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Shiro Morimoto - One of the best experts on this subject based on the ideXlab platform.
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Phosphoramidon sensitive conversion of big endothelin 1 and degradation of endothelin 1 in rat kidney
Hypertension, 1994Co-Authors: Katsuya Fujita, Masanori Takaoka, Yasuo Matsumura, Kazuhiro Hisaki, Satomi Kita, Shiro MorimotoAbstract:We investigated the intrarenal conversion of big endothelin-1 (ET-1) to ET-1 in the isolated perfused rat kidney. Big ET-1 caused a concentration-dependent increase in perfusion pressure, and the pressor molar potency of the peptide was 50-fold less than that of ET-1. The big ET-1 (2 x 10(-8) mol/L)-induced pressor action was accompanied by increases in immunoreactive endothelin levels in both the perfusate and renal tissues. Phosphoramidon (10(-4) mol/L), a metalloproteinase inhibitor, significantly suppressed the big ET-1-induced pressor action and the accumulation of immunoreactive endothelin in renal tissues. On the other hand, Phosphoramidon slightly but significantly sustained the ET-1-induced pressor effect. The effect of kelatorphan (10(-4) mol/L), a specific inhibitor of neutral endopeptidase 24.11, on the ET-1-induced pressor effect was the same as that seen with Phosphoramidon. When ET-1 was exogenously added to the perfusate, Phosphoramidon or kelatorphan significantly increased the immunoreactive endothelin levels in renal tissues after perfusion, without affecting the disappearance rate of immunoreactive endothelin from the perfusate. Therefore, the Phosphoramidon-sensitive ET-1-converting enzyme in the kidney seems to contribute to the functional local conversion of big ET-1 to ET-1, and neutral endopeptidase 24.11 may be responsible for the proteolytic degradation of ET-1 in the kidney. In addition, immunoreactive endothelin levels in renal tissues but not in the perfusate can account for the functional conversion of big ET-1 to ET-1 and for the local proteolytic degradation of ET-1 in the kidney.
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platelets induced stimulation of endothelin 1 production and inhibition by Phosphoramidon
Journal of Pharmacology and Experimental Therapeutics, 1994Co-Authors: Toshiyoshi Umekawa, Masanori Takaoka, Yasuo Matsumura, N Yoshimura, Satoshi Murata, K Takada, Y Tsukahara, Shiro MorimotoAbstract:The effects of platelets on endothelin-1 (ET-1) production were examined by using cultured bovine pulmonary artery endothelial cells (ECs). Platelets (6 x 10(6) to 2 x 10(9) platelets/ml) prepared from rat peripheral arterial blood markedly stimulated immunoreactive (IR)-ET release from ECs into the culture medium, in a time-and platelet number-dependent manner. High-performance liquid chromatography analysis of the culture supernatant following exposure to platelets revealed one major IR-ET component corresponding to the elution position of synthetic ET-1. Northern blot analysis showed that platelets enhanced prepro ET-1 mRNA expression in the ECs. Increased IR-ET release was observed with the supernatant obtained after incubation of platelets, and this increment was significantly inhibited by transforming growth factor-beta 1 neutralizing antibody. Phosphoramidon, an ET converting enzyme inhibitor, significantly decreased the amount of IR-ET accumulating in the culture medium of ECs, incubated with or without platelets, and the decreasing effect of Phosphoramidon in the presence of platelets was greater than that in their absence. A similar effectiveness of Phosphoramidon was seen when transforming growth factor-beta 1 was used instead of platelets. Thus, platelets appear to stimulate the endothelial production of ET-1 in vitro, probably through a release of transforming growth factor-beta 1. We also suggest that the inhibition of ET converting enzyme by Phosphoramidon is more effective in the augmented condition of ET-1 production than in the basal condition.
