同工酶选择性磷酸二酯酶抑制剂对豚鼠和大鼠回肠乙酰甲胆碱诱导收缩的影响。

The effect of isoenzyme-selective PDE inhibitors on methacholine-induced contraction of guinea-pig and rat ileum.

作者信息

Tomkinson A, Raeburn D

机构信息

Rhône-Poulenc Rorer Ltd., Dagenham Research Centre, Essex.

出版信息

Br J Pharmacol. 1996 Aug;118(8):2131-9. doi: 10.1111/j.1476-5381.1996.tb15653.x.

DOI:10.1111/j.1476-5381.1996.tb15653.x

PMID:8864552

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1909903/

Abstract

We have examined the effects of the isoenzyme-selective phosphodiesterase (PDE) inhibitors, vinpocetine (type 1), siguazodan (type 3), rolipram (type 4) and zaprinast (type 5) and the non-selective PDE inhibitor enprofylline on methacholine (MCh) contractile concentration-response curves on guinea-pig and rat isolated ileum. 2. In guinea-pig ileum, vinpocetine (10-300 microM), zaprinast (1-300 microM) and enprofylline (100-1000 microM) produced a concentration-dependent depression of the maximum response (Emax) to MCh only without effect on the MCh EC50 values (rank order of potency: zaprinast > vinpocetine > enprofylline). In contrast, siguazodan (10-300 microM) and rolipram (10-300 microM) produced a rightward displacement of the MCh concentration-response curve (increase in EC50: rank order; rolipram > siguazodan), with effects on the MCh maximum seen only at higher concentrations. 3. In the rat ileum, vinpocetine (10-300 microM), zaprinast (0.1-300 microM) and enprofylline (100-1000 microM) caused depression of the MCh maximum contraction (rank order: zaprinast > vinpocetine > enprofylline). Low concentrations of rolipram and siguazodan had no significant effect on the MCh maximum. In the presence of higher concentrations (> 100 microM) of rolipram and siguazodan, a maximum response was not achieved at the highest concentration of MCh tested. As in the guinea-pig ileum, only rolipram (10-300 microM) and siguazodan (10-300 microM) produced a significant, concentration-dependent, rightward displacement of the MCh concentration-response curve (increase in EC50: rank order: rolipram > siguazodan). 4. In the guinea-pig ileum, isoprenaline (0.1 microM) produced a rightward displacement (approximately 3 fold) of the MCh concentration-response curve, accompanied by a significant depression of the maximum response. Increasing the isoprenaline concentration (1 microM) had no further effect on either parameter. Sodium nitroprusside (SNP, > or = 10 microM) produced a concentration-dependent depression of the MCh maximum without an effect on the EC50. 5. In the rat ileum, isoprenaline (1 microM) produced a concentration-dependent rightward displacement (approximately 2.8 fold) of the MCh concentration-response curve with depression of the MCh maximum at higher (> or = 100 microM) concentrations. SNP produced depression of the MCh maximum at a concentration of 10 microM and above. Effects on the MCh EC50 were seen only at 100 and 300 microM. 6. In guinea-pig ileum, isoprenaline (0.1 microM) in combination with rolipram (10 microM) further increased the MCh EC50 and reduced the MCh maximum. The combination of SNP (10 microM) with zaprinast (0.1 microM) produced no further significant effect than SNP alone. 7. In rat ileum, isoprenaline (1 microM) in combination with rolipram (10 microM) further increased the EC50 and reduced the maximum. SNP (10 microM) had no significant effect on either the MCh maximum or EC50. A combination with zaprinast (1 microM) had no further effect. 8. In conclusion, all the PDE inhibitors tested produced a concentration-dependent inhibition of the MCh concentration-response curve, indicating a modulator role for the PDE isoenzymes in gastrointestinal smooth muscle contractility. The PDE inhibitors that elevate cyclic GMP produced a depression of the MCh maximum response only, whilst those that elevate cyclic AMP produced a rightward displacement of the MCh concentration-response curve. This was confirmed by the use of isoprenaline and SNP. This difference in the type of inhibition produced by these PDE isoenzyme inhibitors may reflect a different intracellular site/mechanism by which the cyclic AMP- and cyclic GMP-activated kinases act functionally to antagonize the contractile response.

