalmol Vis Sci. 2012; 53:8067‐8074) DOI:10.1167/iovs.12-10826

  • changes in corneal innervation and sensitivity and acetylcholine mediated vascular relaxation of the posterior Ciliary Artery in a type 2 diabetic rat
    Investigative Ophthalmology & Visual Science, 2012
    Co-Authors: Eric P Davidson, Mark A. Yorek, Lawrence J Coppey, Amey Holmes
    Abstract:

    Diabetic neuropathy is a common complication of diabetes with no known treatment.1 Translation of effective treatments of diabetic animal models has failed in clinical trials.2 This is due in part to endpoints in animal studies that were insensitive when applied in human studies.2 To address this issue, corneal confocal microscopy has emerged as a tool to measure small nerve fiber damage as a surrogate marker for the early detection of diabetic neuropathy.3 Application of this technology has been successful in human studies, but to date few animal studies have been performed.3–8 To address this issue, we have compared the effect of diabetes on standard nerve functional endpoints in a rat model of type 2 diabetes with changes in corneal innervation and sensitivity and vascular reactivity in the posterior Ciliary Artery. The goal of these studies was to determine whether type 2 diabetes causes changes in corneal innervation and sensitivity and to determine how these changes compare with standard peripheral nerve endpoints. These studies are important for verifying corneal confocal microscopy as a marker of diabetic neuropathy in animal models of diabetes that can be used in preclinical studies for evaluating and developing potential treatments. For these studies we used high-fat-fed/low-dose streptozotocin-treated rats, an animal model for type 2 diabetes.9,10 Rats fed a high-fat diet do not become hyperglycemic, presumably because of compensatory hyperinsulinemia.9 However, treating high-fat-fed rats with a low dose of streptozotocin damages insulin-producing β-cells so that hyperglycemia develops even though insulin levels are similar or even higher than in chow-fed normoglycemic rats.9 The diabetes in these rats is analogous to the development of human type 2 diabetes, when the decline in hyperinsulinemia is not able to compensate for insulin resistance and hyperglycemia occurs.9 In our hands this rat models late-stage type 2 diabetes.11