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Phosphoramidon-sensitive endothelin converting enzyme in cultured vascular smooth muscle cells converts big endothelin-3 to endothelin-3
Life Sciences, 1993Co-Authors: Yaeko Tsukahara, Kazuko Kuninobu, Takayo Kojima, Masanori Takaoka, Yasuo Matsumura, Shiro MorimotoAbstract:Abstract Incubation of big endothelin-3 (big ET-3, 1–41) with the membrane fraction obtained from cultured vascular smooth muscle cells (VSMCs) resulted in time-dependent increases in immunoreactive-ET (IR-ET), which were suppressed by Phosphoramidon. Analysis of the incubation mixture by reverse-phase high performance liquid chromatography (RP-HPLC) confirmed that the IR-ET was due to the mature ET-3(1–21). ET-1 (1–21) generated during incubation of big ET-1 (1–39) with the membrane fraction was markedly suppressed by the addition of big ET-3 into the incubation mixture. When the cultured VSMCs were incubated with big ET-3, a conversion to the mature ET-3 was observed. This ET-3 generation from exogenously applied big ET-3 was also suppressed by Phosphoramidon. We conclude that the Phosphoramidon-sensitive ET converting enzyme in VSMCs converts big ET-1 and big ET-3 to their mature form.
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Big endothelin-3-induced hypertension and its inhibition by Phosphoramidon in anaesthetized rats.
European Journal of Pharmacology, 1993Co-Authors: Yasuo Matsumura, Katsuya Fujita, Masanori Takaoka, Shiro MorimotoAbstract:Abstract Intravenous injection of big endothelin-3 (big ET-3, 1–41 amide) at 3 nmol/kg to ganglion-blocked anaesthetized rats produced a long-lasting hypertensive action, but the action was less potent than that seen with the same dose of ET-3-(1–21). The pressor effect induced by big ET-3 was markedly attenuated by pretreatment with Phosphoramidon, 5 mg/kg i.v., a dose which had no effect on the hypertensive action induced by ET-3. These results strongly suggest that big ET-3 is converted to mature ET-3 by a Phosphoramidon-sensitive metalloproteinase in vivo, in a manner similar to the conversion of big ET-1 to ET-1.
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Phosphoramidon sensitive endothelin converting enzyme in vascular endothelial cells converts big endothelin 1 and big endothelin 3 to their mature form
FEBS Letters, 1992Co-Authors: Yasuo Matsumura, Yaeko Tsukahara, Kazuko Kuninobu, Masanori Takaoka, Shiro MorimotoAbstract:Incubation of big endothelin-3 (big ET-31–41) with the membrane fraction obtained from cultured endothelial cells (ECs) resulted in an increase in immunoreactive-ET (IR-ET). This increasing activity was markedly suppressed by Phosphoramidon, which is known to inhibit the conversion of big ET-11–39 to ET-11–21. Reverse-phase HPLC of the incubation mixture of the membrane fraction with big ET-3 revealed one major IR-ET component corresponding to the elution position of synthetic ET-31–21. When the cultured ECs were incubated with big ET-3, a conversion to the mature ET-3, as well as an endogenous ET-1 generation, was observed. Both responses were markedly suppressed by Phosphoramidon. By the gel filtration of 0.5% CHAPS-solubilized fraction of membrane pellets or ECs, the molecular mass of the proteinase which converts big ET-1 and big ET-3 to their mature form was estimated to be 300–350 kDa. Phosphoramidon almost completely abolished both converting activities of the proteinase. We conclude that the above type of Phosphoramidon-sensitive metalloproteinase functions as an ET-converting enzyme to generate the mature form from big ET-1 and big ET-3 in ECs.
Yasuo Matsumura - One of the best experts on this subject based on the ideXlab platform.
