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Akiyoshi Namiki - One of the best experts on this subject based on the ideXlab platform.
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role of Prostaglandin Receptor subtype ep1 in Prostaglandin e2 induced nociceptive transmission in the rat spinal dorsal horn
Brain Research, 2004Co-Authors: Yoshito Nakayama, Keiichi Omote, Tomoyuki Kawamata, Akiyoshi NamikiAbstract:Abstract It has been indicated that Prostaglandin E2 (PGE2) and the Receptor for PGE2 (EP Receptor) are key factors contributing to the facilitated generation of nociception. This study was designed to investigate the roles of PGE2 and EP1 Receptors in the spinal cord in the nociceptive transmission, using behavioral and intracellular calcium ion concentration ([Ca2+]i) assays and in situ hybridization. Experiments were conducted on Sprague–Dawley rats. In behavioral assays, withdrawal thresholds to mechanical stimuli were evaluated using von Frey filament. The effect of an intrathecally administered selective EP1 antagonist, 6-[(2S,3S)-3-(4-chloro-2-methylphenylsulfonylaminomethyl)-bicyclo[2.2.2]octan-2-yl]-5Z-hexenoic acid (ONO-8711), on the intrathecal PGE2-induced hyperalgesia was examined. In [Ca2+]i assays, we measured [Ca2+]i in the dorsal horn of spinal cord slices and examined the effects of PGE2 and ONO-8711 perfusion on the [Ca2+]i changes. In situ hybridization using EP1 digoxigenin probe was performed on the slice sections of the lumbar spinal cord and bilateral L4 and L5 dorsal root ganglions (DRGs). Mechanical hyperalgesia was observed after intrathecal PGE2 administration. Intrathecal administration of ONO-8711 attenuated the PGE2-induced mechanical hyperalgesia in a dose- and time-dependent manner. Perfusion of ONO-8711 markedly suppressed PGE2-induced [Ca2+]i increment in laminae II–VI in dorsal horn of the spinal cord slice. Moreover, in situ hybridization revealed EP1 hybridization signals in the DRG neurons, but not in the spinal cord. The results of this study suggested that spinal PGE2 activates the EP1 Receptors existing on the central terminals of primary afferents, subsequently increasing in [Ca2+]i in the spinal dorsal horn, which are involved in the mechanisms of spinal PGE2-induced nociceptive transmission.
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role of Prostaglandin Receptor ep1 in the spinal dorsal horn in carrageenan induced inflammatory pain
Anesthesiology, 2002Co-Authors: Yoshito Nakayama, Keiichi Omote, Akiyoshi NamikiAbstract:Background: Prostaglandin E 2 (PGE 2 ) and the Receptor for PGE 2 (EP Receptor) are key factors contributing to the generation of hyperalgesia caused by inflammation. The current study was designed to investigate the roles of PGE 2 and EP 1 Receptors in the spinal cord in the development and maintenance of inflammatory pain, using behavioral, microdialysis, and intracellular calcium ion concentration ([Ca 2+ ] i ) assays. Methods: Inflammation was induced by an injection of carrageenan into the plantar surface of the rat hind paw. The effects of inflammation were evaluated at the time points of 3 h (early phase) and 15 h (late phase) after carrageenan injection. In behavioral assays, withdrawal thresholds to mechanical stimuli were evaluated. The effect of an intrathecally administered selective EP 1 antagonist, ONO-8711, on the carrageenan-induced hyperalgesia was examined. Using a spinal microdialysis method, PGE 2 concentration in the spinal dorsal horn was measured. In [Ca 2+ ] i assays, we measured [Ca 2+ ] i in the spinal dorsal horn in transverse spinal slices and examined the effects of pretreatment with ONO-8711. Sensitivities of the changes in [Ca 2+ ] i to PGE 2 perfusion were also assessed. Results: Mechanical hyperalgesia and paw edema were observed in both the early and late phases. The hyperalgesia was inhibited by intrathecal ONO-8711 in the late, but not early, phase. The concentration of PGE 2 in the spinal dorsal horn increased in the late phase. The [Ca 2+ ] i in the dorsal horn increased on the ipsilateral side to the inflammation in the late, but not early phase. This increase was suppressed by the pretreatment with ONO-8711. Magnitude of the increase in [Ca 2+ ] i on the ipsilateral side in response to PGE 2 perfusion was greater in the late phase than in the early phase. Conclusion: The results suggested that activation of spinal EP 1 Receptors was crucial in the carrageenan-induced mechanical hyperalgesia in the late phase. It seems that some of the mechanisms underlying inflammation-induced plastic changes are mediated by time-dependent increase in PGE 2 concentration, activation of EP 1 Receptors, and increase in [Ca 2+ ] i in the spinal dorsal horn.
