Intracerebroventricular pressure inhibits gastric antral and duodenal contractility but not acid secretion in conscious rabbits.

Acute nausea characteristically accompanies head injury or increased intracranial pressure, or both. The etiology of this symptom is unclear. We studied the effect of increased intracranial pressure on gastric antral and duodenal contractility and gastric acid secretion in conscious rabbits. Intracerebroventricular pressure was maintained at 3, 8, or 13 cmH2O using normal saline perfused into the lateral cerebral ventricle and gastric antral and duodenal contractility was monitored using chronically implanted strain gauge force transducers. Gastric acid secretion was measured in a separate group of rabbits with chronically implanted gastric cannulas. Increased intracerebroventricular pressure (13 cmH2O) resulted in an immediate suppression of the amplitude of gastric and duodenal contractions by greater than 80% and greater than 60%, respectively. After normalization of intracerebroventricular pressure, the contractile pattern returned to basal levels. Intravenous bolus injection of bethanechol reversed the suppression of gastric antral contractility induced by increased intracranial pressure. Increased pressure for 2 h did not modify gastric acid output as compared with normal pressure controls, whereas atropine significantly inhibited and histamine stimulated gastric acid secretion in the same animals maintained at normal pressure. These results demonstrate that acutely increased intracranial pressure rapidly and reversibly inhibits gastric and duodenal motor function in conscious rabbits.

Central nervous system action of TRH to stimulate gastric function and ulceration.

Intracisternal or intracerebroventricular injection of TRH (0.1-10 micrograms) in rats stimulated the secretion of gastric acid and pepsin secretion, increased gastric mucosal blood flow and gastric contractility and emptying, induced gastric hemorrhagic lesions and aggravated experimental ulcers elicited by aspirin, serotonin or indomethacin. TRH action was dose-dependent, rapid in onset and central nervous system-mediated by activation of the parasympathetic outflow to the stomach and cholinergic receptors. The stable TRH analog, RX 77368, was more potent and longer lasting than TRH. TRH and its stable analog appear as new chemical probes to produce centrally-mediated vagal-dependent stimulation of gastric function and experimental ulcers. The physiologic role of endogenous TRH in the central regulation of gastric function and ulceration remains to be established.

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.

Central nervous system action of corticotropin-releasing factor to inhibit gastric emptying in rats.

The present study evaluates the central nervous system action of rat corticotropin-releasing factor (CRF) on gastric emptying of a liquid meal in conscious rats using the phenol red method. Intracisternal injection of CRF (63-210 pmol) dose-dependently inhibited gastric emptying of a liquid meal by 37-80%. Peptide action was rapid in onset, long acting, and not mimicked by intracisternal injection of growth hormone-releasing factor. Intracisternal CRF-induced inhibition of gastric emptying was reversed by subdiaphragmatic vagotomy but not by naloxone pretreatment or adrenalectomy. Intravenous injection of CRF (21-630 pmol) also dose-dependently inhibited gastric emptying. CRF antiserum blocked the effect of intravenous but not of intracisternal injection of CRF (63 pmol). These results demonstrated that CRF injected in a picomole amount into the cerebrospinal fluid acts within the brain to inhibit gastric emptying of a liquid meal through vagal-dependent pathways.

Central nervous system action of TRH to stimulate gastric emptying in rats.

The effects of intracisternal injection of TRH on gastric emptying of a liquid meal was investigated in 24 h fasted rats using the phenol red method. Intracisternal injection of TRH, RX 77368, or [N-Val2]-TRH, an analog devoid of TSH-releasing activity, 5 min prior to a meal, stimulated gastric emptying measured 20 min later. TRH action was dose dependent (1-100 ng), and rapid in onset. The calculated time for emptying half of the meal was decreased from 16 +/- 3 min (control group) to 4 +/- 1 min (TRH 30 ng). The stable analog, RX 77368, unlike TRH, stimulated gastric emptying when the meal was given 60 min after peptide injection. Intravenous injection of atropine (2.5 micrograms) inhibited and that of carbachol (1 microgram) stimulated gastric emptying whereas i.v. injection of TRH (0.1-1 microgram) had no effect. Vagotomy but not adrenalectomy reversed the increase in gastric emptying induced by intracisternal TRH. Atropine blocked the stimulatory effect of TRH and carbachol. These results demonstrate that TRH acts within the brain to stimulate gastric emptying through vagus-dependent and cholinergic pathways whereas alterations of adrenal and pituitary-thyroid secretion do not play an important role.

Influence of clonidine and a new related imidazoline derivative (tizanidine) on rat gastric mucosa.

