Cholinergic stimulation enhances colonic motor activity, transit, and sensation in humans

Abstract

The cholinesterase inhibitor neostigmine indirectly stimulates muscarinic M(1)/M(2)/M(3) receptors, thereby reducing colonic distension in acute colonic pseudo-obstruction. We investigated the dose-response profile for the colonic sensorimotor effects of neostigmine and bethanechol, a direct muscarinic M(2)/M(3) agonist in humans. A barostat-manometric assembly recorded phasic pressures, tone, and pressure-volume relationships (compliance) in the descending colon and rectum of 30 healthy subjects who received intravenous neostigmine (0.25, 0.75, or 1.5 mg; n = 15) or subcutaneous bethanechol (2.5, 5, or 10 mg; n = 15). Sensation to luminal distension was also assessed. Thereafter, the effects of neostigmine and bethanechol on colonic transit (geometric center) were compared with those of saline by scintigraphy in 21 subjects. Both drugs increased colonic phasic pressure activity, reduced rectal compliance, and enhanced urgency during rectal distension. Neostigmine also reduced colonic and rectal balloon volumes, reflecting increased tone by an average of 12% and 25% for the highest dose, respectively. Only neostigmine reduced colonic compliance, accelerated colonic transit [mean geometric center at 90 min 2.5 vs. 1.0 (placebo)], and increased pain perception during colonic distension. We conclude that neostigmine has more prominent colonic motor and sensory effects than bethanechol. Moreover, neostigmine induces coordinated colonic propulsion, perhaps by stimulating muscarinic M(1) receptors in the myenteric plexus.