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The Effects of Peripheral Administration of a Novel Selective Antagonist for Prostaglandin E Receptor Subtype EP1, ONO-8711, in a Rat Model of Postoperative Pain
Anesthesia and analgesia, 2001Co-Authors: Keiichi Omote, Yoshito Nakayama, Tomoyuki Kawamata, Mikito Kawamata, Koji Hazama, Akiyoshi NamikiAbstract:UNLABELLED Mechanically evoked pain, also known as incident pain, induced by coughing or deep breathing after surgery leads to potentially devastating consequences. It is generally thought that the Prostaglandin Receptor- (especially, the Receptor for Prostaglandin E(2), EP Receptor) mediated sensitization of sensory nerve fibers is a key contributor to the generation of hyperalgesia. We examined whether a peripherally administered novel selective EP(1) antagonist, ONO-8711, would be a potential analgesic for incision-induced mechanical hyperalgesia. We used a rat model of postoperative pain introduced by Brennan et al. (1). Withdrawal thresholds to punctate stimulation and response frequencies to nonpunctate mechanical stimulation were determined by using von Frey filaments applied adjacent to the wound and directly to the incision site of the hind paw, respectively. Mechanical hyperalgesia to punctate and nonpunctate stimuli was observed 2 and 24 h after the incision. ONO-8711 (2, 10, or 50 microg) or saline was administered subcutaneously into the hind paw on the ipsilateral side to the incision. ONO-8711 significantly (P < 0.01) increased the withdrawal thresholds to punctate mechanical stimulation and significantly (P < 0.01) decreased the response frequencies to nonpunctate mechanical stimulation in a dose- and time-dependent manner 2 and 24 h after the incision. We conclude that EP(1) Receptor-mediated sensitization of sensory nerve fibers may contribute to the generation of mechanical hyperalgesia produced by incisional surgery, and that the EP(1) Receptor antagonist ONO-8711 may be an option for treatment of postoperative pain, especially incident pain. IMPLICATIONS The peripheral administration of an antagonist for EP(1) Receptor that is a subtype of Prostaglandin E Receptors can inhibit the mechanical hyperalgesia induced by a surgical incision.
Yoshito Nakayama - One of the best experts on this subject based on the ideXlab platform.
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role of Prostaglandin Receptor subtype ep1 in Prostaglandin e2 induced nociceptive transmission in the rat spinal dorsal horn
Brain Research, 2004Co-Authors: Yoshito Nakayama, Keiichi Omote, Tomoyuki Kawamata, Akiyoshi NamikiAbstract:Abstract It has been indicated that Prostaglandin E2 (PGE2) and the Receptor for PGE2 (EP Receptor) are key factors contributing to the facilitated generation of nociception. This study was designed to investigate the roles of PGE2 and EP1 Receptors in the spinal cord in the nociceptive transmission, using behavioral and intracellular calcium ion concentration ([Ca2+]i) assays and in situ hybridization. Experiments were conducted on Sprague–Dawley rats. In behavioral assays, withdrawal thresholds to mechanical stimuli were evaluated using von Frey filament. The effect of an intrathecally administered selective EP1 antagonist, 6-[(2S,3S)-3-(4-chloro-2-methylphenylsulfonylaminomethyl)-bicyclo[2.2.2]octan-2-yl]-5Z-hexenoic acid (ONO-8711), on the intrathecal PGE2-induced hyperalgesia was examined. In [Ca2+]i assays, we measured [Ca2+]i in the dorsal horn of spinal cord slices and examined the effects of PGE2 and ONO-8711 perfusion on the [Ca2+]i changes. In situ hybridization using EP1 digoxigenin probe was performed on the slice sections of the lumbar spinal cord and bilateral L4 and L5 dorsal root ganglions (DRGs). Mechanical hyperalgesia was observed after intrathecal PGE2 administration. Intrathecal administration of ONO-8711 attenuated the PGE2-induced mechanical hyperalgesia in a dose- and time-dependent manner. Perfusion of ONO-8711 markedly suppressed PGE2-induced [Ca2+]i increment in laminae II–VI in dorsal horn of the spinal cord slice. Moreover, in situ hybridization revealed EP1 hybridization signals in the DRG neurons, but not in the spinal cord. The results of this study suggested that spinal PGE2 activates the EP1 Receptors existing on the central terminals of primary afferents, subsequently increasing in [Ca2+]i in the spinal dorsal horn, which are involved in the mechanisms of spinal PGE2-induced nociceptive transmission.
