GR-94800

Background  The origin and modulation mechanisms controlling timing and amplitude of esophageal body peristalsis are not fully understood. We aimed to characterize the neurotransmitters involved in the origin and modulation of circular smooth muscle esophageal body (EB) contractions.Methods  Responses of porcine EB strips to electrical stimulation of motor neurons (MNs) were assessed in organ baths and with microelectrodes. The effect of antagonists of inhibitory (L‐NAME 1 mmol L−1, MRS2179 10 μmol L−1) and excitatory neurotransmitters (atropine 1 μmol L−1; SR140333 1 μmol L−1‐NK1ra‐, GR94800 1 μmol L−1‐NK2ra‐) and of ganglionic neurotransmitters (hexamethonium 100 μmol L−1, ondansetron 1 μmol L−1, NF279 10 μmol L−1) were characterized.Key Results  Electrical field stimulation (EFS) induced a frequency‐dependent off‐contraction (16.8 ± 0.8 g) following a latency period. Latency was significantly reduced by L‐NAME (−66.1 ± 4.1%) and MRS2179 (−25.9 ± 5.6%), and strongly increased by atropine (+36.8 ± 5.8%). Amplitude was reduced by L‐NAME (−69.9 ± 10.4%), MRS2179 (−34.1 ± 6.0%), atropine (−42.3 ± 4.7%), hexamethonium (−18.9 ± 3.3%), NF279 (−20.7 ± 3.5%), ondansetron (−16.3 ± 3.2%), GR94800 (−28.0 ± 4.8%) SR140333 (−20.9 ± 7.1%), and α‐chymotrypsin (−31.3 ± 7.0%). The EFS induced a monophasic nitrergic inhibitory junction potential.Conclusions & Inferences  Our results suggest that timing (latency) and amplitude of esophageal contractions are determined by a balance of complex interactions between excitatory and inhibitory MNs. Latency depends on the activation of inhibitory MNs releasing NO and a minor purinergic contribution through P2Y1 receptors, and excitatory MNs releasing ACh. Amplitude depends on a major contribution of excitatory MNs releasing ACh and tachykinins, and also on inhibitory MNs releasing NO, ATP or related purines, and peptidergic neurotransmitters acting as strong modulators of the excitatory neuroeffector transmission.

To study the role of the tachykinin receptors in spontaneous contractions of longitudinal and circular smooth muscle from rabbit small intestine and to determine the mechanism of action of Substance P (SP).

Rabbit duodenum, jejunum and ileum segments were prepared. The spontaneous contractions of longitudinal and circular smooth muscle were recorded using a computer via an isometric force transducer. The specific agonists and antagonists of tachykinin receptors were added into the organ bath.

The agonists of tachykinin NK1 receptor (SP and [Sar9] SP), NK2 receptor (NKA and (β-Ala8)-NKA), and NK3 receptor (NKB and Senktide) all induced contractions in the small intestine. The contractions were diminished by NK1 receptor antagonist L-733,060, NK2 receptor antagonist GR-94800, and NK3 receptor antagonist SB 218795. Contractions caused by SP were also reduced by atropine, verapamil, PKC inhibitor staurosporine, and PLC inhibitor U73122.

Ttachykinin NK1, NK2, and NK3 receptors mediate the contractions of the smooth muscle in rabbit intestine. Furthermore, SP acts directly on smooth muscle cells through the tachykinin NK1 receptor.