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Endothelin-1 in Rat Kidney
2014Co-Authors: K Fujita, Katsuya Fujita, Yasuo Matsumura, Kazuhiro Hisaki, Satomi Kita, Y Matsumura, S Kita, M Takaoka, S MorimotoAbstract:in rat kidney. Phosphoramidon-sensitive conversion of big endothelin-1 and degradation of endothelin-
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Phosphoramidon sensitive conversion of big endothelin 1 and degradation of endothelin 1 in rat kidney
Hypertension, 1994Co-Authors: Katsuya Fujita, Masanori Takaoka, Yasuo Matsumura, Kazuhiro Hisaki, Satomi Kita, Shiro MorimotoAbstract:We investigated the intrarenal conversion of big endothelin-1 (ET-1) to ET-1 in the isolated perfused rat kidney. Big ET-1 caused a concentration-dependent increase in perfusion pressure, and the pressor molar potency of the peptide was 50-fold less than that of ET-1. The big ET-1 (2 x 10(-8) mol/L)-induced pressor action was accompanied by increases in immunoreactive endothelin levels in both the perfusate and renal tissues. Phosphoramidon (10(-4) mol/L), a metalloproteinase inhibitor, significantly suppressed the big ET-1-induced pressor action and the accumulation of immunoreactive endothelin in renal tissues. On the other hand, Phosphoramidon slightly but significantly sustained the ET-1-induced pressor effect. The effect of kelatorphan (10(-4) mol/L), a specific inhibitor of neutral endopeptidase 24.11, on the ET-1-induced pressor effect was the same as that seen with Phosphoramidon. When ET-1 was exogenously added to the perfusate, Phosphoramidon or kelatorphan significantly increased the immunoreactive endothelin levels in renal tissues after perfusion, without affecting the disappearance rate of immunoreactive endothelin from the perfusate. Therefore, the Phosphoramidon-sensitive ET-1-converting enzyme in the kidney seems to contribute to the functional local conversion of big ET-1 to ET-1, and neutral endopeptidase 24.11 may be responsible for the proteolytic degradation of ET-1 in the kidney. In addition, immunoreactive endothelin levels in renal tissues but not in the perfusate can account for the functional conversion of big ET-1 to ET-1 and for the local proteolytic degradation of ET-1 in the kidney.
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platelets induced stimulation of endothelin 1 production and inhibition by Phosphoramidon
Journal of Pharmacology and Experimental Therapeutics, 1994Co-Authors: Toshiyoshi Umekawa, Masanori Takaoka, Yasuo Matsumura, N Yoshimura, Satoshi Murata, K Takada, Y Tsukahara, Shiro MorimotoAbstract:The effects of platelets on endothelin-1 (ET-1) production were examined by using cultured bovine pulmonary artery endothelial cells (ECs). Platelets (6 x 10(6) to 2 x 10(9) platelets/ml) prepared from rat peripheral arterial blood markedly stimulated immunoreactive (IR)-ET release from ECs into the culture medium, in a time-and platelet number-dependent manner. High-performance liquid chromatography analysis of the culture supernatant following exposure to platelets revealed one major IR-ET component corresponding to the elution position of synthetic ET-1. Northern blot analysis showed that platelets enhanced prepro ET-1 mRNA expression in the ECs. Increased IR-ET release was observed with the supernatant obtained after incubation of platelets, and this increment was significantly inhibited by transforming growth factor-beta 1 neutralizing antibody. Phosphoramidon, an ET converting enzyme inhibitor, significantly decreased the amount of IR-ET accumulating in the culture medium of ECs, incubated with or without platelets, and the decreasing effect of Phosphoramidon in the presence of platelets was greater than that in their absence. A similar effectiveness of Phosphoramidon was seen when transforming growth factor-beta 1 was used instead of platelets. Thus, platelets appear to stimulate the endothelial production of ET-1 in vitro, probably through a release of transforming growth factor-beta 1. We also suggest that the inhibition of ET converting enzyme by Phosphoramidon is more effective in the augmented condition of ET-1 production than in the basal condition.
