Zagorodnyuk V, Santicioli P, Maggi C A
Department of Neuro-muscular Physiology, Bogomoletz Institute of Physiology, Kiev, Ukraine.
Eur J Pharmacol. 1994 Apr 1;255(1-3):9-15. doi: 10.1016/0014-2999(94)90076-0.
We used an electrophysiological approach (single sucrose gap) to compare the mechanism of action of selective tachykinin NK1 and NK2 receptor agonists ([Sar9]substance P sulfone and [beta ala8]neurokinin A-(4-10), respectively) in producing contraction of the circular muscle of the guinea-pig proximal colon. [Sar9]Substance P sulfone produced a marked depolarization, action potentials and increase in membrane conductance. On the other hand, [beta Ala8]neurokinin A-(4-10) produced less depolarization of the cell membrane and did not change membrane resistance. Nifedipine (1 microM) greatly reduced (80% inhibition) the contraction due to [Sar9]substance P sulfone while that due to [beta Ala8]neurokinin A-(4-10) was slightly affected (13% inhibition). Action potentials induced by either agonist were suppressed by nifedipine, while depolarization was reduced only to a minor extent. When tested in a Ca(2+)-free medium, the contraction produced by either agonist was greatly reduced (84-89%) as compared to the control. In organ bath experiments [Sar9]substance P sulfone and [beta Ala8]neurokinin A-(4-10) produced concentration-dependent contraction of the circular muscle of the colon (EC50 8 and 12 nM, respectively). Nifedipine (1 microM) markedly suppressed the response to [Sar9]substance P sulfone while that to [beta Ala8]neurokinin A-(4-10) was only slightly depressed. These findings demonstrate that NK1 receptor-mediated contraction is strictly linked to membrane depolarization and action potentials generation through nifedipine-sensitive Ca2+ channels (electromechanical coupling) while the NK2 receptor-mediated contraction is substantially unrelated to depolarization and, while being largely dependent upon extracellular Ca2+, is nifedipine-resistant, possibly linked to the opening of non-selective (Ca(2+)-permeable) receptor-gated cation channels (pharmacomechanical coupling).
我们采用电生理方法（单蔗糖间隙法）比较了选择性速激肽NK1和NK2受体激动剂（分别为[Sar9]P物质砜和[βala8]神经激肽A-(4-10)）对豚鼠近端结肠环行肌收缩作用的机制。[Sar9]P物质砜可引起明显的去极化、动作电位和膜电导增加。另一方面，[βAla8]神经激肽A-(4-10)引起的细胞膜去极化较小，且不改变膜电阻。硝苯地平（1微摩尔）可显著降低（80%抑制）由[Sar9]P物质砜引起的收缩，而对[βAla8]神经激肽A-(4-10)引起的收缩仅有轻微影响（13%抑制）。两种激动剂诱导的动作电位均被硝苯地平抑制，而去极化仅略有降低。当在无钙培养基中进行测试时，与对照组相比，两种激动剂引起的收缩均显著降低（84-89%）。在器官浴实验中，[Sar9]P物质砜和[βAla8]神经激肽A-(4-10)可引起结肠环行肌浓度依赖性收缩（EC50分别为8和12纳摩尔）。硝苯地平（1微摩尔）可显著抑制对[Sar9]P物质砜的反应，而对[βAla8]神经激肽A-(4-10)的反应仅有轻微抑制。这些发现表明，NK1受体介导的收缩与膜去极化和通过硝苯地平敏感的Ca2+通道产生动作电位密切相关（电机械偶联），而NK2受体介导的收缩与去极化基本无关，虽然在很大程度上依赖细胞外Ca2+，但对硝苯地平耐药，可能与非选择性（Ca(2+)通透）受体门控阳离子通道的开放有关（药物机械偶联）。
