Idiopathic chronic constipation: tachykinins as cotransmitters in colonic contraction

Background Tachykinins (TKs) have been shown to be involved in the excitato ry enteric motor pathway. This study aimed to examine the direct and nerve- mediated effect of specific NK1, NK2 and NK3 receptor agonists and antagoni sts in colonic preparations from control subjects and patients with idiopat hic chronic constipation (ICC). Materials and methods Cumulative concentrations of Sar(9)Met(O-2)(11) subst ance P (selective NK1 receptor agonist), [Ala(5),b-Ala(8)]-neurokinin A (4- 10) (selective NK2 receptor agonist) and [MePhe(7)]-neurokinin B (selective NK3 receptor agonist) were tested on colonic circular muscle strips to eva luate the direct drug effects. In addition, in the presence of atropine, th e role of TKs in the off-contraction that follows the typical inhibitory re sponse 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: NK2 recepto r-selective agonist > NK3 receptor-selective agonist > NK1 receptor-selecti ve agonist. The off-contraction was found to be reduced by about 30-40% in colonic circular muscle from ICC patients with respect to controls. Incubat ion with the NK1 receptor agonist did not modify the off-contraction measur ements in either control or ICC preparations. Conversely, both NK2 and NK3 receptor agonists significantly (P < 0.01) increased the off-contraction in ICC preparations only. This increased response was fully antagonized by ME N-10627, a NK2 and NK3 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 NK2 and NK3 receptor agonists.