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Phosphoramidon-sensitive endothelin converting enzyme in cultured vascular smooth muscle cells converts big endothelin-3 to endothelin-3
Life Sciences, 1993Co-Authors: Yaeko Tsukahara, Kazuko Kuninobu, Takayo Kojima, Masanori Takaoka, Yasuo Matsumura, Shiro MorimotoAbstract:Abstract Incubation of big endothelin-3 (big ET-3, 1–41) with the membrane fraction obtained from cultured vascular smooth muscle cells (VSMCs) resulted in time-dependent increases in immunoreactive-ET (IR-ET), which were suppressed by Phosphoramidon. Analysis of the incubation mixture by reverse-phase high performance liquid chromatography (RP-HPLC) confirmed that the IR-ET was due to the mature ET-3(1–21). ET-1 (1–21) generated during incubation of big ET-1 (1–39) with the membrane fraction was markedly suppressed by the addition of big ET-3 into the incubation mixture. When the cultured VSMCs were incubated with big ET-3, a conversion to the mature ET-3 was observed. This ET-3 generation from exogenously applied big ET-3 was also suppressed by Phosphoramidon. We conclude that the Phosphoramidon-sensitive ET converting enzyme in VSMCs converts big ET-1 and big ET-3 to their mature form.
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Big endothelin-3-induced hypertension and its inhibition by Phosphoramidon in anaesthetized rats.
European Journal of Pharmacology, 1993Co-Authors: Yasuo Matsumura, Katsuya Fujita, Masanori Takaoka, Shiro MorimotoAbstract:Abstract Intravenous injection of big endothelin-3 (big ET-3, 1–41 amide) at 3 nmol/kg to ganglion-blocked anaesthetized rats produced a long-lasting hypertensive action, but the action was less potent than that seen with the same dose of ET-3-(1–21). The pressor effect induced by big ET-3 was markedly attenuated by pretreatment with Phosphoramidon, 5 mg/kg i.v., a dose which had no effect on the hypertensive action induced by ET-3. These results strongly suggest that big ET-3 is converted to mature ET-3 by a Phosphoramidon-sensitive metalloproteinase in vivo, in a manner similar to the conversion of big ET-1 to ET-1.
Masanori Takaoka - One of the best experts on this subject based on the ideXlab platform.
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Phosphoramidon sensitive conversion of big endothelin 1 and degradation of endothelin 1 in rat kidney
Hypertension, 1994Co-Authors: Katsuya Fujita, Masanori Takaoka, Yasuo Matsumura, Kazuhiro Hisaki, Satomi Kita, Shiro MorimotoAbstract:We investigated the intrarenal conversion of big endothelin-1 (ET-1) to ET-1 in the isolated perfused rat kidney. Big ET-1 caused a concentration-dependent increase in perfusion pressure, and the pressor molar potency of the peptide was 50-fold less than that of ET-1. The big ET-1 (2 x 10(-8) mol/L)-induced pressor action was accompanied by increases in immunoreactive endothelin levels in both the perfusate and renal tissues. Phosphoramidon (10(-4) mol/L), a metalloproteinase inhibitor, significantly suppressed the big ET-1-induced pressor action and the accumulation of immunoreactive endothelin in renal tissues. On the other hand, Phosphoramidon slightly but significantly sustained the ET-1-induced pressor effect. The effect of kelatorphan (10(-4) mol/L), a specific inhibitor of neutral endopeptidase 24.11, on the ET-1-induced pressor effect was the same as that seen with Phosphoramidon. When ET-1 was exogenously added to the perfusate, Phosphoramidon or kelatorphan significantly increased the immunoreactive endothelin levels in renal tissues after perfusion, without affecting the disappearance rate of immunoreactive endothelin from the perfusate. Therefore, the Phosphoramidon-sensitive ET-1-converting enzyme in the kidney seems to contribute to the functional local conversion of big ET-1 to ET-1, and neutral endopeptidase 24.11 may be responsible for the proteolytic degradation of ET-1 in the kidney. In addition, immunoreactive endothelin levels in renal tissues but not in the perfusate can account for the functional conversion of big ET-1 to ET-1 and for the local proteolytic degradation of ET-1 in the kidney.
