1 The role of cannabinoid (CB) receptors in the regulation of gastric acid secretion was investigated in the rat by means of functional experiments and by immunohistochemistry. 2 In anaesthetized rats with lumen-perfused stomach, the non selective CB-receptor agonist WIN 55,212-2 (0.30 ± 4.00 mmol kg 71 , i.v.) and the selective CB 1 -receptor agonist HU-210 (0.03 ± 1.50 mmol kg 71 , i.v.), dose-dependently decreased the acid secretion induced by both pentagastrin (30 nmol kg 71 h 71 ) and 2-deoxy-D-glucose (1.25 mmol kg 71 , i.v.). By contrast, neither WIN 55,212-2 (1 ± 4 mmol kg 71 , i.v.) nor HU-210 (0.03 ± 1.50 mmol kg 71 , i.v.) did modify histamine-induced acid secretion (20 mmol kg 71 h 71 ). The selective CB 2 -receptor agonist JWH-015 (3 ± 10 mmol kg 71 , i.v.) was ine ective. 3 The gastric antisecretory e ects of WIN 55,212-2 and HU-210 on pentagastrin-induced acid secretion were prevented by the selective CB 1 -receptor antagonist SR141716A (0.65 mmol kg 71 , i.v.) and una ected by the selective CB 2 -receptor antagonist SR144528 (0.65 ± 2 mmol kg 71 , i.v.). 4 Bilateral cervical vagotomy and ganglionic blockade with hexamethonium (10 mg kg 71 , i.v., followed by continuous infusion of 10 mg kg 71 h 71 ) signi®cantly reduced, but not abolished, the maximal inhibitory e ect of HU-210 (0.3 mmol kg 71 , i.v.) on pentagastrin-induced acid secretion; by contrast, pretreatment with atropine (1 mg kg 71 , i.v.) did not modify the antisecretory e ect of HU-210. 5 Immunoreactivity to the CB 1 receptor was co-localized with that of the cholinergic marker choline acetyltransferase in neural elements innervating smooth muscle, mucosa and submucosal blood vessels of rat stomach fundus, corpus and antrum. In contrast, CB 2 receptor-like immunoreactivity was not observed. 6 These results indicate that gastric antisecretory e ects of cannabinoids in the rat are mediated by suppression of vagal drive to the stomach through activation of CB 1 receptors, located on pre-and postganglionic cholinergic pathways. However, the ine ectiveness of atropine in reducing the e ect of HU-210 suggests that the release of non cholinergic excitatory neurotransmitters may be regulated by CB 1 receptors.
1. In the intact conscious dog, caerulein causes emesis and evacuation of the bowel. The mean effective dose by the intravenous route is 0.4-0.5 jig/kg, and by the subcutaneous route 3-4 jg/kg. 2. The gall bladder in situ or as an isolated preparation is highly sensitive to caerulein. A few ng/kg injected intravenously are sufficient to stimulate the gall bladder in situ and less than 1 ng/kg per min is effective when infused intravenously. The isolated gall bladder is contracted by caerulein in concentrations as low as 0.03-2 ng/ml. Krebs solution. There is no tachyphylaxis but, generally, a good dose-response relationship. Hence the gall bladder, especially that of the guinea-pig, appears to be very suitable for the bioassay of caerulein and related peptides. 3. In situ, the musculature of the gastrointestinal tract is also highly sensitive to caerulein. Doses as low as 1-5 ng/kg, administered intravenously, have a spasmogenic action on jejunal loops of the dog, and slightly larger doses contract the small intestine of the cat. The stomach and the large intestine seem to be somewhat less sensitive to the polypeptide. Caerulein has a considerable spasmogenic action on the rat pylorus but relaxes the sphincter of Oddi of the guinea-pig. 4. Isolated preparations of the gastrointestinal tract are relatively insensitive to caerulein and tachyphylaxis occurs readily.5. Blockade with atropine produces different effects in different intestinal segments and in different animal species. The spasmogenic action of caerulein on the gall bladder is atropine-resistant. 6. The effects of caerulein are -similar to those of cholecystokininpancreozymin in the organs tested in situ or as isolated preparations. Caerulein, however, is always more potent than cholecystokinin-pancreozymin, even on a molar basis. Compared with caerulein, human gastrin I has negligible activity. 7. The possible use of caerulein in cholecystography is discussed.In a preceding paper the actions of caerulein on the systemic arterial blood pressure of some common laboratory animals were reported
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