毒蕈碱受体阻断对犬活体胃张力和顺应性的影响。

Moro Elisabetta, Crema Francesca, Dandolo Cosimo, De Ponti Fabrizio, Frigo Gianmario

Department of Internal Medicine and Therapeutics, University of Pavia, Piazza Botta, 10, 27100 Pavia PV, Italy.

Pharmacol Res. 2005 Apr;51(4):289-96. doi: 10.1016/j.phrs.2004.09.007.

Muscarinic pathways are involved in maintaining gastric tone during fasting and atropine is known to decrease gastric tone via blockade of a tonic vagal cholinergic input. Our aim was to assess the role of different muscarinic receptors in modulating canine gastric tone and compliance in vivo by using "selective" muscarinic receptor antagonists (telenzepine, AF-DX 116 and 4-DAMP for M1, M2, and M3 receptors, respectively) and the non-selective muscarinic receptor antagonist atropine. In four fasting, conscious dogs, we characterized the pressure-volume relationship in the proximal stomach by using a barostat. Drug effects were investigated by studying pressure-volume relationships before and 15 min after intravenous administration telenzepine, AF-DX 116, 4-DAMP or atropine. Pressure-volume curves were fitted by non-linear regression analysis. Before drug administration, the curve that best fitted the pressure-volume relationship was exponential. Atropine (100 microg kg-1) immediately decreased baseline gastric tone, i.e. relaxed the stomach (Deltavolume at 2 mmHg=236+/-15 ml; P<0.05), and significantly (P<0.01) shifted the pressure-volume curve to the left. Telenzepine, at the lowest dose (3 microg kg-1), shifted the pressure-volume curve to the right (P<0.01). AF-DX 116 at the lower dose (422 microg kg-1) had no effect on baseline gastric tone or the gastric pressure-volume curve, whereas the higher dose (2532 microg kg-1) significantly shifted the pressure-volume curve to the left (P<0.01), but did not increase baseline gastric volume. Finally, 4-DAMP (13.5, 45, 135 microg kg-1) immediately decreased baseline gastric tone (Deltavolume at 2 mmHg=97+/-29 ml, 110+/-35 ml and 155+/-21 ml, respectively) and significantly shifted the pressure-volume curve to the left (P<0.01). We conclude that muscarinic pathways are involved in modulating canine gastric tone and compliance during fasting: M3 receptors seem to play a key role in excitatory pathways, whereas the shift of pressure-volume curve to the right observed with the lowest dose of telenzepine is consistent with the existence of M1 receptors on inhibitory pathways.

毒蕈碱通路参与禁食期间胃张力的维持，已知阿托品可通过阻断迷走神经的紧张性胆碱能输入来降低胃张力。我们的目的是通过使用“选择性”毒蕈碱受体拮抗剂（分别用于M1、M2和M3受体的替仑西平、AF-DX 116和4-二甲基氨基吡啶）和非选择性毒蕈碱受体拮抗剂阿托品，评估不同毒蕈碱受体在体内调节犬胃张力和顺应性中的作用。在四只禁食的清醒犬中，我们使用压力调节器对胃近端的压力-容积关系进行了表征。通过研究静脉注射替仑西平、AF-DX 116、4-二甲基氨基吡啶或阿托品前及给药后15分钟的压力-容积关系来研究药物的作用。压力-容积曲线通过非线性回归分析进行拟合。在给药前，最能拟合压力-容积关系的曲线是指数曲线。阿托品（100μg/kg-1）立即降低了基线胃张力，即使胃松弛（2mmHg时的容积变化=236±15ml；P<0.05），并使压力-容积曲线显著（P<0.01）向左移位。替仑西平在最低剂量（3μg/kg-1）时使压力-容积曲线向右移位（P<0.01）。较低剂量（422μg/kg-1）的AF-DX 116对基线胃张力或胃压力-容积曲线无影响，而较高剂量（2532μg/kg-1）则使压力-容积曲线显著向左移位（P<0.01），但未增加基线胃容积。最后，4-二甲基氨基吡啶（13.5、45、135μg/kg-1）立即降低了基线胃张力（2mmHg时的容积变化分别为97±29ml、110±35ml和155±21ml），并使压力-容积曲线显著向左移位（P<0.01）。我们得出结论，毒蕈碱通路参与禁食期间犬胃张力和顺应性的调节：M3受体似乎在兴奋性通路中起关键作用，而最低剂量替仑西平观察到的压力-容积曲线向右移位与抑制性通路上存在M1受体一致。