Central nervous system action of calcitonin gene-related peptide to inhibit gastric emptying in the conscious rat.

The central nervous system action of rat alpha-calcitonin gene-related peptide (alpha-CGRP) on gastric emptying of a liquid, noncaloric, methylcellulose solution was assessed in 24-hr fasted, conscious rats using phenol red method as a marker. Intracisternal injection of alpha-CGRP (0.75-250 pmol) dose-dependently inhibited gastric emptying by 27-94% as measured 20 min after oral administration of the solution. The ED50 was 6.2 pmol. alpha-CGRP injected intravenously at 250 pmol delayed gastric emptying by 71% whereas a lower dose (75 pmol) was inactive. Intracisternal alpha-CGRP-induced inhibition of gastric emptying was completely abolished by bilateral adrenalectomy and partially suppressed by subdiaphragmatic vagotomy or coeliac/superior mesenteric ganglionectomy. Adrenalectomy or vagotomy in saline-treated animals did not significantly modify the rate of gastric emptying whereas coeliac/superior mesenteric ganglionectomy caused a significant 29% inhibition as compared to the nonoperated group. These results demonstrate that alpha-CGRP is a potent centrally acting inhibitor of gastric emptying of a nonnutrient liquid. The inhibitory effect of intracisternal injection of CGRP appears to be mediated by the adrenal gland and in part by the sympathetic and parasympathetic nervous system.

Role of prostanoids in experimental duodenal ulcer in rat.

The purposes of this study were to determine whether inhibition of cyclooxygenase is a mechanism by which cysteamine and mepirizole produce duodenal ulcers, identify qualitative or quantitative differences in prostanoid production between gastric mucosa and duodenum, and determine whether differences in cyclooxygenase sensitivity to inhibition by aspirin exist between these two tissues. In fed female rats, gastric mucosal prostaglandin E2 (PGE2) and prostacyclin (PGI2) generation was 235 +/- 25 and 832 +/- 40 ng/g/min, respectively, whereas full-thickness duodenal PGE2 and PGI2 generation was 665 +/- 46 and 662 +/- 49 ng/g/min, respectively. Over an intraperitoneal dose range of 0-25 mg/kg, aspirin-induced cyclooxygenase inhibition was dose-dependent and similar for the two tissues. Duodenal ulceration (16.7 mm2) produced by cysteamine, 425 mg/kg, was associated with a 46% reduction in duodenal PGE2 generation, while having no effect on PGI2 generation; however, cysteamine, 213 mg/kg, produced no visible duodenal mucosa injury yet reduced duodenal PGE2 generation 39% compared to control values. In fed male rats, gastric mucosal PGE2 and PGI2 generation was 179 +/- 18 and 813 +/- 61 ng/g/min, respectively, whereas duodenal PGE2 and PGI2 generation was 321 +/- 27 and 454 +/- 38 ng/g/min, respectively. Duodenal ulceration (7.7 +/- 2.3 mm2) produced by oral mepirizole was associated with a 63% reduction in duodenal PGE2 generation compared to control values, while having no effect on PGI2 generation. Subcutaneous aspirin, 100 mg/kg, which reduced duodenal PGE2 generation to a greater degree than either ulcerogen, given in conjunction with pentagastrin, did not produce visible duodenal ulceration.(ABSTRACT TRUNCATED AT 250 WORDS)

Central nervous system action of calcitonin to alter experimental gastric ulcers in rats.