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role of Prostaglandin Receptor ep1 in the spinal dorsal horn in carrageenan induced inflammatory pain
Anesthesiology, 2002Co-Authors: Yoshito Nakayama, Keiichi Omote, Akiyoshi NamikiAbstract:Background: Prostaglandin E 2 (PGE 2 ) and the Receptor for PGE 2 (EP Receptor) are key factors contributing to the generation of hyperalgesia caused by inflammation. The current study was designed to investigate the roles of PGE 2 and EP 1 Receptors in the spinal cord in the development and maintenance of inflammatory pain, using behavioral, microdialysis, and intracellular calcium ion concentration ([Ca 2+ ] i ) assays. Methods: Inflammation was induced by an injection of carrageenan into the plantar surface of the rat hind paw. The effects of inflammation were evaluated at the time points of 3 h (early phase) and 15 h (late phase) after carrageenan injection. In behavioral assays, withdrawal thresholds to mechanical stimuli were evaluated. The effect of an intrathecally administered selective EP 1 antagonist, ONO-8711, on the carrageenan-induced hyperalgesia was examined. Using a spinal microdialysis method, PGE 2 concentration in the spinal dorsal horn was measured. In [Ca 2+ ] i assays, we measured [Ca 2+ ] i in the spinal dorsal horn in transverse spinal slices and examined the effects of pretreatment with ONO-8711. Sensitivities of the changes in [Ca 2+ ] i to PGE 2 perfusion were also assessed. Results: Mechanical hyperalgesia and paw edema were observed in both the early and late phases. The hyperalgesia was inhibited by intrathecal ONO-8711 in the late, but not early, phase. The concentration of PGE 2 in the spinal dorsal horn increased in the late phase. The [Ca 2+ ] i in the dorsal horn increased on the ipsilateral side to the inflammation in the late, but not early phase. This increase was suppressed by the pretreatment with ONO-8711. Magnitude of the increase in [Ca 2+ ] i on the ipsilateral side in response to PGE 2 perfusion was greater in the late phase than in the early phase. Conclusion: The results suggested that activation of spinal EP 1 Receptors was crucial in the carrageenan-induced mechanical hyperalgesia in the late phase. It seems that some of the mechanisms underlying inflammation-induced plastic changes are mediated by time-dependent increase in PGE 2 concentration, activation of EP 1 Receptors, and increase in [Ca 2+ ] i in the spinal dorsal horn.
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The Effects of Peripheral Administration of a Novel Selective Antagonist for Prostaglandin E Receptor Subtype EP1, ONO-8711, in a Rat Model of Postoperative Pain
Anesthesia and analgesia, 2001Co-Authors: Keiichi Omote, Yoshito Nakayama, Tomoyuki Kawamata, Mikito Kawamata, Koji Hazama, Akiyoshi NamikiAbstract:UNLABELLED Mechanically evoked pain, also known as incident pain, induced by coughing or deep breathing after surgery leads to potentially devastating consequences. It is generally thought that the Prostaglandin Receptor- (especially, the Receptor for Prostaglandin E(2), EP Receptor) mediated sensitization of sensory nerve fibers is a key contributor to the generation of hyperalgesia. We examined whether a peripherally administered novel selective EP(1) antagonist, ONO-8711, would be a potential analgesic for incision-induced mechanical hyperalgesia. We used a rat model of postoperative pain introduced by Brennan et al. (1). Withdrawal thresholds to punctate stimulation and response frequencies to nonpunctate mechanical stimulation were determined by using von Frey filaments applied adjacent to the wound and directly to the incision site of the hind paw, respectively. Mechanical hyperalgesia to punctate and nonpunctate stimuli was observed 2 and 24 h after the incision. ONO-8711 (2, 10, or 50 microg) or saline was administered subcutaneously into the hind paw on the ipsilateral side to the incision. ONO-8711 significantly (P < 0.01) increased the withdrawal thresholds to punctate mechanical stimulation and significantly (P < 0.01) decreased the response frequencies to nonpunctate mechanical stimulation in a dose- and time-dependent manner 2 and 24 h after the incision. We conclude that EP(1) Receptor-mediated sensitization of sensory nerve fibers may contribute to the generation of mechanical hyperalgesia produced by incisional surgery, and that the EP(1) Receptor antagonist ONO-8711 may be an option for treatment of postoperative pain, especially incident pain. IMPLICATIONS The peripheral administration of an antagonist for EP(1) Receptor that is a subtype of Prostaglandin E Receptors can inhibit the mechanical hyperalgesia induced by a surgical incision.
Fenling Fan - One of the best experts on this subject based on the ideXlab platform.
