Evidence that PAR‐1 and PAR‐2 mediate prostanoid‐dependent contraction in isolated guinea‐pig gallbladder
Evidence that PAR‐1 and PAR‐2 mediate prostanoid‐dependent contraction in isolated guinea‐pig gallbladder
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DOI：
10.1038/sj.bjp.0703618
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发表时间：
2000-10
影响因子：
7.3
通讯作者：
M. Tognetto;M. Trevisani;B. Maggiore;G. Navarra;A. Turini;R. Guerrini;N. Bunnett;P. Geppetti;S. Harrison
中科院分区：
文献类型：
--
作者：
M. Tognetto;M. Trevisani;B. Maggiore;G. Navarra;A. Turini;R. Guerrini;N. Bunnett;P. Geppetti;S. Harrison
我们研究了蛋白酶激活受体-1（PAR-1）、PAR-2、PAR-3和PAR-4激动剂诱导离体豚鼠胆囊收缩反应的能力。凝血酶、胰蛋白酶、小鼠PAR-1活化（SFLLRN-NH 2）肽和小鼠PAR-2活化（SLIGRL‐ NH 2）和人PAR‐2活化（SLIGKV-NH 2）肽产生浓度依赖性收缩反应。（GYPGKF-NH 2）肽，小鼠PAR-1逆转（NRLLFS-NH 2）肽，小鼠PAR-2逆转（LRGILS-NH 2）和人PAR-2反向（VKGILS-NH2）肽在最高浓度下引起的收缩反应可以忽略不计。胰蛋白酶或凝血酶，并添加不同的PAR激动剂（分别为SFLLRN-NH 2和SLIGRL-NH 2）。对PAR-2激活肽的脱敏减弱了对胰蛋白酶的反应，但未能减弱对PAR-1激动剂的反应，相反地，对PAR-1的脱敏减弱了对凝血酶的反应，但未能改变对PAR-2激动剂的收缩反应。凝血酶、胰蛋白酶、SFLLRN-NH 2和SLIGRL-NH 2产生的收缩反应在环加氧酶抑制剂吲哚美辛的存在下显著降低，对凝血酶、胰蛋白酶、SFLLRN-NH 2和SLIGRL-NH 2的收缩反应不受非选择性毒蕈碱拮抗剂阿托品、一氧化氮合酶抑制剂L-NAME、钠通道阻断剂河豚毒素、一氧化氮合酶（NOS）抑制剂精氨酸甲酯（L-NAME）和一氧化氮合酶（NOS）抑制剂精氨酸甲酯（L-NAME）的影响。选择性速激肽NK 1和NK 2受体拮抗剂（S）-1-[2-[3-（3，4-dichlorophenyl）-1（3-异丙氧基苯乙酰基）哌啶-3-基]乙基]-4-苯基-1氮杂双环[2.2.2]辛烷氯化物（SR 140333）和（S）-N-甲基-N-[4-乙酰氨基-4-苯基哌啶子基-2-结果表明PAR-1和PAR-2激活引起豚鼠胆囊收缩反应，一种主要由前列腺素释放介导的作用，不依赖于神经机制，British Journal of Pharmacology（2000）131，689-694; doi：10.1038/sj.bjp.0703618
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.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.An additive effect was observed following the contractile response induced by either trypsin or thrombin, with the addition of a different PAR agonist (SFLLRN‐NH2and 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.The contractile responses produced by thrombin, trypsin, SFLLRN‐NH2and SLIGRL‐NH2were markedly reduced in the presence of the cyclo‐oxygenase inhibitor, indomethacin, whilst the small contractile response produced by NRLLFS‐NH2and LRGILS‐NH2were insensitive to indomethacin.The contractile responses to thrombin, trypsin, SFLLRN‐NH2and SLIGRL‐NH2were unaffected 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 NK1and NK2receptor antagonists, (S)‐1‐[2‐[3‐(3,4‐dichlorphenyl)‐1 (3‐isopropoxyphenylacetyl) 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.The results indicate that PAR‐1 and PAR‐2 activation causes contractile responses in the guinea‐pig gallbladder, an effect that is mediated principally by prostanoid release, and is independent of neural mechanisms.British Journal of Pharmacology(2000)131, 689–694; doi:10.1038/sj.bjp.0703618