REGIONAL DIFFERENCES IN MOTOR RESPONSIVENESS TO ANTIMUSCARINIC DRUGS IN RABBIT ISOLATED SMALL AND LARGE-INTESTINE

The pirenzepine-related analogue, nuvenzepine, and the antagonists selective for the three muscarinic receptor subtypes 4-DAMP (M(1) and M(3) receptors), pirenzepine (M(1) receptors), methoctramine (M(2) receptors) have been tested on rabbit isolated small and large intestinal regions provided with spontaneous motor activity. The employed drugs differently affected intestinal motility patterns. The ileum pendular movements as well as the proximal colon and taenia coli tone, spike amplitude and frequency were concentration-dependently inhibited by the compounds here employed. Their pIC(50) values followed the rank order of potency generally reported for the involvement of the M(3) muscarinic receptors (4-DAMP greater than or equal to atropine>nuvenzepine greater than or equal to pirenzepine>methoctramine). Unlike nuvenzepine and the other antimuscarinics assayed, the M(1) selective antagonist pirenzepine, at nanomolar concentrations, was able to enhance the proximal taenia coli motility patterns suggesting that a M(1)-inhibitory pathway might operate in the physiological modulation of taenia coli motility. At variance with longitudinal ileum and colon contractile activity, proximal circular colon motility was resistant to muscarinic as well as to alpha(1)-, H-1-, 5-HT-blockade indicating that NANC neuronal mechanisms could act at this level. In summary, these data provide evidence that, at intestinal level, nuvenzepine is almost completely devoid of reliable M(1)-linked effect thus possessing a different pharmacological selectivity at muscarinic receptor subtypes with respect to pirenzepine. Furthermore, it emerges that rabbit spontaneous small and large intestinal motility is probably driven by different physiological mechanisms regional-related. The peculiar circular colon refractoriness deserves further studies to be extended to the human tissue.