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mechanism of beraprost effects on pulmonary hypertension contribution of cross binding to pge2 Receptor 4 and modulation of o2 sensitive voltage gated k channels
Frontiers in Pharmacology, 2019Co-Authors: Fenling Fan, Hua Tian, Jie Geng, Jizhao Deng, Ya Liu, Chunyan Chen, Songlin Zhang, Yushun Zhang, Hongyan TianAbstract:Abstract Background: The purpose of this study is to elucidate mechanism(s) by which the orally active PGI2 analogue, beraprost, ameliorates pulmonary hypertension. Prostaglandins are an important treatment for pulmonary hypertension. Mechanisms of their action are not fully elucidated in relation to Receptor subtype and effects on O2 sensitive Kv channels. Methods: Distal (3rd order and beyond) pulmonary arteries from chronically hypoxic rats and from humans with established pulmonary hypertension were studied. Measurements included pulmonary haemodynamics and histology, vascular reactivity, prostanoid Receptor expression and activity of the O2 sensitive Kv channels. Results: Prostacyclin Receptor (IP), Prostaglandin Receptor E3 (EP3) and Prostaglandin Receptor E4 (EP4) are the main pulmonary artery Receptor subtypes in both rat and human pulmonary arteries. Circulating levels of PGI2 and PGE2 were reduced in PH. PH was also associated with reduced Receptor expression of IP but not of EP4. The effects on IP expression were overcome with beraprost. Dilatory responses in PH to beraprost were reduced in the presence of EP4 blockade. Expression and activity of oxygen sensitive Kv channels were reduced in PASMC from rats and humans with PAH and were also overcome by administration of beraprost. Effects of beraprost on oxygen sensitive Kv channels were reduced in the presence of EP4 blockade implicating the EP4 Receptor, as well as the IP Receptor, in mediating beraprost effects. Conclusion: Reduced expression of pulmonary IP Receptors and reduced activity of O2 sensitive Kv channels are found in PH in both humans and rats. The orally active prostacyclin analogue, beraprost, is able to reverse these changes, partly through binding to the EP4 Receptor.
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Presentation_1_Mechanism of Beraprost Effects on Pulmonary Hypertension: Contribution of Cross-Binding to PGE2 Receptor 4 and Modulation of O2 Sensitive Voltage-Gated K+ Channels.PPTX
2019Co-Authors: Fenling Fan, Hua Tian, Jie Geng, Jizhao Deng, Ya Liu, Chunyan Chen, Songlin Zhang, Yushun Zhang, Hongyan TianAbstract:Background: The purpose of this study is to elucidate mechanism(s) by which the orally active PGI2 analog, Beraprost (BPS), ameliorates pulmonary hypertension (PH). Prostaglandins are an important treatment for PH. Mechanisms of their action are not fully elucidated in relation to Receptor subtype and effects on O2 sensitive Kv channels.Methods: Distal (3rd order and beyond) pulmonary arteries from chronically hypoxic rats and from humans with established PH were studied. Measurements included pulmonary haemodynamics and histology, vascular reactivity, prostanoid Receptor expression and activity of the O2 sensitive Kv channels.Results: Prostacyclin Receptor (IP), Prostaglandin Receptor E3 (EP3) and Prostaglandin Receptor E4 (EP4) are the main pulmonary artery Receptor subtypes in both rat and human pulmonary arteries. Circulating levels of PGI2 and PGE2 were reduced in PH. PH was also associated with reduced Receptor expression of IP but not of EP4. The effects on IP expression were overcome with BPS. Dilatory responses in PH to BPS were reduced in the presence of EP4 blockade. Expression and activity of oxygen sensitive Kv channels were reduced in pulmonary artery smooth muscle cell from rats with PH and humans with PAH and were also overcome by administration of BPS. Effects of BPS on oxygen sensitive Kv channels were reduced in the presence of EP4 blockade implicating the EP4 Receptor, as well as the IP Receptor, in mediating BPS effects.Conclusion: Reduced expression of pulmonary IP Receptors and reduced activity of O2 sensitive Kv channels are found in PH in both humans and rats. The orally active prostacyclin analogue, BPS, is able to reverse these changes, partly through binding to the EP4 Receptor.
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Mechanism of Beraprost Effects on Pulmonary Hypertension: Contribution of Cross-Binding to PGE2 Receptor 4 and Modulation of O2 Sensitive Voltage-Gated K+ Channels
Frontiers Media S.A., 2019Co-Authors: Fenling Fan, Hua Tian, Jie Geng, Jizhao Deng, Ya Liu, Chunyan Chen, Songlin Zhang, Yushun ZhangAbstract:Background: The purpose of this study is to elucidate mechanism(s) by which the orally active PGI2 analog, Beraprost (BPS), ameliorates pulmonary hypertension (PH). Prostaglandins are an important treatment for PH. Mechanisms of their action are not fully elucidated in relation to Receptor subtype and effects on O2 sensitive Kv channels.Methods: Distal (3rd order and beyond) pulmonary arteries from chronically hypoxic rats and from humans with established PH were studied. Measurements included pulmonary haemodynamics and histology, vascular reactivity, prostanoid Receptor expression and activity of the O2 sensitive Kv channels.Results: Prostacyclin Receptor (IP), Prostaglandin Receptor E3 (EP3) and Prostaglandin Receptor E4 (EP4) are the main pulmonary artery Receptor subtypes in both rat and human pulmonary arteries. Circulating levels of PGI2 and PGE2 were reduced in PH. PH was also associated with reduced Receptor expression of IP but not of EP4. The effects on IP expression were overcome with BPS. Dilatory responses in PH to BPS were reduced in the presence of EP4 blockade. Expression and activity of oxygen sensitive Kv channels were reduced in pulmonary artery smooth muscle cell from rats with PH and humans with PAH and were also overcome by administration of BPS. Effects of BPS on oxygen sensitive Kv channels were reduced in the presence of EP4 blockade implicating the EP4 Receptor, as well as the IP Receptor, in mediating BPS effects.Conclusion: Reduced expression of pulmonary IP Receptors and reduced activity of O2 sensitive Kv channels are found in PH in both humans and rats. The orally active prostacyclin analogue, BPS, is able to reverse these changes, partly through binding to the EP4 Receptor
Najam A Sharif - One of the best experts on this subject based on the ideXlab platform.