The effects of a novel imidazoline derivative (tizanidine) on experimental ulcers and glycoproteins in the gastric mucosa and juice of rats were examined and compared with that of clonidine. Tizanidine and clonidine inhibited indomethacin ulcer and aspirin ulcers. Tizanidine, however, did not influence stress ulcer while clonidine showed an inhibitory effect. Although tizanidine and clonidine did not increase glycoproteins in the gastric mucosa, they prevented aspirin-induced changes of glycoproteins in the gastric mucosa and juice, as well as aspirin-induced gastric ulcers. The results suggest that, as with clonidine, tizanidine inhibits drug-induced gastric ulcers and that tizanidine-mediated gastric mucosal protection may prevent gastric ulcers induced by anti-inflammatory agents.

Antidopaminergic effects of bisbenzyl and benzyl tetrahydroisoquinoline alkaloids.

Several bisbenzyl and benzyl tetrahydroisoquinoline (THIQ) alkaloids and bulbocapnine were examined for their abilities to displace 3H-spiperone binding from rat striatal membranes and to antagonize apomorphine-induced rotation in mice with unilateral striatal 6-hydroxydopamine lesions. Receptor binding study showed that bulbocapnine, bisbenzyl and benzyl THIQs exhibited an affinity for dopamine receptors spanning a seven-fold range. In lesioned mice, dauricine, several benzyl THIQs and THIQs antagonized apomorphine-induced rotation. The order of potencies in this test was: dauricine greater than hydrastinine greater than M-9260 greater than demethylcoclaurine, bulbocapnine much greater than cycleanine. In this test, the order of potency did not parallel that in the dopamine receptor binding test. These results suggest that dauricine, THIQs and several benzyl THIQ alkaloids have dopamine receptor blocking activity.

Inhibitory effects of intrahypothalamic injection of calcitonin on TRH-stimulated gastric acid secretion in rats.

Effects of the peripheral and central administration of porcine (PCT) and salmon (SCT) calcitonin on the gastric acid secretion stimulated by various secretagogues were studied in the perfused stomach of anaesthetized rats. The intraperitoneal administration of PCT and SCT inhibited gastric acid secretion stimulated by thyrotropin-releasing hormone (TRH) and 2-deoxy-D-glucose, but neither bethanechol nor tetragastrin. The intracerebroventricular PCT and SCT blocked TRH-induced acid secretion. The intrahypothalamic injection of PCT and SCT reduced the acid secretion stimulated by the intrahypothalamic administration of TRH. The present study indicates that PCT and SCT may in part suppress gastric acid secretion due to an interaction with TRH in the hypothalamus.

Reduction of centrally-stimulated gastric acid secretion by tizanidine, a new imidazoline derivative, in anesthetized rats.

The effect of a novel imidazoline derivative (tizanidine) on stimulated gastric acid secretion was studied in the perfused stomach of anesthetized rats. Tizanidine, which did not prevent peripherally-stimulated gastric acid secretion, inhibited 2DG- or TRH-stimulated gastric acid secretion. Yohimbine and phentolamine reduced the inhibition of TRH-stimulated acid secretion by tizanidine. Clonidine was found to have similar effects to tizanidine at a lower dose. These results indicate that tizanidine may inhibit gastric acid secretion via the central alpha-adrenergic system similar to clonidine in anesthetized rats.

Intracerebroventricular injection of a TRH analogue, gamma-butyrolactone-gamma-carbonyl-L-histidyl-prolinamide, induces gastric lesions and gastric acid stimulation in rats.

The effects of TRH and its biologically stable analogue, gamma-butyrolactone-gamma-carbonyl-L-histidyl-L-prolinamide (DN-1417), on gastric mucosa and acid secretion were examined in rats. Intracerebroventricular (ICV) injection of DN-1417 (0.1-10 micrograms) caused a dose-dependent gastric lesion in the corpus and antrum 6 h after administration. The gastric lesions produced by 1 microgram of DN-1417 were more severe than those produced by ICV TRH (10 micrograms), intravenous DN-1417 (200 micrograms) and stress. Although the lesion-generating effect of TRH (10 micrograms) tended to be reduced 6 h after the injection, that of DN-1417 (1 microgram) was sustained during 6 h. Atropine (0.1 and 1 mg/kg s.c.) inhibited DN-1417-induced gastric lesions in a dose-related manner while sulpiride (10 and 30 mg/kg s.c.), haloperidol (1 mg/kg i.p.), phentolamine (1 and 5 mg/kg s.c.) and yohimbine (5 mg/kg s.c.) did not prevent the lesions. ICV DN-1417 also stimulated basal gastric acid secretion and the effect was stronger and longer-lasting than that of TRH. Atropine (0.1 mg/kg s.c.) stopped DN-1417-stimulated gastric acid secretion. In conclusion, the possibility that TRH may be involved in the CNS modulation of gastric mucosal integrity deserves further attention. The enhanced potency of action of DN-1417 over TRH could make ICV injection of this peptide a useful tool for inducing centrally-mediated gastric lesions in rats.