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platelets induced stimulation of endothelin 1 production and inhibition by Phosphoramidon
Journal of Pharmacology and Experimental Therapeutics, 1994Co-Authors: Toshiyoshi Umekawa, Masanori Takaoka, Yasuo Matsumura, N Yoshimura, Satoshi Murata, K Takada, Y Tsukahara, Shiro MorimotoAbstract:The effects of platelets on endothelin-1 (ET-1) production were examined by using cultured bovine pulmonary artery endothelial cells (ECs). Platelets (6 x 10(6) to 2 x 10(9) platelets/ml) prepared from rat peripheral arterial blood markedly stimulated immunoreactive (IR)-ET release from ECs into the culture medium, in a time-and platelet number-dependent manner. High-performance liquid chromatography analysis of the culture supernatant following exposure to platelets revealed one major IR-ET component corresponding to the elution position of synthetic ET-1. Northern blot analysis showed that platelets enhanced prepro ET-1 mRNA expression in the ECs. Increased IR-ET release was observed with the supernatant obtained after incubation of platelets, and this increment was significantly inhibited by transforming growth factor-beta 1 neutralizing antibody. Phosphoramidon, an ET converting enzyme inhibitor, significantly decreased the amount of IR-ET accumulating in the culture medium of ECs, incubated with or without platelets, and the decreasing effect of Phosphoramidon in the presence of platelets was greater than that in their absence. A similar effectiveness of Phosphoramidon was seen when transforming growth factor-beta 1 was used instead of platelets. Thus, platelets appear to stimulate the endothelial production of ET-1 in vitro, probably through a release of transforming growth factor-beta 1. We also suggest that the inhibition of ET converting enzyme by Phosphoramidon is more effective in the augmented condition of ET-1 production than in the basal condition.
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Phosphoramidon-sensitive endothelin converting enzyme in cultured vascular smooth muscle cells converts big endothelin-3 to endothelin-3
Life Sciences, 1993Co-Authors: Yaeko Tsukahara, Kazuko Kuninobu, Takayo Kojima, Masanori Takaoka, Yasuo Matsumura, Shiro MorimotoAbstract:Abstract Incubation of big endothelin-3 (big ET-3, 1–41) with the membrane fraction obtained from cultured vascular smooth muscle cells (VSMCs) resulted in time-dependent increases in immunoreactive-ET (IR-ET), which were suppressed by Phosphoramidon. Analysis of the incubation mixture by reverse-phase high performance liquid chromatography (RP-HPLC) confirmed that the IR-ET was due to the mature ET-3(1–21). ET-1 (1–21) generated during incubation of big ET-1 (1–39) with the membrane fraction was markedly suppressed by the addition of big ET-3 into the incubation mixture. When the cultured VSMCs were incubated with big ET-3, a conversion to the mature ET-3 was observed. This ET-3 generation from exogenously applied big ET-3 was also suppressed by Phosphoramidon. We conclude that the Phosphoramidon-sensitive ET converting enzyme in VSMCs converts big ET-1 and big ET-3 to their mature form.
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Big endothelin-3-induced hypertension and its inhibition by Phosphoramidon in anaesthetized rats.
European Journal of Pharmacology, 1993Co-Authors: Yasuo Matsumura, Katsuya Fujita, Masanori Takaoka, Shiro MorimotoAbstract:Abstract Intravenous injection of big endothelin-3 (big ET-3, 1–41 amide) at 3 nmol/kg to ganglion-blocked anaesthetized rats produced a long-lasting hypertensive action, but the action was less potent than that seen with the same dose of ET-3-(1–21). The pressor effect induced by big ET-3 was markedly attenuated by pretreatment with Phosphoramidon, 5 mg/kg i.v., a dose which had no effect on the hypertensive action induced by ET-3. These results strongly suggest that big ET-3 is converted to mature ET-3 by a Phosphoramidon-sensitive metalloproteinase in vivo, in a manner similar to the conversion of big ET-1 to ET-1.
