Onori L, Aggio A, Taddei G, Tonini M
Department of Internal Medicine and Public Health, University of L'Aquila, 67100 L'Aquila, Italy.
Am J Physiol Gastrointest Liver Physiol. 2000 Jan;278(1):G137-47. doi: 10.1152/ajpgi.2000.278.1.G137.
The role of the tachykinin neurokinin (NK)(2) receptors on rabbit distal colon propulsion was investigated by using two selective NK(2)-receptor antagonists, MEN-10627 and SR-48968. Experiments on colonic circular muscle strips showed that contractile responses to [beta-Ala(8)]NKA-(4-10) (1 nM-1 microM), a selective NK(2)-receptor agonist, were competitively antagonized by MEN-10627 (1-100 nM), whereas SR-48968 (0.1-10 nM) caused an insurmountable antagonism, thus confirming the difference in the mode of action of the two compounds. Colonic propulsion was elicited by distending a mobile rubber balloon with 0.3 ml (submaximal stimulus) or 1.0 ml (maximal stimulus) of water. The velocity of anal displacement of the balloon (mm/s) was considered the main propulsion parameter. At low concentrations (1.0-100 nM and 0.1-10 nM, respectively), MEN-10627 and SR-48968 facilitated the velocity of propulsion, whereas at high concentrations (100 nM and 1 microM, respectively) they decelerated propulsion. The excitatory and inhibitory effects of both antagonists were observed only with submaximal stimulus. We focused on the hypothesis that the facilitatory effect on propulsion may result from blockade of neuronal NK(2) receptors and the inhibitory effect from suppression of the excitatory transmission mediated by NK(2) receptors on smooth muscle cells. In the presence of N(G)-nitro-L-arginine (300 microM), a nitric oxide synthase inhibitor, MEN-10627, at a concentration (10 nM) that was found to accelerate propulsion in control experiments inhibited the velocity of propulsion. In the presence of threshold (1-10 nM) or full (1 microM) concentration of atropine, which inhibited to a great extent the velocity of propulsion, the inhibitory effect of MEN-10627 (1 microM) was markedly increased. In conclusion, in the rabbit distal colon NK(2) receptors may decelerate propulsion by activating a nitric oxide-dependent neuronal mechanism and may accelerate it by a postjunctional synergistic interaction with cholinergic muscarinic receptors.
通过使用两种选择性神经激肽（NK）（2）受体拮抗剂MEN-10627和SR-48968，研究了速激肽神经激肽（NK）（2）受体对兔远端结肠推进作用的影响。对结肠环形肌条的实验表明，选择性NK（2）受体激动剂[β-丙氨酸（8）]NKA-（4-10）（1 nM - 1 μM）引起的收缩反应被MEN-10627（1 - 100 nM）竞争性拮抗，而SR-48968（0.1 - 10 nM）引起不可克服的拮抗作用，从而证实了这两种化合物作用方式的差异。通过向可移动的橡胶球囊中注入0.3 ml（次最大刺激）或1.0 ml（最大刺激）水来引发结肠推进。球囊肛门位移速度（mm/s）被视为主要推进参数。在低浓度（分别为1.0 - 100 nM和0.1 - 10 nM）时，MEN-10627和SR-48968促进推进速度，而在高浓度（分别为100 nM和1 μM）时它们使推进减速。两种拮抗剂的兴奋和抑制作用仅在次最大刺激时观察到。我们关注这样一种假设，即对推进的促进作用可能源于神经元NK（2）受体的阻断，而抑制作用源于NK（2）受体介导的平滑肌细胞兴奋传递的抑制。在一氧化氮合酶抑制剂N（G）-硝基-L-精氨酸（300 μM）存在的情况下，在对照实验中发现能加速推进的浓度（10 nM）的MEN-10627抑制了推进速度。在阈值（1 - 10 nM）或完全（1 μM）浓度的阿托品存在的情况下，阿托品在很大程度上抑制了推进速度，MEN-1（1 μM）的抑制作用明显增强。总之，在兔远端结肠中，NK（2）受体可能通过激活一氧化氮依赖性神经元机制使推进减速，并可能通过与胆碱能毒蕈碱受体的接头后协同相互作用使其加速。
