M1-MUSCARINIC MECHANISMS REGULATE INTERDIGESTIVE CYCLING OF MOTOR ANDSECRETORY ACTIVITY IN HUMAN UPPER GUT

We determined the influence of M1-muscarinic pathways in modulating te mporal cycling of motor and secretory activity in the fasting upper gu t. Eight healthy subjects were studied on two separate days, following a double-blind, randomized protocol. Antroduodenal motility (migratin g motor complex, MMC), pancreatic exocrine secretion (amylase, lipase, trypsin, chymotrypsin), and plasma levels of associated hormones [mot ilin, pancreatic polypeptide (PP)] were monitored for two consecutive cycles during background infusion of placebo or telenzepine, a selecti ve M1-muscarinic receptor antagonist. On placebo days, pancreatic enzy mes and hormones cycled in synchrony with motor activity, as expected. During M1 blockade, duodenal output of each enzyme was decreased by 8 5-90% in phase I and by >90% in phase III. Similarly, plasma concentra tions of hormones were decreased during all phases and cycling was abs ent. Despite the loss of these putative influences, intestinal motilit y continued to cycle, albeit in an altered fashion. Intermittent phase II activity was replaced by phase I quiescence, while phase III-like fronts were diminished (contraction frequency, amplitude, propagation velocity reduced 30-60%, duration not altered) but recurred at expecte d intervals (cycle length 105 +/- 14 min vs 109 +/- 12 in placebo). Ga stric motor activity was virtually abolished. These data suggest or ex tend several working hypotheses: (1) Motilin is released and/or acts v ia cholinergic (M1-muscarinic) pathways to initiate antral, but not du odenal, phase III activity. (2) M1 receptors mediate all components of the gastric MMC and phase II activity throughout the gut, but intesti nal phase III activity arises via alternate pathways. (3) M1-muscarini c mechanisms regulate interdigestive cycling of pancreatic enzymes and PP. (4) Secretions from the endocrine/exocrine pancreas are not prima ry mediators of intestinal motility.