Traserra Sara, Alcalá-González Luis Gerardo, Barber Claudia, Landolfi Stefania, Malagelada Carolina, Lange Robert, Appelqvist Terence, Corsetti Maura, Jimenez Marcel
Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona, Spain.
Digestive System Research Unit, Vall d'Hebron University Hospital, Barcelona, Spain.
Front Pharmacol. 2025 Apr 22;16:1491123. doi: 10.3389/fphar.2025.1491123. eCollection 2025.
Antispasmodic agents are used to treat abdominal pain. The mode of action of pinaverium bromide and propinox in the colonic tissue has never been characterized. This study aimed to explore whether HBB can complement the antispasmodic effects of these drugs.
Colon samples were procured from the macroscopically normal regions of 33 patients undergoing colon cancer surgery and subjected to muscle bath experiments. Pinaverium bromide and propinox alone and in combination with HBB were assessed under the following conditions: (1) spontaneous phasic contractions (SPCs) induced by isometric stretch (with 1 µM tetrodotoxin); (2) contractility induced by 10 M carbachol; (3) the electrical field stimulation (EFS) of the excitatory pathway (in the presence of 1 mM Nω-nitro-L-arginine and 10 µM MRS2179); and (4) an EFS-induced selective excitation of the inhibitory pathway (under nonadrenergic, noncholinergic pharmacological conditions). An isobolographic study was performed to evaluate the possible interaction between pinaverium bromide, or propinox and HBB.
Pinaverium bromide and propinox concentration-dependently reduced SPC (10 M: 29%-47% reduction) in both muscle layers. Carbachol-induced contractions were partially reduced by pinaverium bromide (10 M: 37%-46% reduction) and propinox (10 M: 32%-44% reduction) and almost totally inhibited by the combination with HBB. EFS-induced contractions were slightly decreased by pinaverium bromide (10 M; circular muscle: 39% reduction, but no effect on longitudinal muscle) and propinox (10 M: circular 48% and longitudinal 37%), and to a greater extent, by the combination with HBB. Both pinaverium bromide (10 M: 11%) and propinox (10 M: 42%) reduced the EFS-induced off-response but not the on-relaxation. The interaction index measured for the combined activity of HBB with pinaverium bromide or propinox was less than 1 in SPC, carbachol-induced contractions, and EFS-induced contractions.
The pharmacological profile obtained in this study was consistent with an L-type calcium channel blocker for both pinaverium bromide and propinox, with an unlikely or a weak antimuscarinic effect for the latter. When combined with the antimuscarinic agent HBB, both pinaverium bromide and propinox showed a synergistic inhibition of contractile responses. This finding could have clinical implications, suggesting a combination treatment approach for greater therapeutic benefits.
解痉剂用于治疗腹痛。溴哌维林和丙哌卡因在结肠组织中的作用模式尚未明确。本研究旨在探讨HBB是否能增强这些药物的解痉作用。
从33例接受结肠癌手术患者的宏观正常区域获取结肠样本，进行肌肉浴实验。分别评估溴哌维林和丙哌卡因单独使用以及与HBB联合使用时在以下条件下的情况：（1）等长拉伸诱导的自发相性收缩（SPCs）（使用1 μM河豚毒素）；（2）10 μM卡巴胆碱诱导的收缩性；（3）兴奋性通路的电场刺激（EFS）（在存在1 mM Nω-硝基-L-精氨酸和10 μM MRS2179的情况下）；（4）EFS诱导的抑制性通路的选择性兴奋（在非肾上腺素能、非胆碱能药理学条件下）。进行等张线图研究以评估溴哌维林或丙哌卡因与HBB之间可能的相互作用。
溴哌维林和丙哌卡因均浓度依赖性地降低了两层肌肉中的SPC（10 μM：降低29%-47%）。卡巴胆碱诱导的收缩被溴哌维林（10 μM：降低37%-46%）和丙哌卡因（10 μM：降低32%-44%）部分降低，与HBB联合使用时几乎完全被抑制。EFS诱导的收缩被溴哌维林（10 μM；环形肌：降低39%，但对纵行肌无影响）和丙哌卡因（10 μM：环形肌降低48%，纵行肌降低37%）轻微降低，与HBB联合使用时降低程度更大。溴哌维林（10 μM：降低11%）和丙哌卡因（10 μM：降低42%）均降低了EFS诱导的舒张后反应，但不影响舒张前松弛。在SPC、卡巴胆碱诱导的收缩和EFS诱导的收缩中，HBB与溴哌维林或丙哌卡因联合活性的相互作用指数小于1。
本研究中获得的药理学特征表明，溴哌维林和丙哌卡因均与L型钙通道阻滞剂一致，后者抗毒蕈碱作用不太可能或较弱。当与抗毒蕈碱剂HBB联合使用时，溴哌维林和丙哌卡因均显示出对收缩反应的协同抑制作用。这一发现可能具有临床意义，提示联合治疗方法可能带来更大的治疗益处。