摘要

我们研究了同工酶选择性磷酸二酯酶（PDE）抑制剂长春西汀（1型）、西呱唑旦（3型）、咯利普兰（4型）和扎普司特（5型）以及非选择性PDE抑制剂恩丙茶碱对豚鼠和大鼠离体回肠上乙酰甲胆碱（MCh）收缩浓度 - 反应曲线的影响。2. 在豚鼠回肠中，长春西汀（10 - 300μM）、扎普司特（1 - 300μM）和恩丙茶碱（100 - 1000μM）仅使对MCh的最大反应（Emax）产生浓度依赖性降低，而对MCh的半数有效浓度（EC50）值无影响（效力顺序：扎普司特＞长春西汀＞恩丙茶碱）。相比之下，西呱唑旦（10 - 300μM）和咯利普兰（10 - 300μM）使MCh浓度 - 反应曲线向右移位（EC50增加：顺序为；咯利普兰＞西呱唑旦），仅在较高浓度时才对MCh的最大值有影响。3. 在大鼠回肠中，长春西汀（10 - 300μM）、扎普司特（0.1 - 300μM）和恩丙茶碱（100 - 1000μM）导致MCh最大收缩降低（顺序：扎普司特＞长春西汀＞恩丙茶碱）。低浓度的咯利普兰和西呱唑旦对MCh的最大值无显著影响。在存在较高浓度（＞100μM）的咯利普兰和西呱唑旦时，在测试的最高MCh浓度下未达到最大反应。与豚鼠回肠一样，仅咯利普兰（10 - 300μM）和西呱唑旦（10 - 300μM）使MCh浓度 - 反应曲线产生显著的、浓度依赖性的向右移位（EC50增加：顺序：咯利普兰＞西呱唑旦）。4. 在豚鼠回肠中，异丙肾上腺素（0.1μM）使MCh浓度 - 反应曲线向右移位（约3倍），同时最大反应显著降低。增加异丙肾上腺素浓度（1μM）对这两个参数均无进一步影响。硝普钠（SNP，≥10μM）使MCh的最大值产生浓度依赖性降低，而对EC50无影响。。5. 在大鼠回肠中，异丙肾上腺素（1μM）使MCh浓度 - 反应曲线产生浓度依赖性向右移位（约2.8倍），在较高（≥100μM）浓度时MCh的最大值降低。SNP在浓度为10μM及以上时使MCh的最大值降低。仅在100和300μM时观察到对MCh EC50的影响。6. 在豚鼠回肠中，异丙肾上腺素（0.1μM）与咯利普兰（10μM）联合使用进一步增加了MCh的EC50并降低了MCh的最大值。SNP（10μM）与扎普司特（0.1μM）联合使用比单独使用SNP没有产生进一步的显著影响。7. 在大鼠回肠中，异丙肾上腺素（1μM）与咯利普兰（10μM）联合使用进一步增加了EC50并降低了最大值。SNP（10μM）对MCh的最大值或EC50均无显著影响。与扎普司特（1μM）联合使用没有进一步影响。8. 总之，所有测试的PDE抑制剂均对MCh浓度 - 反应曲线产生浓度依赖性抑制，表明PDE同工酶在胃肠平滑肌收缩性中起调节作用。升高环鸟苷酸（cGMP）的PDE抑制剂仅使MCh的最大反应降低，而升高环磷酸腺苷（cAMP）的抑制剂使MCh浓度 - 反应曲线向右移位。这通过使用异丙肾上腺素和SNP得到证实。这些PDE同工酶抑制剂产生的抑制类型的差异可能反映了cAMP和cGMP激活的激酶在功能上拮抗收缩反应的不同细胞内位点/机制。