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Human Trabecular Meshwork Cell Responses Induced by Bimatoprost, Travoprost, Unoprostone, and other FP Prostaglandin Receptor Agonist Analogues MATERIALS AND METHODS
2020Co-Authors: Najam A Sharif, Curtis R Kelly, Julie Y CriderAbstract:PURPOSE. To determine the functional agonist potencies of the intraocular pressure (IOP)-lowering Prostaglandin F (FP)-class Prostaglandin (PG) analogues (e.g., travoprost, latanoprost, bimatoprost, and unoprostone isopropyl ester) in human trabecular meshwork (h-TM) cells, by using phosphoinositide (PI) turnover and intracellular Ca 2ϩ ([Ca 2ϩ ] i ) mobilization, and to confirm the FP nature of these Receptors by using an FP Receptor antagonist, 11-fluoro-15-epi-15-indanyl-PGF 2␣ 2 and unoprostone isopropyl ester 3 lower intraocular pressure (IOP) in a number of mammalian species, including humans, and are used to treat ocular hypertension and glaucoma
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human trabecular meshwork cell responses induced by bimatoprost travoprost unoprostone and other fp Prostaglandin Receptor agonist analogues
Investigative Ophthalmology & Visual Science, 2003Co-Authors: Najam A Sharif, Curtis R Kelly, J Y CriderAbstract:PURPOSE. To determine the functional agonist potencies of the intraocular pressure (TOP)-Iowering Prostaglandin F (FP)-class Prostaglandin (PG) analogues (e.g., travoprost, latanoprost, bimatoprost, and unoprostone isopropyl ester) in human trabecular meshwork (h-TM) cells, by using phosphoinositide (PI) turnover and intracellular Ca 2+ ([Ca 2+ ] i ) mobilization, and to confirm the FP nature of these Receptors by using an FP Receptor antagonist, 11β-fluoro-15-epi-15-indanyl-PGF 2α (AL-8810). METHODS. FP-Receptor-mediated PI turnover and [Ca 2+] mobilization were measured in h-TM cells by determining the accumulation of [ 3 H-inositol phosphates ([ 3 H]-IPs) by anion-exchange chromatography and real-time fluorescence imaging, respectively. RESULTS. Various PG analogues concentration-dependently stimulated production of [ 3 H]-IPs in h-TM cells with the following agonist potencies (median effective concentration; EC 50 ): travoprost acid (EC 50 = 2.4 nM) > cloprostenol (EC 50 = 4.5 nM) > (±)-fluprostenol (EC 50 = 10.8 nM) > latanoprost acid (EC 50 = 34.7 nM) > bimatoprost acid (EC 50 = 112 nM) > PGF 2α (EC 50 = 120 nM) >> unoprostone (UF-021; EC 50 = 3280 nM) > S-1033 (EC 50 = 4570 nM; all n = 3-9). Prodrug derivatives of these compounds exhibited the following potencies: travoprost (isopropyl ester; EC 50 = 89.1 nM) > latanoprost (isopropyl ester; EC 50 = 778 nM) > bimatoprost (amide; EC 50 = 1410-6940 nM). Travoprost acid, PGF 2α, unoprostone, and S-1033 were tested in addition for [Ca 2+ ] i mobilization and found to have rapid and dose-dependent effects. The FP Receptor-selective antagonist AL-8810 antagonized the (±)-fluprostenol-induced PI turnover in these cells (K; = 2.56 ± 0.62 μM) as well as that induced by bimatoprost and acids of latanoprost and travoprost. The agonist and antagonist potencies of the PG analogues from the PI turnover assays in h-TM cells correlated well with PI turnover data obtained from the cloned human ciliary body FP Receptor (r = 0.92; P < 0.0001). CONCLUSIONS. The pharmacology of the h-TM cell FP-Receptor-mediated PI turnover and [Ca 2 +] i mobilization was defined using numerous synthetic (FP-selective) PG agonist analogues and an FP Receptor antagonist, AL-8810. Bimatoprost, travoprost, latanoprost, unoprostone isopropyl ester, and their respective free acids were shown to he FP agonists in the h-TM cells.
