M₁Receptor-Mediated Nitric Oxide-Dependent Relaxation Unmasked in Stomach Fundus from M₃Receptor Knockout Mice

Abstract

Muscarinic receptors can mediate both contractile and relaxant responses in smooth muscle. The stomach fundus from wildtype mice possesses a neuronal M 1 receptor that mediates relaxation to carbamylcholine and (4-hydroxy-2-butynyl)-1-trimethylammonium-3-chlorocarbanilate chloride but is masked by M 3 receptor-mediated contraction to both agonists. When the M 3 receptor was deleted, cholinergic-induced relaxation was unmasked. M 1 receptor antagonism with pirenzepine, nitric oxide (NO) synthase inhibition with N -nitro-L-arginine methyl ester hydrochloride, and inhibition of neuronal activation with tetrodotoxin abolished relaxation to McN-A-343 in tissues from M 3 receptor knockout mice, supporting the neuronal localization of an M 1 receptor that activated NO release to effect relaxation. However, the cyclooxygenase inhibitor indomethacin did not affect contraction or relaxation to carbamylcholine in stomach fundus from wild-type or M 3 receptor knockout mice, indicating that cyclooxygenase products played no role in these responses. The neuronal M 1 receptor modulated relaxation induced by carbamylcholine and McN-A-343 but not relaxation induced by electric field stimulation of the stomach fundus. These data support the presence of M 1 receptor-mediated relaxation in the stomach and suggest that when the M 3 receptor is eliminated or blocked, M 1 receptor-mediated gastric relaxation may be enhanced, possibly leading to alterations in gastric emptying and subsequent effects on body weight.

Roles of PACAP and PHI as inhibitory neurotransmitters in the circular muscle of mouse antrum

“…This result indicates that activation of muscarinic receptors is involved in the inhibitory response. A number of previous reports have examined this point; a relationship between the activation of muscarinic receptors and the relaxation has been reported in the rat jejunum [33] and the mouse fundus [36]. However, further study is necessary to clarify how the muscarinic receptor regulates the sustained relaxation.…”

Gastrointestinal Function Regulation by Nitrergic Efferent Nerves

“…It was reported that the ability of the nitrergic neurotransmitter to induce relaxation of the rat gastric fundus was influenced by the mechanism used to induce tone, and sarcoplasmic/endoplasmic reticulum Ca 2ϩ ATPase appeared to play a role in nitrergic relaxation . From studies using wild-type and M 3 muscarinic receptor knockout mice, Stengel and Cohen (2003) …”

Effect of Muscarinic and Nicotinic Receptor Antagonism on Rat Gastric Motor Activity

“…Furthermore, it was recently suggested that a muscarinic receptor other than M 1 or M 3 stimulates NO synthase in the guinea pig gastric fundus [10] . In M 3 knockout mice, evidence was found for M 1 receptor-mediated gastric fundus relaxation [18] . It is also generally known that vagal motor pathways to the stomach consist of parallel inhibitory and excitatory cholinergic pathways that activate separate myenteric neurons via nicotinic receptors [3] .…”