Inhibition by central alpha-2 adrenergic mechanism of thyrotropin-releasing hormone-induced gastric acid secretion in the rat.

Influences of central alpha-2 adrenergic agonists on thyrotropin-releasing hormone (TRH)-stimulated gastric acid secretion were examined in the perfused stomach of anesthetized rats. Clonidine, an alpha-2 adrenergic agonist, given subcutaneously or intracerebroventricularly inhibited the gastric acid secretion stimulated by intracerebroventricular TRH. Intracerebroventricular injection of norepinephrine tended to reduce the acid secretion, while phenylephrine, serotonin and quipazine (serotonin agonist) did not influence the acid secretion. Subcutaneous clonidine enhanced the acid secretion peripherally stimulated by electrical vagus stimulation. The inhibitory effect of clonidine on TRH-induced acid secretion was reversed by yohimbine, an alpha-2 adrenergic antagonist, and phentolamine. In conclusion, the present study suggests that the central alpha-2 adrenergic receptor system participates in the TRH-mediated central nervous system control of gastric acid secretion in anesthetized rats.

Effects on gastric acid secretion of a steroidal alkaloid, epipachysamine-A, extracted from Pachysandra terminalis Sieb. et Zucc.

Effect of a steroidal alkaloid, epipachysamine-A, extracted from Pachysandra terminalis Sieb. et Zucc. on gastric acid secretion was studied in rats. Epipachysamine-A prevented 2-deoxy-D-glucose- or thyrotropin-releasing hormone-stimulated gastric acid secretion in anesthetized rats. However, the compound did not influence bethanechol- or electrical vagal stimulation-induced gastric acid secretion. These results suggest that the effect of epipachysamine-A is due to the influence on the central nervous regulatory mechanism in the gastric acid secretion.

Enhancement by intracerebroventricular thyrotropin-releasing hormone of indomethacin-induced gastric lesions in the rat.

Effects of the intracerebroventricular thyrotropin-releasing hormone (TRH) on gastric mucosa were studied in rats. TRH (3 and 10 micrograms rat-1 i.c.v.) produced slight gastric lesions and also aggravated indomethacin-, aspirin- or 5-hydroxytryptamine (5-HT)-induced gastric lesions, while restraint and cold stress-induced lesions were not influenced by TRH. Bethanechol used at a dose sufficient to produce acid secretion did not influence the gastric mucosa in intact or indomethacin-treated rats. Enhancement of indomethacin-induced gastric lesions by TRH was not inhibited to any significant degree by atropine 0.1 mg kg-1 s.c., which prevented TRH-induced gastric acid secretion, but tended to be inhibited by phentolamine, 2.5 mg kg-1 i.p. It is concluded that the enhancement by TRH of indomethacin-induced gastric lesions is due to a combination of the central and peripheral actions of the ulcerogenic agents.

gamma-butyrolactone enhances the activity of GABA in the gastric acid secretion of anesthetized rats.

Influences of gamma-butyrolactone (GBL) on GABA agonists-induced gastric acid secretion were studied in anesthetized rats. GBL potentiated the effect of GABA and GABA agonists on gastric acid secretion, and gamma-hydroxybutyric acid, a metabolite of GBL, tended to enhance the effect of GABA. However, GBL did not influence 2-deoxy-D-glucose- or bethanechol-stimulated acid secretion. A benzodiazepine, diazepam, also increased the secretagogue action of baclofen. A GABA antagonist, bicuculline, but not picrotoxin, inhibited the acid secretion stimulated by the combination of GBL and GABA or muscimol. Aminooxyacetic acid, an inhibitor of GABA transaminase, potentiated the effect of GABA. Dopamine receptor agonists and antagonist did not modify the effect of GABA. Neither GABA mimetic action of GBL nor its influences on the dopaminergic system are involved in the effect of the compound on gastric acid secretion. Although the possibility that GBL inhibits GABA degradation is not excluded, the compound appears to increase the sensitivity of GABA receptor to GABA mimetics in the gastric acid secretion.

[Influence of a muscle relaxant, tizanidine, on gastric acid secretion and gastric ulcer in rats].