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Phosphoramidon sensitive endothelin converting enzyme in vascular endothelial cells converts big endothelin 1 and big endothelin 3 to their mature form
FEBS Letters, 1992Co-Authors: Yasuo Matsumura, Yaeko Tsukahara, Kazuko Kuninobu, Masanori Takaoka, Shiro MorimotoAbstract:Incubation of big endothelin-3 (big ET-31–41) with the membrane fraction obtained from cultured endothelial cells (ECs) resulted in an increase in immunoreactive-ET (IR-ET). This increasing activity was markedly suppressed by Phosphoramidon, which is known to inhibit the conversion of big ET-11–39 to ET-11–21. Reverse-phase HPLC of the incubation mixture of the membrane fraction with big ET-3 revealed one major IR-ET component corresponding to the elution position of synthetic ET-31–21. When the cultured ECs were incubated with big ET-3, a conversion to the mature ET-3, as well as an endogenous ET-1 generation, was observed. Both responses were markedly suppressed by Phosphoramidon. By the gel filtration of 0.5% CHAPS-solubilized fraction of membrane pellets or ECs, the molecular mass of the proteinase which converts big ET-1 and big ET-3 to their mature form was estimated to be 300–350 kDa. Phosphoramidon almost completely abolished both converting activities of the proteinase. We conclude that the above type of Phosphoramidon-sensitive metalloproteinase functions as an ET-converting enzyme to generate the mature form from big ET-1 and big ET-3 in ECs.
Yaeko Tsukahara - One of the best experts on this subject based on the ideXlab platform.
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Phosphoramidon-sensitive endothelin converting enzyme in cultured vascular smooth muscle cells converts big endothelin-3 to endothelin-3
Life Sciences, 1993Co-Authors: Yaeko Tsukahara, Kazuko Kuninobu, Takayo Kojima, Masanori Takaoka, Yasuo Matsumura, Shiro MorimotoAbstract:Abstract Incubation of big endothelin-3 (big ET-3, 1–41) with the membrane fraction obtained from cultured vascular smooth muscle cells (VSMCs) resulted in time-dependent increases in immunoreactive-ET (IR-ET), which were suppressed by Phosphoramidon. Analysis of the incubation mixture by reverse-phase high performance liquid chromatography (RP-HPLC) confirmed that the IR-ET was due to the mature ET-3(1–21). ET-1 (1–21) generated during incubation of big ET-1 (1–39) with the membrane fraction was markedly suppressed by the addition of big ET-3 into the incubation mixture. When the cultured VSMCs were incubated with big ET-3, a conversion to the mature ET-3 was observed. This ET-3 generation from exogenously applied big ET-3 was also suppressed by Phosphoramidon. We conclude that the Phosphoramidon-sensitive ET converting enzyme in VSMCs converts big ET-1 and big ET-3 to their mature form.
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Phosphoramidon sensitive endothelin converting enzyme in vascular endothelial cells converts big endothelin 1 and big endothelin 3 to their mature form
FEBS Letters, 1992Co-Authors: Yasuo Matsumura, Yaeko Tsukahara, Kazuko Kuninobu, Masanori Takaoka, Shiro MorimotoAbstract:Incubation of big endothelin-3 (big ET-31–41) with the membrane fraction obtained from cultured endothelial cells (ECs) resulted in an increase in immunoreactive-ET (IR-ET). This increasing activity was markedly suppressed by Phosphoramidon, which is known to inhibit the conversion of big ET-11–39 to ET-11–21. Reverse-phase HPLC of the incubation mixture of the membrane fraction with big ET-3 revealed one major IR-ET component corresponding to the elution position of synthetic ET-31–21. When the cultured ECs were incubated with big ET-3, a conversion to the mature ET-3, as well as an endogenous ET-1 generation, was observed. Both responses were markedly suppressed by Phosphoramidon. By the gel filtration of 0.5% CHAPS-solubilized fraction of membrane pellets or ECs, the molecular mass of the proteinase which converts big ET-1 and big ET-3 to their mature form was estimated to be 300–350 kDa. Phosphoramidon almost completely abolished both converting activities of the proteinase. We conclude that the above type of Phosphoramidon-sensitive metalloproteinase functions as an ET-converting enzyme to generate the mature form from big ET-1 and big ET-3 in ECs.