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human trabecular meshwork cell responses induced by bimatoprost travoprost unoprostone and other fp Prostaglandin Receptor agonist analogues
Investigative Ophthalmology & Visual Science, 2003Co-Authors: Najam A Sharif, Curtis R Kelly, J Y CriderAbstract:PURPOSE To determine the functional agonist potencies of the intraocular pressure (IOP)-lowering Prostaglandin F (FP)-class Prostaglandin (PG) analogues (e.g., travoprost, latanoprost, bimatoprost, and unoprostone isopropyl ester) in human trabecular meshwork (h-TM) cells, by using phosphoinositide (PI) turnover and intracellular Ca(2+) ([Ca(2+)](i)) mobilization, and to confirm the FP nature of these Receptors by using an FP Receptor antagonist, 11beta-fluoro-15-epi-15-indanyl-PGF(2alpha) (AL-8810). METHODS FP-Receptor-mediated PI turnover and [Ca(2+)](i) mobilization were measured in h-TM cells by determining the accumulation of [(3)H]-inositol phosphates ([(3)H]-IPs) by anion-exchange chromatography and real-time fluorescence imaging, respectively. RESULTS Various PG analogues concentration-dependently stimulated production of [(3)H]-IPs in h-TM cells with the following agonist potencies (median effective concentration; EC(50)): travoprost acid (EC(50) = 2.4 nM) > cloprostenol (EC(50) = 4.5 nM) > (+/-)-fluprostenol (EC(50) = 10.8 nM) > latanoprost acid (EC(50) = 34.7 nM) > bimatoprost acid (EC(50) = 112 nM) > PGF(2alpha) (EC(50) = 120 nM) >> unoprostone (UF-021; EC(50) = 3280 nM) > S-1033 (EC(50) = 4570 nM; all n = 3-9). Prodrug derivatives of these compounds exhibited the following potencies: travoprost (isopropyl ester; EC(50) = 89.1 nM) > latanoprost (isopropyl ester; EC(50) = 778 nM) > bimatoprost (amide; EC(50) = 1410-6940 nM). Travoprost acid, PGF(2alpha,) unoprostone, and S-1033 were tested in addition for [Ca(2+)](i) mobilization and found to have rapid and dose-dependent effects. The FP Receptor-selective antagonist AL-8810 antagonized the (+/-)-fluprostenol-induced PI turnover in these cells (K(i) = 2.56 +/- 0.62 micro M) as well as that induced by bimatoprost and acids of latanoprost and travoprost. The agonist and antagonist potencies of the PG analogues from the PI turnover assays in h-TM cells correlated well with PI turnover data obtained from the cloned human ciliary body FP Receptor (r = 0.92; P < 0.0001). CONCLUSIONS The pharmacology of the h-TM cell FP-Receptor-mediated PI turnover and [Ca(2+)](i) mobilization was defined using numerous synthetic (FP-selective) PG agonist analogues and an FP Receptor antagonist, AL-8810. Bimatoprost, travoprost, latanoprost, unoprostone isopropyl ester, and their respective free acids were shown to be FP agonists in the h-TM cells.
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agonist activity of bimatoprost travoprost latanoprost unoprostone isopropyl ester and other Prostaglandin analogs at the cloned human ciliary body fp Prostaglandin Receptor
Journal of Ocular Pharmacology and Therapeutics, 2002Co-Authors: Najam A Sharif, Curtis R Kelly, J Y CriderAbstract:We have determined the agonist activity of a number of natural Prostaglandins and Prostaglandin analogs at the FP Prostaglandin Receptor cloned from a human ciliary body cDNA library using phosphoinositide (PI) turnover assays. Travoprost acid (EC50 = 3.2 ± 0.6 nM) was the most potent agonist in these cells followed by bimatoprost free acid (17-phenyl-trinor PGF2α; EC50 = 5.8 ± 2.6 nM), fluprostenol (EC50 = 6.1 ± 1.5 nM), and latanoprost 50 free acid (PHXA85; EC50 = 54.6 ± 12.4 nM) which was 17-fold weaker (p < 0.001) than travoprost acid. Unoprostone and S-1033 were significantly (p < 0.001) weaker than travoprost acid. The amide prodrug, bimatoprost (EC50= 694 ± 293 nM), activated this FP Receptor with an intermediate potency. The isopropyl ester prodrugs, travoprost (EC50 = 42.3 ± 6.7 nM), latanoprost (EC50 = 126 ± 347 nM) and unoprostone isopropyl ester (EC50 = 9100 ± 2870 nM), also exhibited FP agonist activity. However, other compounds such as PGI2, bradykinin, histamine, and serotonin were inactive...
