Actions of 5‐hydroxytryptamine and Histamine on the Neural Structures and Muscularis Mucosae of the Guinea‐pig Oesophagus

Abstract

The striped external muscle of the isolated guinea-pig oesophagus is insensitive to drugs and the lumen does not seem to be patent; thus the preparation does not respond to drugs until they have penetrated the external muscle and stimulated the intramural nerves or the plain muscle of the muscularis mucosae. The innervation of the external muscle of the guinea-pig oesophagus is not blocked by hexamethonium and is apparently without ganglia, so a stimulant of ganglion-cells produces a contraction of the muscularis mucosae only, which is distinguishable from a contraction of the external muscle. Furthermore, the external muscle and the muscularis mucosae can be separated, so that the actions of drugs on the muscularis mucosae in situ can be compared with those on the separated muscularis mucosae (Bartlet, 1968a, b). Hence the structure of the guinea-pig oesophagus makes it a suitable preparation for analysing the actions of drugs on the intramural nervous plexuses and muscularis mucosae of the alimentary tract, and a description of the actions of 5-hydroxytryptamine (5-HT) and histamine on this preparation follows. METHODSPreparations of muscularis mucosae, external muscle, oesophagus and oesophagus with vagus nerve attached were made as before (Bartlet, 1968a). The term " oesophagus " in the text, tables and figures refers to the whole organ, and the terms " external muscle " and " muscularis mucosae " refer to the separated oesophageal layers. The preparations were exposed to agonists for 1-3 min in every 15 min. Antagonists were added to the Krebs solution bathing the preparation when reproducible responses to an agonist had been obtained, only one agonist being tested in any such experiment with an antagonist. The effect of antagonists was expressed in terms of the dose ratio (Gaddum, Hameed, Hathway & Stephens, 1955), which is the ratio of equi-active doses of agonist in the presence and absence of antagonist. The inverse ratio was used to express the effect of drugs which potentiated agonists.The following drugs were used: acetylcholine chloride, acetyl-/3-methylcholine chloride, atropine sulphate, carbachol chloride, cocaine hydrochloride, eserine salicylate, hexamethonium bromide, histamine acid phosphate, 5-hydroxytryptamine creatinine sulphate, hyoscine hydrobromide, mepyramine maleate, methysergide bimaleate, muscarine iodide and tubocurarine chloride. The muscarine iodide was kindly supplied by J. R. Geigy & Co., Basel, Switzerland. Quantities of the drugs in the text, tables and figures refer to the above salts.

Indirect action of 5‐hydroxytryptamine on the isolated muscularis mucosae of the guinea‐pig oesophagus

“…However, the contractile responses to both 5-HT and Nic are probably mediated by separate receptors, since cross tachyphylaxis between 5-HT and Nic was not observed and hexamethonium, an antagonist of nicotinic receptors in autonomic ganglia, abolished the response to Nic, but not that to 5-HT. The lack of a direct action of 5-HT on the muscularis mucosae contrasts with previous results obtained on the same tissue (Bartlet, 1968), in which hyoscine-sensitive, hyoscine-resistant and methysergide-sensitive contractions had been produced by 5-HT. The pattern of 5-HT contracture observed was also different from those obtained in the present investigation.…”

“…Methysergide never inhibited, but rather slightly augmented the 5-HT-induced contraction, in spite of evidence to the contrary (Bartlet, 1968). Methysergide does antagonize the direct action of 5-HT on some smooth muscles (Day & Vane, 1963;Gyermek, 1966;Drakontides & Gershon, 1968;Frankhuijzen & Bonta, 1974;Carrol & Nasveld, 1978).…”

“…However, there are few reports based on experiments using the muscularis mucosae (Bartlet, 1968) and the submucous plexus (Hirst & Silinsky, 1975) which are located in submucosal layers. The isolated muscularis mucosae of the guinea-pig oesophagus contains a submucous plexus which includes cholinergic nerve cell bodies, independent of the myenteric plexus (Kamikawa & Shimo, 1979).…”

Pharmacological characterization of the histamine receptor in the isolated muscularis mucosae of the guinea‐pig oesophagus

“…The latter might involve the stimulation of intramural cholinergic nerves and of endogenous prostaglandin biosynthesis, since the response to histamine was slightly inhibited by tetrodotoxin, atropine, indomethacin or aspirin (Table 3). Previously, Bartlet (1968) found that atropine increased the dose-ratio for the histamine-induced contraction of the guinea-pig whole oesophagus by 1.8. Partial mediation by cholinergic nerves of the histamineinduced contraction has also been observed in some external muscles of the mammalian gut (Bertaccini, 1982).…”

Muscularis mucosae - the forgotten sibling

“…Also, morphine and opioid peptides inhibited the cholinergic neurotransmission via the activation of prejunctional κ-opioid receptors but lower concentrations of serotonin enhanced that by the activation of prejunctional 5-HT3 receptors Shimo,1983a;Kamikawa and Shimo, 1983b;Karim et al, 1996). Higher concentrations of serotonin produced a transient contraction of the muscularis mucosae which was abolished by the pretreatment with tetrodotoxin or atropine, indicating an indirect action via the stimulation of intramural cholinergic nerves (Bartlet, 1968b;Kamikawa and Shimo, 1983a). In the rat esophageal muscularis mucosae, however, serotonin did not produce a contraction but relaxed the cholinergically-induced tone via the stimulation of postjunctional 5-HT4 receptor which was coupled to the adenylate cyclase-cyclic AMP pathway (Baxter et al, 1991;Moummi et al, 1992;Ford et al, 1992;Ohia et al, 1992;Yang et al, 1993;Leung et al, 1996;Goldhill et al, 1997).…”