Characterisation Of Functional Endothelin Receptors In The Canine Isolated Perfused Spleen

The endothelin receptor subtypes involved in the vasoconstriction, capsular smooth muscle contraction, prostaglandin E2 and prostacyclin release induced by endothelin-1 have been investigated in the canine isolated perfused spleen using both the endothelin ETA receptor antagonist FR 139317 and the endothelin ETB receptor agonist IRL 1620. The isolated canine spleen was perfused with warmed (37°C) and oxygenated (95% O2/5% CO2) Krebs solution at constant flow with continuous recording of splenic arterial perfusion pressure and spleen weight. Samples of splenic venous effluent were collected to determine the amounts of prostaglandin E2 and prostacyclin, measured by radioimmunoassay. Endothelin-1 (4-200 pmol) and IRL 1620 (20-1000 pmol) dose-dependently increased splenic arterial perfusion pressure but the former was more potent on a molar basis (the molar dose ratio IRL/endothelin-1 required to increase splenic arterial vascular resistance by 25% was approximately 33). The infusion of the nitric oxide inibitor Nω-nitro-l-arginine methyl ester (10 μM), but not of the enantiomer Nω-nitro-l-arginine methyl ester, significantly potentiated the increase in splenic arterial vascular resistance induced by endothelin-1. The infusion of FR 139317 (1 μM) markedly attenuated the increased splenic arterial perfusion pressure induced by endothelin-1 without affecting that evoked by IRL 1620. At the highest dose (200 pmol), endothelin-1 induced a small but significant capsule contraction as reflected by the reduction in the spleen weight. The infusion of FR 139317 (1 μM) abolished this contractile effect. IRL 1620 (in doses up to 1000 pmol) did not significantly affect the capsule tone. The administration of either endothelin-1 (20-200 pmol) or IRL 1620 (20-1000 pmol) caused the release of 6-oxo-prostaglandin F1α (breakdown product of prostacyclin) and prostaglandin E2 into the splenic venous effluent. The amount of both prostanoids released by endothelin-1 was significantly greater than that induced by IRL 1620. FR 139317 (1 μM) significantly reduced (P < 0.05) the release of both 6-oxo-prostaglandin F1α and prostaglandin E2 by endothelin-1 without affecting that released by IRL 1620. The results demonstrate that the release of prostaglandins and nitric oxide modulates the vasoconstrictor activity of endothelin-1 in the splenic circulation. Furthermore, the vasoconstriction and eicosanoids (prostacyclin and prostaglandin E2) release by endothelin-1 are due to activation of both endothelin ETA and ETB receptors, although the former seems to be the predominant form. 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Characterization of endothelin receptors in isolated, perfused human spleen

FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ – CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOAt present, there is no information on endothelin-1 (ET-1)-mediated vascular effects in the human spleen. The objectives of this study were to investigate the in vitro vascular responses to ET-1 using pharmacologic probes (selective ET receptor agonists/antagonists) and to characterize the ET receptor population in the human spleen. Spleens (n = 6) were removed from patients for treatment of underlying disease. The organs were perfused with warmed (37degreesC), oxygenated (95% O-2/5% CO2) Krebs solution at constant flow, with continuous recording of splenic arterial perfusion pressure (SAPP). The increases in SAPP caused by injection of ET-1 (ETA/ETB agonist) were markedly reduced in the presence of the selective ETA antagonist FR-139317, whereas those induced by IRL-1620 (an ETB agonist) and norepinephrine (NE) were unchanged. The increases in SAPP induced by intra-arterial bolus injections of NE and ET-1 were significantly (p < 0.05) potentiated by indomethacin [INDO; a cyclo-oxygenase (COX) inhibitor] alone and the responses to both peptides (ET-1 and IRL-1620) were significantly (p < 0.05) potentiated by INDO and L-NAME [a nitric oxide (NO) synthase inhibitor] together. We conclude that ET-1 contributes to the regulation of vascular tone in human spleen through activation of both ETA and ETB receptors and that these responses are modulated by concomitant release of prostaglandins and NOLippincott Williams & Wilkins311S551S553FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ – CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ – CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOsem informaçãosem informaçãoPhiladelphia, P

BERTIL OHLIN: Handelns teori. Akademisk avhandling. 169 Sider. Stockholm 1924.

FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCAPES - COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL E NÍVEL SUPERIORThe vascular effects of endothelin-1 (ET-1; ET(A)/ET(B) agonist), sarafotoxin 6b (S6b; ET(A) agonist), and IRL 1620 (ET(B) agonist) were investigated in the isolated canine liver arterial circuit before and alter infusions of indomethacin (cyclo-oxygenase inhibitor) and N(ω)L-nitro- arginine methyl ester (L-NAME; nitric oxide synthesis inhibitor). Norepinephrine (NE) was used as vasoconstrictor control agent. The portal vein, hepatic artery, and vena cava were cannulated in vitro and the liver was perfused via the hepatic artery and portal vein with oxygenated (95% O2/5% CO2) Krebs solution at 37°C. Intra-arterial bolus injections of either ET-1 (0.4-400 pmol) or S6b (0,4-400 pmol) induced dose-dependent and long-lasting vasoconstriction accompanied by significant prostacyclin release. The vasoconstrictor responses to these peptides were slightly increased during infusion of indomethacin. Subsequent infusion of L-NAME potentiated both ET-1- and S6b-induced vasoconstriction (p &lt; 0.05). IRL 1620 (up to 1.2 nmol) had no effect on the hepatic arterial vascular resistance even during indomethacin and L-NAME infusions. Infusion of the ET(A) receptor antagonist FR-139317 (0.3 μM) markedly reduced both ET-1- and S6b-induced vasoconstriction without affecting that evoked by NE. Our results indicate that pressor responses to ET-1 and S6b in the isolated canine liver are modulated by concomitant release of vasodilator mediators, including prostacyclin and nitric oxide. These effects appear to depend primarily on the activation of ET(A) receptor subtypes. IRL 1620 (but not ET-1) induced a significant release of hemoglobin into the venous effluent, suggesting that ET(B) receptors are located in the venous side of the intrahepatic circulation.The vascular effects of endothelin-1 (ET-1; ET(A)/ET(B) agonist), sarafotoxin 6b (S6b; ET(A) agonist), and IRL 1620 (ET(B) agonist) were investigated in the isolated canine liver arterial circuit before and alter infusions of indomethacin (cyclo-oxygenase inhibitor) and N(ω)L-nitro- arginine methyl ester (L-NAME; nitric oxide synthesis inhibitor). Norepinephrine (NE) was used as vasoconstrictor control agent. The portal vein, hepatic artery, and vena cava were cannulated in vitro and the liver was perfused via the hepatic artery and portal vein with oxygenated (95% O2/5% CO2) Krebs solution at 37°C. Intra-arterial bolus injections of either ET-1 (0.4-400 pmol) or S6b (0,4-400 pmol) induced dose-dependent and long-lasting vasoconstriction accompanied by significant prostacyclin release. The vasoconstrictor responses to these peptides were slightly increased during infusion of indomethacin. Subsequent infusion of L-NAME potentiated both ET-1- and S6b-induced vasoconstriction (p &lt; 0.05). IRL 1620 (up to 1.2 nmol) had no effect on the hepatic arterial vascular resistance even during indomethacin and L-NAME infusions. Infusion of the ET(A) receptor antagonist FR-139317 (0.3 μM) markedly reduced both ET-1- and S6b-induced vasoconstriction without affecting that evoked by NE. Our results indicate that pressor responses to ET-1 and S6b in the isolated canine liver are modulated by concomitant release of vasodilator mediators, including prostacyclin and nitric oxide. These effects appear to depend primarily on the activation of ET(A) receptor subtypes. IRL 1620 (but not ET-1) induced a significant release of hemoglobin into the venous effluent, suggesting that ET(B) receptors are located in the venous side of the intrahepatic circulation26S204S207FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCAPES - COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL E NÍVEL SUPERIORFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCAPES - COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL E NÍVEL SUPERIORsem informaçãosem informaçã