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pharmacology of 3h Prostaglandin e1 3h Prostaglandin e2 and 3h Prostaglandin f2alpha binding to ep3 and fp Prostaglandin Receptor binding sites in bovine corpus luteum characterization and correlation with functional data
Journal of Pharmacology and Experimental Therapeutics, 1998Co-Authors: Najam A Sharif, Julie Y Crider, Gary W Williams, Brenda W Griffin, T L DavisAbstract:Specific binding of [3H]Prostaglandin (PG) E1, [3H]PGE2 and [3H]PGF2alpha to washed total particulate homogenates of bovine corpus luteum comprised 60 to 82% of total binding. Scatchard analysis of competition data revealed the presence of an apparent single population of binding sites for [3H]PGE1 and [3H]PGE2 with dissociation constants (Kds) of 2.76 to 3.39 nM and apparent Receptor density (Bmax) of 1.5 to 1.56 pmol/g wet weight (n = 3-4). However, [3H]PGF2alpha appeared to interact with two classes/states of binding sites (Kd1 = 6.51 +/- 0.65 nM, Bmax1 = 2.33 +/- 0.26 pmol/g wet weight; Kd2 = 986 +/- 269 nM; Bmax2 = 44.8 +/- 11.3 pmol/g wet weight, n = 11). Specific [3H]PGE1 and [3H]PGE2 binding was most potently (nanomolar affinity) inhibited by PGs with high selectivity for the EP3 Receptor subtype (e.g., GR63799, sulprostone, enprostil) but was weakly (Kis > 1 microM) influenced by EP1-selective (SC-19220), FP-selective (fluprostenol, PHXA85), DP-selective (BWA868C; ZK118182), IP-selective (iloprost) and TP-selective (U46619) PGs. Specific [3H]PGF2alpha binding was potently displaced by FP-selective agents such as fluprostenol, PHXA85 and cloprostenol with nanomolar affinities (n = 3-25), but weakly (Kis > 1 microM) by other PGs showing high selectivity for other PG Receptor subtypes mentioned above. The relative specificities and potencies of EP3- and FP-selective PGs tested in the binding assays were confirmed using various functional assays. These studies have provided strong pharmacological evidence for the similarity of [3H]PGE1 and [3H]PGE2 binding to EP3 Receptors and for [3H]PGF2alpha binding to FP Receptors in washed bovine corpus luteum homogenates.
J Y Crider - One of the best experts on this subject based on the ideXlab platform.
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human trabecular meshwork cell responses induced by bimatoprost travoprost unoprostone and other fp Prostaglandin Receptor agonist analogues
Investigative Ophthalmology & Visual Science, 2003Co-Authors: Najam A Sharif, Curtis R Kelly, J Y CriderAbstract:PURPOSE. To determine the functional agonist potencies of the intraocular pressure (TOP)-Iowering Prostaglandin F (FP)-class Prostaglandin (PG) analogues (e.g., travoprost, latanoprost, bimatoprost, and unoprostone isopropyl ester) in human trabecular meshwork (h-TM) cells, by using phosphoinositide (PI) turnover and intracellular Ca 2+ ([Ca 2+ ] i ) mobilization, and to confirm the FP nature of these Receptors by using an FP Receptor antagonist, 11β-fluoro-15-epi-15-indanyl-PGF 2α (AL-8810). METHODS. FP-Receptor-mediated PI turnover and [Ca 2+] mobilization were measured in h-TM cells by determining the accumulation of [ 3 H-inositol phosphates ([ 3 H]-IPs) by anion-exchange chromatography and real-time fluorescence imaging, respectively. RESULTS. Various PG analogues concentration-dependently stimulated production of [ 3 H]-IPs in h-TM cells with the following agonist potencies (median effective concentration; EC 50 ): travoprost acid (EC 50 = 2.4 nM) > cloprostenol (EC 50 = 4.5 nM) > (±)-fluprostenol (EC 50 = 10.8 nM) > latanoprost acid (EC 50 = 34.7 nM) > bimatoprost acid (EC 50 = 112 nM) > PGF 2α (EC 50 = 120 nM) >> unoprostone (UF-021; EC 50 = 3280 nM) > S-1033 (EC 50 = 4570 nM; all n = 3-9). Prodrug derivatives of these compounds exhibited the following potencies: travoprost (isopropyl ester; EC 50 = 89.1 nM) > latanoprost (isopropyl ester; EC 50 = 778 nM) > bimatoprost (amide; EC 50 = 1410-6940 nM). Travoprost acid, PGF 2α, unoprostone, and S-1033 were tested in addition for [Ca 2+ ] i mobilization and found to have rapid and dose-dependent effects. The FP Receptor-selective antagonist AL-8810 antagonized the (±)-fluprostenol-induced PI turnover in these cells (K; = 2.56 ± 0.62 μM) as well as that induced by bimatoprost and acids of latanoprost and travoprost. The agonist and antagonist potencies of the PG analogues from the PI turnover assays in h-TM cells correlated well with PI turnover data obtained from the cloned human ciliary body FP Receptor (r = 0.92; P < 0.0001). CONCLUSIONS. The pharmacology of the h-TM cell FP-Receptor-mediated PI turnover and [Ca 2 +] i mobilization was defined using numerous synthetic (FP-selective) PG agonist analogues and an FP Receptor antagonist, AL-8810. Bimatoprost, travoprost, latanoprost, unoprostone isopropyl ester, and their respective free acids were shown to he FP agonists in the h-TM cells.