Effects of tizanidine, a centrally acting muscle relaxant, on gastric acid secretion and gastric ulcers were studied in the rat. Tizanidine (5 mg/kg, s.c.) did not influence basal acid secretion, but inhibited the centrally stimulated acid secretion in anesthetized rats. Intraduodenal administration of tizanidine (10 mg/kg) also inhibited the centrally stimulated acid secretion. The compound potentiated bethanechol-induced acid secretion at 10 mg/kg, s.c. Clonidine was found to have similar effects to tizanidine at the lower dose. Both tizanidine and clonidine inhibited basal acid secretion at a relatively low dose in conscious rats. Tizanidine (5 mg/kg, s.c.) did not modify indomethacin- and stress-induced ulcers, but Shay ulcers were slightly inhibited by the drug. Indomethacin ulcers were significantly inhibited by 10 mg/kg, s.c., 10 mg/kg, p.o. or 20 mg/kg, p.o. of tizanidine. Clonidine also was found to be a strong inhibitory agent of indomethacin-, stress- and Shay-ulcers. These results suggest that similar to clonidine, a high dosage of tizanidine influences gastric acid secretion and gastric ulcers, although the activity is lower than that of clonidine.

Gastric antral ulcers produced by the combined administration of indomethacin with 2-deoxy-D-glucose in the rat.

The influence of 2-deoxy-D-glucose (2DG) on indomethacin ulcers was studied in rats. 2DG (200 mg/kg i.v.) produced large round ulcers in the lesser curvature of the antrum and aggravated lesions of the corpus 6 h after treatments in indomethacin (40 mg/kg i.p.)-treated rats. Insulin (5 units/kg i.v.) also produced gastric antral ulcers similarly to 2DG. Antral ulcers were revealed rather clearly 48 h after the administration of indomethacin and 2DG when the corpus lesion index was reduced. 2DG or insulin had only a slight influence on the severity of other experimental gastric ulcers. Peripheral gastric secretagogues, bethanechol (1 mg/kg s.c. X 2) or histamine (10 mg/kg s.c. X 2) did not produce antral ulcers at the gastric secretory dose in the indomethacin-treated rats. High doses of atropine (1.0 and 10 mg/kg s.c.) prevented gastric antral ulcers. The combined administration of indomethacin with 2DG produced gastric antral ulcers similar to human gastric ulcers in rats. The combination of gastric acid secretion, vagus nerve stimulation and some other factors may be involved in gastric antral ulcers produced in rats.

Bromocriptine inhibits 2-deoxy-D-glucose-stimulated gastric acid secretion in the rat.

The influence of bromocriptine on the secretagogue-induced gastric acid secretion was examined in rats. The drug inhibited the gastric acid secretion centrally stimulated by 2-deoxy-D-glucose (2DG) in anesthetized or conscious rats. Apomorphine also prevented 2DG-induced acid secretion in anesthetized rats but not in conscious rats. Neither bromocriptine nor apomorphine significantly influenced the acid secretion induced peripherally by electrical vagus stimulation or gastrin. The antisecretory effect of bromocriptine was reversed by dopamine antagonists in anesthetized or conscious rats, but not by apomorphine in anesthetized rats. The results suggest that in rats, the antisecretory effect of bromocriptine on 2DG-stimulated acid secretion is partly due to its central dopamine agonistic action, but that of apomorphine may be due to dopaminergic plus other mechanisms.

Influence of dopamine receptor agonists on gastric acid secretion induced by intraventricular administration of thyrotropin-releasing hormone in the perfused stomach of anaesthetized rats.

1 The influence of dopamine receptor agonists on gastric acid secretion stimulated by thyrotropin-releasing hormone (TRH) was studied in the perfused stomach of anaesthetized rats. 2 Intraventricular TRH produced a dose-dependent stimulation of basal gastric acid secretion. 3 Pretreatment with apomorphine, bromocriptine or methamphetamine inhibited the TRH-stimulated gastric acid secretion; these drugs did not influence bethanechol-induced acid secretion. 4 Haloperidol and metoclopramide prevented the antisecretory effects of apomorphine, bromocriptine and methamphetamine. 5 The present study suggests that central dopamine receptor stimulation inhibits intraventricular TRH-induced gastric acid secretion in rats.

Gastric secretagogue action of ergot alkaloids in the perfused stomach of anesthetized rats.

The gastric secretagogue action of ergot alkaloids was studied in the perfused stomach of anesthetized rats. Ergometrine dose-dependently increased gastric acid secretion and other ergot alkaloids, methysergide, methylergometrine, ergotamine and dihydroergotamine were also found to stimulate gastric secretion. However, Hydergine and bromocriptine did not influence the basal secretion. The gastric secretagogue action of ergometrine was completely inhibited by atropine and was markedly reduced but not abolished by vagotomy. Intraventricular administration of ergometrine produced an increase of acid secretion. Ergometrine did not affect the blood glucose level while insulin decreased it. The effect of ergometrine was not inhibited by serotonin agonistic or dopamine antagonistic agents. These results suggest that some ergot alkaloids have a gastric secretagogue action mainly due to their central effect in anesthetized rats and these actions cannot be explained by serotonin antagonistic, dopamine agonistic and alpha-adrenergic blocking effects of ergot alkaloids. The mechanism of the secretagogue action of ergometrine was different from that of insulin.