Idiopathic chronic constipation: tachykinins as cotransmitters in colonic contraction

Background Tachykinins (TKs) have been shown to be involved in the excitatory enteric motor pathway. This study aimed to examine the direct and nerve-mediated effect of specific NK 1 , NK 2 and NK 3 receptor agonists and antagonists in colonic preparations from control subjects and patients with idiopathic chronic constipation (ICC). Materials and methods Cumulative concentrations of Sar 9 Met(O 2 ) 11 substance P (selective NK 1 receptor agonist), [Ala 5 ,b-Ala 8 ]-neurokinin A (4-10) (selective NK 2 receptor agonist) and [MePhe 7 ]-neurokinin B (selective NK 3 receptor agonist) were tested on colonic circular muscle strips to evaluate the direct drug effects. In addition, in the presence of atropine, the role of TKs in the off-contraction that follows the typical inhibitory response evoked by low frequencies of electrical field stimulation (0.5-10 Hz, 20 V, 1 ms pulse trains lasting 1 min) was investigated. Results In control preparations, the rank order of potency was: NK 2 receptor-selective agonist > NK 3 receptor-selective agonist > NK 1 receptor-selective agonist. The off-contraction was found to be reduced by about 30-40% in colonic circular muscle from ICC patients with respect to controls. Incubation with the NK 1 receptor agonist did not modify the off-contraction measurements in either control or ICC preparations. Conversely, both NK 2 and NK 3 receptor agonists significantly (P < 0.01) increased the off-contraction in ICC preparations only. This increased response was fully antagonized by MEN-10627, a NK 2 and NK 3 receptor antagonist depending on the dose. Conclusions We may conclude that ICC is hyporesponsive to TKs and that the contractile reflex to distension is greatly reduced in ICC disease, but can be restored by incubation with NK 2 and NK 3 receptor agonists.