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human trabecular meshwork cell responses induced by bimatoprost travoprost unoprostone and other fp Prostaglandin Receptor agonist analogues
Investigative Ophthalmology & Visual Science, 2003Co-Authors: Najam A Sharif, Curtis R Kelly, J Y CriderAbstract:PURPOSE To determine the functional agonist potencies of the intraocular pressure (IOP)-lowering Prostaglandin F (FP)-class Prostaglandin (PG) analogues (e.g., travoprost, latanoprost, bimatoprost, and unoprostone isopropyl ester) in human trabecular meshwork (h-TM) cells, by using phosphoinositide (PI) turnover and intracellular Ca(2+) ([Ca(2+)](i)) mobilization, and to confirm the FP nature of these Receptors by using an FP Receptor antagonist, 11beta-fluoro-15-epi-15-indanyl-PGF(2alpha) (AL-8810). METHODS FP-Receptor-mediated PI turnover and [Ca(2+)](i) mobilization were measured in h-TM cells by determining the accumulation of [(3)H]-inositol phosphates ([(3)H]-IPs) by anion-exchange chromatography and real-time fluorescence imaging, respectively. RESULTS Various PG analogues concentration-dependently stimulated production of [(3)H]-IPs in h-TM cells with the following agonist potencies (median effective concentration; EC(50)): travoprost acid (EC(50) = 2.4 nM) > cloprostenol (EC(50) = 4.5 nM) > (+/-)-fluprostenol (EC(50) = 10.8 nM) > latanoprost acid (EC(50) = 34.7 nM) > bimatoprost acid (EC(50) = 112 nM) > PGF(2alpha) (EC(50) = 120 nM) >> unoprostone (UF-021; EC(50) = 3280 nM) > S-1033 (EC(50) = 4570 nM; all n = 3-9). Prodrug derivatives of these compounds exhibited the following potencies: travoprost (isopropyl ester; EC(50) = 89.1 nM) > latanoprost (isopropyl ester; EC(50) = 778 nM) > bimatoprost (amide; EC(50) = 1410-6940 nM). Travoprost acid, PGF(2alpha,) unoprostone, and S-1033 were tested in addition for [Ca(2+)](i) mobilization and found to have rapid and dose-dependent effects. The FP Receptor-selective antagonist AL-8810 antagonized the (+/-)-fluprostenol-induced PI turnover in these cells (K(i) = 2.56 +/- 0.62 micro M) as well as that induced by bimatoprost and acids of latanoprost and travoprost. The agonist and antagonist potencies of the PG analogues from the PI turnover assays in h-TM cells correlated well with PI turnover data obtained from the cloned human ciliary body FP Receptor (r = 0.92; P < 0.0001). CONCLUSIONS The pharmacology of the h-TM cell FP-Receptor-mediated PI turnover and [Ca(2+)](i) mobilization was defined using numerous synthetic (FP-selective) PG agonist analogues and an FP Receptor antagonist, AL-8810. Bimatoprost, travoprost, latanoprost, unoprostone isopropyl ester, and their respective free acids were shown to be FP agonists in the h-TM cells.
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agonist activity of bimatoprost travoprost latanoprost unoprostone isopropyl ester and other Prostaglandin analogs at the cloned human ciliary body fp Prostaglandin Receptor
Journal of Ocular Pharmacology and Therapeutics, 2002Co-Authors: Najam A Sharif, Curtis R Kelly, J Y CriderAbstract:We have determined the agonist activity of a number of natural Prostaglandins and Prostaglandin analogs at the FP Prostaglandin Receptor cloned from a human ciliary body cDNA library using phosphoinositide (PI) turnover assays. Travoprost acid (EC50 = 3.2 ± 0.6 nM) was the most potent agonist in these cells followed by bimatoprost free acid (17-phenyl-trinor PGF2α; EC50 = 5.8 ± 2.6 nM), fluprostenol (EC50 = 6.1 ± 1.5 nM), and latanoprost 50 free acid (PHXA85; EC50 = 54.6 ± 12.4 nM) which was 17-fold weaker (p < 0.001) than travoprost acid. Unoprostone and S-1033 were significantly (p < 0.001) weaker than travoprost acid. The amide prodrug, bimatoprost (EC50= 694 ± 293 nM), activated this FP Receptor with an intermediate potency. The isopropyl ester prodrugs, travoprost (EC50 = 42.3 ± 6.7 nM), latanoprost (EC50 = 126 ± 347 nM) and unoprostone isopropyl ester (EC50 = 9100 ± 2870 nM), also exhibited FP agonist activity. However, other compounds such as PGI2, bradykinin, histamine, and serotonin were inactive...
