The effects of indomethacin on electrical and mechanical responses produced by transmural nerve stimulation (TNS) were investigated in isolated circular smooth muscle of the guinea-pig gastric fundus. TNS evoked a cholinergic excitatory junction potential (e.j.p.). The e.j.p.s were inhibited by 1-10 μM indomethacin, in a concentration-dependent manner, with no marked alteration of the resting membrane potential. Exogenously applied acetylcholine caused a depolarization of the membrane that was not altered by indomethacin. TNS evoked a cholinergic twitch contraction at low frequencies (0.1 Hz). A train of TNS's at high frequency (1 Hz) produced a transient contraction with a subsequent sustained relaxation. Indomethacin reduced the resting tension and inhibited these TNS-induced contractions. Application of N^ω-nitro-L-arginine (NOLA), an inhibitor of nitric oxide (NO) synthesis, increased the amplitude of twitch contractions, and altered transient contractions to tetanic contractions during TNS at a frequency of 1 Hz, also with an increased amplitude. In the presence of NOLA, indomethacin (5 μM) again reduced the resting tension and inhibited TNS-induced contractions. This inhibition was greater for twitch contractions than for tetanic contractions. Nifedipine reduced the TNS-induced contractions, while addition of indomethacin further reduced the amplitude of contractions. Contractions produced by low concentrations of acetylcholine (0.1 μM) were inhibited by indomethacin, while those produced by 1 μM were not. These results indicate that the inhibitory actions of indomethacin on TNS-induced contractions do not involve enhanced production of NO or selective inhibition of voltage-gated Ca-channels. Prejunctional autoregulatory mechanisms may also not be altered by indomethacin. As indomethacin inhibits the enzyme cyclooxygenase, it is speculated that endogenously produced prostaglandins exert excitatory actions on gastric smooth muscle, and act mainly postjunctionally to facilitate spontaneous and neurogenic electrical and mechanical activity.

View full abstract

The present study reports light microscopical observations of the distribution of muscle in the esophagus and stomach of both the bull frog (Rana catesbeiana) and the African clawed frog (Xenopus laevis). The external muscle coat of the upper half of the esophagus in both species had several collagen coated bundles of striated muscle fibres around the circumference. These striated muscle bundles ran longitudinally from the pharynx to around the vicinity of the center of the esophagus. Beneath these striated muscle bundles was an inner circular layer of smooth muscle. In both species, the inner circular layer of smooth muscle was particularly thick in the region close to the pharynx. In the bull frog, the lower half of the esophagus lacked striated muscle. However, the circular smooth muscle layer, extending from the upper half of the esophagus, was also observed throughout the lower half of the esophagus. An outer longitudinal layer of smooth muscle developed towards the terminal portion of the esophagus such that in this region, both outer longitudinal and inner circular layers of smooth muscle were observed. Similarly in the African clawed frog, the inner circular layer of smooth muscle was continuous along the full length of the esophagus. Again, no striated muscle bundles were observed in the lower half of the esophagus. However, the outer longitudinal layer of smooth muscle was seen to develop in the middle region of the esophagus. Its muscle layer extended to the terminal portion of the esophagus. Thus, both outer longitudinal and inner circular layers of smooth muscle were observed throughout the lower half of the esophagus. In both frogs, the thickness of the outer longitudinal and inner circular layers of smooth muscle changed before and after the esophago-gastric junction. In both frogs, no muscularis mucosa was observed in the esophageal wall. However, in the lower half of the esophagus of the African clawed frog, small bundles of smooth muscle were observed here and there in the submucosa. A fully developed muscularis mucosa with both outer longitudinal and inner circular layers was observed in the upper stomach of both frogs.

View full abstract

(±)-Terbutaline and (±)-fenoterol are both arylethanolamine analogs that have tert-butyl and aryliso-propyl substituents respectively at the α position on the nitrogen of the ethanolamine side chain. In the present study, we have investigated the structure-activity relationships of (±)-terbutaline and (±)-fenoterol as β₃-adrenoceptor agonists in the guinea pig gastric fundus. (±)-Terbutaline and (±)-fenoterol induced concentration-dependent relaxation of the precontracted gastric fundus with pD₂ values of 4.45 ± 0.10 and 5.90 ± 0.09, and intrinsic activities of 1.00 ± 0.03 and 0.99 ± 0.01 respectively. The combination of the selective β₁-adrenoceptor antagonist (±)-atenolol (100 μM), and the selective β₂-adrenoceptor antagonist (±)-butoxamine (100 μM), produced a 2 and 6 fold rightward shift of the concentration-response curves for (±)-terbutaline and (±)-fenoterol respectively, without depressing the maximal responses. The order of potency of these agonists was (pD₂ value): (±)-fenoterol (5.09 ± 0.10) > (±)-terbutaline (4.13 ± 0.08). In the presence of (±)-atenolol and (±)-butoxamine, however, the non-selective β₁, β₂- and β₃-adrenoceptor antagonist (±)-bupranolol caused a concentration-dependent rightward shift of the concentration-response curves for (±)-terbutaline and (±)-fenoterol. Schild plot analyses of the effects of (±)-bupranolol against these agonists gave pA₂ values of 6.21 ± 0.07 ((±)-terbutaline) and 6.37 ± 0.06 ((±)-fenoterol) respectively, and the slopes of the Schild plot were not significantly different from unity (p>0.05). These results suggest that the relaxant responses to (±)-terbutaline and (±)-fenoterol are mainly mediated through β₃-adrenoceptors in the guinea pig gastric fundus. The β₃-adrenoceptor agonist potencies of arylethanolamine analogs depend on the size of the end of the alkylamine side chain.

View full abstract