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.