Telenzepine inhibits electrically-stimulated, acetylcholine plus histamine-mediated acid secretion in the mouse isolated stomach by blockade of M1 muscarine receptors

Abstract

1. The muscarine receptor mediating electrically-stimulated acid secretion in the mouse isolated stomach was characterized using a variety of muscarine receptor antagonists confirming the M1 nature of the antagonist effect of telenzepine. 2. Field stimulation (7 V, 10 Hz, 0.5 ms) resulted in a plateau acid secretion over at least 90 min which was completely blocked by either 1 mumol/l TTX or H2 receptor antagonists (100 mumol/l cimetidine or 10 mumol/l lupitidine). Ranitidine, which is known to potently inhibit mucosal acetylcholine esterase, was ineffective. Compound 48/80 at 100 mumol/l, which depletes mucosal histamine stores, initially mimicked electrical stimulation but subsequently prevented it from inducing acid secretion. 3. 10 muscarine receptor antagonists with differing relative affinities for M1, M2 and M3 receptors were introduced at 1 mumol/l to inhibit electrically-stimulated acid secretion. The percentages inhibition were plotted against binding affinities of the antagonists at either M1, M2 or M3 binding sites. A statistically significant correlation between functional and binding data was detected only when based on M1 affinities. 4. It is concluded that field stimulation, which probably mimicks vagal drive, results in muscarinic M1 receptor activation on paracrine cells to release histamine. Histamine then stimulates parietal cells to secrete acid. Hence, according to the present and our previous data, telenzepine inhibits acid secretion under these conditions by blocking M1 receptors at least partially located on histamine-releasing paracrine cells.

Comparative Effects of Cimetidine and Famotidine on the Vagally Stimulated Acid Secretion in the Isolated Mouse Whole Stomach

“…On the other hand, cimetidine concentration dependently blocked the vagally stimulated, bethanechol induced or histamine-induced gastric acid secretion. In previous studies by other investigators (3,11), cimetidine and metiamide completely inhibited the acid secretion elic ited by electrical field stimulation as well as that induced by histamine. Furthermore, metiamide also inhibited the acid secretion stimulated by carbachol (3).…”

“…The electrical stimulation described here was considered to selectively activate the parasympathetic preganglionic fibers, be cause of the complete blockade by hexamethonium, atro pine or tetrodotoxin. In contrast, the secretory response to electrical field stimulation was not completely blocked by hexamethonium at 100 pM (3,11); the reduction was approximately 80%. It is supposed that the acid secretory response to electrical field stimulation occurs through more complicated neuronal mediation, since the stimula tion is capable of acting on all kinds of neurons including the vagus nerves and sympathetic nerves, regardless of the pre or post-synaptic fibers.…”

“…For this purpose, we devised a novel method to in duce acid secretion by electrical vagal stimulation at the position of the esophagus. The electrical vagal stimula tion is thought to be more physiological than the electrical field stimulation of the stomach undertaken by previous investigators (3,11).…”

“…Furthermore, Ishikawa et al (13) reported that cimetidine (1-100 pM) inhibited the acid secretion induced by forskolin, which directly activates adenylate cyclase to increase intracellular cyclic AMP. The dosage of cimetidine employed is not so high in comparison with that used for H2-antagonism (9) or for the inhibitory effect on the acid secretion induced by electrical field stimulation (11). Famotidine is at least 50 times more potent in H2-receptor antagonism than cimeti dine (14), but it remains to be clarified whether or not famotidine inhibits cholinergic or nerve-mediated acid secretion in vitro.…”

Comparison of Effects of Famotidine on Vagally and Field-Electrically Stimulated Acid Secretion in the Isolated Mouse Whole Stomach

“…Angus and Black (10) first succeeded in measuring the acid secretion in response to electrical field stimulation in mice. They, together with other researchers, reported that the acid secretion evoked by field stimulation was completely inhibited by histamine H2-antagonists such as metiamide (10), cimetidine (11) and tiotidine (8,12), suggesting that the neuronally evoked acid secretion is via histamine release. Furthermore, Black and his co-workers found that the acid response to a combination of field stimulation and physostigmine, an acetylcholine esterase inhibitor, was refractory to H2-antagonist treatment (3,12).…”