1 We have investigated the ability of protease-activated receptor-1 (PAR-1), PAR-2, PAR-3 and PAR-4 agonists to induce contractile responses in isolated guinea-pig gallbladder. Thrombin, trypsin, mouse PAR-1 activating (SFLLRN-NH2) peptide, and mouse PAR-2 activating (SLIGRL- NH2) and human PAR-2 activating (SLIGKV-NH2) peptides produced a concentration-dependent contractile response. 2 Mouse PAR-4 activating (GYPGKF-NH2) peptide, the mouse PAR-1 reverse (NRLLFS-NH2) peptide, the mouse PAR-2 reverse (LRGILS-NH2) and human PAR-2 reverse (VKGILS-NH2) peptides caused negligible contractile responses at the highest concentrations tested. 3 An additive e ect was observed following the contractile response induced by either trypsin or thrombin, with the addition of a di erent PAR agonist (SFLLRN-NH2 and SLIGRL-NH2, respectively). Desensitization to PAR-2 activating peptide attenuated the response to trypsin but failed to attenuate the response to PAR-1 agonists, and conversely desensitization to PAR-1 attenuated the response to thrombin but failed to alter contractile responses to PAR-2 agonists. 4 The contractile responses produced by thrombin, trypsin, SFLLRN-NH2 and SLIGRL-NH2 were markedly reduced in the presence of the cyclo-oxygenase inhibitor, indomethacin, whilst the small contractile response produced by NRLLFS-NH2 and LRGILS-NH2 were insensitive to indomethacin. 5 The contractile responses to thrombin, trypsin, SFLLRN-NH2 and SLIGRL-NH2 were una ected by the presence of: the non-selective muscarinic antagonist, atropine; the nitric oxide synthase inhibitor, L-NAME; the sodium channel blocker, tetrodotoxin; the combination of selective tachykinin NK1 and NK2 receptor antagonists, (S)-1-[2-[3-(3,4-dichlorphenyl)-1 (3-isopropoxyphe- nylacetyl) piperidin-3-yl] ethyl]-4-phenyl-1 azaniabicyclo [2.2.2] octane chloride (SR140333) and (S)- N-methyl-N-[4-acetylamino-4-phenylpiperidino-2-(3,4-dichlorophenyl)-butyl] benzamide (SR48968), respectively. 6 The results indicate that PAR-1 and PAR-2 activation causes contractile responses in the guinea- pig gallbladder, an e ect that is mediated principally by prostanoid release, and is independent of neural mechanisms.

Evidence that PAR-1 and PAR-2 mediate prostanoid-dependent contraction in isolated guinea-pig gallbladder

GUERRINI, Remo;
2000

Abstract

1 We have investigated the ability of protease-activated receptor-1 (PAR-1), PAR-2, PAR-3 and PAR-4 agonists to induce contractile responses in isolated guinea-pig gallbladder. Thrombin, trypsin, mouse PAR-1 activating (SFLLRN-NH2) peptide, and mouse PAR-2 activating (SLIGRL- NH2) and human PAR-2 activating (SLIGKV-NH2) peptides produced a concentration-dependent contractile response. 2 Mouse PAR-4 activating (GYPGKF-NH2) peptide, the mouse PAR-1 reverse (NRLLFS-NH2) peptide, the mouse PAR-2 reverse (LRGILS-NH2) and human PAR-2 reverse (VKGILS-NH2) peptides caused negligible contractile responses at the highest concentrations tested. 3 An additive e ect was observed following the contractile response induced by either trypsin or thrombin, with the addition of a di erent PAR agonist (SFLLRN-NH2 and SLIGRL-NH2, respectively). Desensitization to PAR-2 activating peptide attenuated the response to trypsin but failed to attenuate the response to PAR-1 agonists, and conversely desensitization to PAR-1 attenuated the response to thrombin but failed to alter contractile responses to PAR-2 agonists. 4 The contractile responses produced by thrombin, trypsin, SFLLRN-NH2 and SLIGRL-NH2 were markedly reduced in the presence of the cyclo-oxygenase inhibitor, indomethacin, whilst the small contractile response produced by NRLLFS-NH2 and LRGILS-NH2 were insensitive to indomethacin. 5 The contractile responses to thrombin, trypsin, SFLLRN-NH2 and SLIGRL-NH2 were una ected by the presence of: the non-selective muscarinic antagonist, atropine; the nitric oxide synthase inhibitor, L-NAME; the sodium channel blocker, tetrodotoxin; the combination of selective tachykinin NK1 and NK2 receptor antagonists, (S)-1-[2-[3-(3,4-dichlorphenyl)-1 (3-isopropoxyphe- nylacetyl) piperidin-3-yl] ethyl]-4-phenyl-1 azaniabicyclo [2.2.2] octane chloride (SR140333) and (S)- N-methyl-N-[4-acetylamino-4-phenylpiperidino-2-(3,4-dichlorophenyl)-butyl] benzamide (SR48968), respectively. 6 The results indicate that PAR-1 and PAR-2 activation causes contractile responses in the guinea- pig gallbladder, an e ect that is mediated principally by prostanoid release, and is independent of neural mechanisms.
2000
Tognetto, M; Trevisani, M; Maggiore, B; Navarra, G; Turini, A; Guerrini, Remo; Bunnett, Nw; Geppetti, P; Harrison, S.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/470845
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