The central nervous system action of calcitonin to influence various experimental models of gastric ulcers and gastric function was studied in rats fasted for 24 h. Intracisternal injection of salmon calcitonin (5 micrograms) completely suppressed gastric ulcerations induced by exposure to cold restraint stress, intracisternal injection of a stable thyrotropin-releasing hormone analogue, or peroral administration of aspirin. By contrast, intracisternal calcitonin enhanced gastric lesions elicited by peroral administration of 40% ethanol or 0.6 N HCl. Calcitonin action was dose-dependent (0.01-1 microgram) and central nervous system mediated inasmuch as intravenous calcitonin, given at a dose 50-fold higher than that effective intracisternally, did not significantly modify gastric mucosal injuries elicited by aspirin or ethanol. Intracisternal injection of calcitonin at 0.01 microgram inhibited gastric acid output by 90% in pylorus-ligated rats and suppressed gastric emptying of a liquid meal by 63%-94% in doses ranging from 0.01 to 5 micrograms. Prostaglandin generation in the gastric mucosa was not modified by intracisternal injection of calcitonin. These results demonstrate that intracisternal calcitonin acts within the brain to potently prevent ulcer formation elicited by stress, thyrotropin-releasing hormone analogue, or aspirin, but is not cytoprotective against necrotizing agents. Calcitonin action is not related to modification of gastric prostaglandin generation but it may involve the inhibition of gastric secretory and motor function.

Potent CNS action of calcitonin to inhibit cysteamine-induced duodenal ulcers in rat.

Intracisternal injection of calcitonin (0.01-5 micrograms) dose dependently prevented the development of duodenal ulcers induced by cysteamine in female rats. By contrast, intravenous infusion of the peptide at a dose 50 times higher than an effective intracisternal dose, had no effect. Intracisternal injection of calcitonin increased by three fold the generation of 6-keto-PGF1 alpha, the stable hydrolysis product of PGI2, in the duodenal mucosa. These studies demonstrated that calcitonin acts within the brain to potently suppress duodenal ulcers induced by cysteamine. The mechanisms of the antiulcer effect may involve changes in prostaglandin generation along with alterations of gastrointestinal secretion and motility associated the central injection of calcitonin. Growing evidence suggests that salmon calcitonin may act as a neuromodulator or neurotransmitter in the central nervous system. Specific binding sites have been demonstrated for calcitonin in the hypothalamus, brain stem and dorsal horn of the spinal cord using homogenate and membrane preparations or in vitro autoradiography methods. The peptide injected into the cerebrospinal fluid (CSF) produces a wide spectrum of biological effects including analgesia, hyperthermia, changes in pituitary hormone release, decrease in food and water intake, locomotor activity, and blood pressure. Numerous studies also demonstrated that calcitonin acts within the brain to markedly influence gastrointestinal secretory and motor function in rats and dogs and gastric ulceration in rats. In particular, intracisternal injection of salmon calcitonin was found very potent to selectively inhibit gastric ulcers elicited by stress, aspirin and central thyrotropin-releasing factor but not by necrotizing agents. In the present study, we further investigated the antiulcer effect of salmon calcitonin using the well established cysteamine experimental model to induce duodenal ulcers in rats. Part of this work has been reported in abstract form.

Prostaglandin requirements are greater for protection in cold restraint-induced than alcohol-induced gastric mucosal injury.

Exogenous prostaglandins inhibit visible gastric mucosal lesions produced by both absolute ethanol and cold restraint in the rat. Pretreatment with "mild irritants" significantly reduces the magnitude of ethanol-induced lesions presumably by stimulating endogenous prostanoid production. The effect of mild irritant pretreatment on cold restraint-induced lesion formation has not been previously reported. This study was designed to compare the protective effect of pretreatment with two "mild irritants," 4% NaCl and 0.35 M HCl, and the synthetic prostanoid, 16,16 dimethyl PGE2(16,16-dm PGE2), on lesions produced by cold restraint or absolute ethanol. Pretreatment with both mild irritants produced complete visible protection against ethanol-induced injury but had variable effects against cold restraint-induced injury. Whereas 5 micrograms/kg 16,16-dmPGE2 provided complete visible protection against ethanol-induced injury, 20 micrograms/kg 16,16-dmPGE2 was required for complete visible protection against cold restraint-induced injury. We conclude that prostaglandin requirements for protection against cold restraint injury are greater than for protection against ethanol-induced gastric mucosal injury.