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Phosphoramidon inhibits the generation of endothelin 1 from exogenously applied big endothelin 1 in cultured vascular endothelial cells and smooth muscle cells
FEBS Letters, 1991Co-Authors: Ruriko Ikegawa, Yaeko Tsukahara, Masanori Takaoka, Yasuo Matsumura, Shiro MorimotoAbstract:Abstract When cultured porcine aortic endothelial cells (ECs) were incubated with porcine big endothelin-1 (bit ET-I1–39), there was a time-dependent increase in immunoreactive (IR)-ET in the culture supernatant, in addition to an endogenous IR-ET release fron the cells. Reverse-phase HPLC of the culture supernatant revealed one major IR-ET component corresponding to the elution position of synthetic ET-1, thereby indicating that the additional increase in IR-ET was due to the conversion of big ET-1 to mature ET-11–21. Phosphoramidon, a metalloproteinase inhibitor, strongly suppressed this increase in IR-ET as well as the endogenous IR-ET release. Cultured vascular smooth muscle cells (VSMCs) also released IR-ET. The apparent conversion of exogenously applied big ET-1 to ET-1 and its inhibition by Phosphoramidon were observed using cultured VSMCs, although the enzyme inhibitor did not influence the basal secretion of IR-ET from VSMCs. These results suggest that both cultured ECs and VSMCs can generate ET-1 from exogenously applied big ET-1 via action of the same type of Phosphoramidon-sensitive metalloproteinase, which is also involved in the endogenous ET-1 generation in ECs.
Terry J. Opgenorth - One of the best experts on this subject based on the ideXlab platform.
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In vivo characterization of a Phosphoramidon-sensitive endothelin-converting enzyme in the rat.
European journal of pharmacology, 1993Co-Authors: David M. Pollock, Barbara J. Divish, Ivan Milicic, Eugene I. Novosad, Neal S. Burres, Terry J. OpgenorthAbstract:Abstract Experiments were conducted to characterize the nature of a Phosphoramidon-sensitive endothelin-converting enzyme in vivo by evaluating the pressor response to a bolus intravenous (i.v.) injection of endothelin family peptides following administration of Phosphoramidon in anesthetized Sprague-Dawley rats. Phosphoramidon given i.v. at 10 mg/kg completely prevented the pressor response to human big endothelin-1-(1–38) (big ET-1). The EC 50 for Phosphoramidon was determined to be in the range of 1 to 3 mg/kg. The pressor response to big ET-1 60 min after Phosphoramidon injection was attenuated by roughly 60% indicating a long inhibitory half-life. Very high doses of big ET-1 (> 20 mg/kg) were capable of over-riding the effect of Phosphoramidon and produced characteristic pressor responses suggesting that the inhibition by Phosphoramidon can be considered competitive in nature. Human big endothelin-3-(1–41) (big ET-3) produced significant increases in arterial pressure although with less potency and efficacy compared to big ET-1. The pressor response to big ET-3 was also inhibited by Phosphoramidon. Phosphoramidon does not act indirectly by interfering with ET-1 receptor-mediated actions since the inhibitor has no effect on the in vivo pressor response to ET-1 and does not antagonize [ 125 I]ET-1 receptor binding or constrictor responses in vitro. These results are consistent with the idea that a Phosphoramidon-sensitive endothelin-converting enzyme is capable of cleaving both big ET-1 and big ET-3 to the active peptides in the rat.
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rhamnose moiety of Phosphoramidon is not required for in vivo inhibition of endothelin converting enzyme
Biochemical and Biophysical Research Communications, 1992Co-Authors: David M. Pollock, Kazumi Shiosaki, Gerard M Sullivan, Terry J. OpgenorthAbstract:Abstract Experiments were conducted to determine the importance of the carbohydrate moiety of Phosphoramidon in the inhibition of the pressor response to big endothelin-1 in anesthetized rats. Big endothelin-1 produced a 42% increase in mean arterial pressure which was nearly abolished by co-infusion of Phosphoramidon. Similarly, when an analog of Phosphoramidon lacking the rhamnose group (phosphoryl-leu-trp-OH) was co-infused, a significant attenuation of the pressor response was observed. These findings indicate that the rhamnose moiety of Phosphoramidon is not responsible for distinguishing this compound as an inhibitor of the response to big endothelin-1 in the rat.