The effect of clonidine on gastric acid secretion in rats and dogs

Summary The effect of clonidine on gastric acid secretion was investigated using rats and dogs. In the stomach lumen perfused rat basal gastric acid secretion was increased by clonidine in the anaesthetized rat but inhibited in the conscious animal. Clonidine also reduced the basal gastric acid secretion in rats with chronic gastric fistula, (ED₅₀ 12 g/kg p.o.). In addition, gastric secretion stimulated by insulin hypoglycaemia was inhibited by clonidine in anaesthetized stomach lumen perfused rats and in conscious dogs with gastric fistula. In the rat gastric secretion stimulated by electrical vagus stimulation was inhibited as well. However, clonidine had no effect on the gastric acid secretion stimulated by carbachol in stomach lumen perfused rats and in dogs with denervated fundic pouch.These results suggest that the inhibition of gastric acid secretion by clonidine probably is due to an inhibition of acetylcholine release at the vagus nerve endings. Additional central gastric antisecretory effects can, however, not be excluded by this study.     

Differential effects of capsaicin on the content of somatostatin,substance P,and neurotensin in the nervous system of the rat

Summary The distribution of immunoreactive substance P (I-SP), somatostatin (I-SRIF), and neurotensin (I-NT) and the effect of capsaicin treatment on the concentration of these peptides was studied in the peripheral and central nervous system of the rat.Neonatal capsaicin treatment (50 mg/kg s.c.) caused a depletion of I-SRIF as well as of I-SP in sensory nerves and in the dorsal half of the spinal cord. No recovery of the peptide content was found when examined 4 months later suggesting an irrerersible effect. I-NT, not a constituent of primary sensory neurons, was not changed in the spinal cord. None of the peptides studied was depleted in the hypothalamus or preoptic area.Capsaicin treatment of adult rats also led to a decrease of I-SRIF and I-SP in primarh sensory neurons. The highest dose used (950 mg/kg s.c.) induced no greater depletion than the lowest one (50 mg/kg), except for I-SP in dorsal root ganglia. Intraperitoneal injection of capsaicin led to a higher degree of depletion than subcutaneous administration as examined 1 week after treatment. In contrast to neonatal treatment, the I-SRIF content was completely restored within 4 months after treatment of adult rats. The I-SP content, however, did not completely recover in all areas but remained reduced in cornea, vagus nerve, dorsal spinal cord, and medulla oblongata for up to 9 months.Intraventricular administration of capsaicin (200 g) caused a depletion of I-SP in the medulla oblongata but had no effect on the content of all 3 peptides in hypothalamus or preoptic area. In contrast to systemic treatment, no depletion of I-SP or I-SRIF was found in the trigeminal ganglion. Chemosensitivity of the eye was abolished after intraventricular or systemic treatment. Repeated topical application of a capsaicin solution (10 mg/ml) to the eye led within 4 h to a nearly complete depletion of I-SP in the cornea.These experiments show that capsaicin treatment of rats caused a depletion of both I-SRIF and I-SP in primary sensory neurons. While topical or systemic capsaicin administration causes depletion in terminals, the failure of intraventricular injections of capsaicin to deplete the peptides in the trigeminal ganglion suggests that depletion of the entire neuron requires an action of capsaicin on the peripheral branch and/or the cell body.     

Centrally applied histamine increases gastric acid secretion in rats

Summary Administration of 10–100 g of histamine into the lateral cerebral ventricle of anaesthetized rats stimulated gastric acid secretion in a dose-dependent manner, while subcutaneous (s. c.) injections of the same doses produced clearly less pronounced increases in the acid output. In vagotomized rats only a marginal response to histamine given into the lateral ventricle was observed. When injected into the third cerebral ventricle the doses of histamine needed for the stimulation of gastric acid secretion were 1–10 g, the effect being totally abolished by vagotomy. The results indicate that histamine is capable of stimulating gastric acid secretion by a central, vagal-dependent mechanism.Send offprint requests to J. Puurunen at the above address     

Capsaicin and nociception in the rat and mouse

Summary Newborn or adult rats and mice were treated with capsaicin. The effect of systemic or intrathecal treatment on thermonociception, chemonociception, content and release of immunoreactive substance P (I-SP) was investigated.Treatment of two day old rats caused a small, but life-long elevation of the hot plate or tail withdrawal latency. Treatment of adult rats led to a large increase in the reaction time on the hot plate for 4–10 days but the tail withdrawal latency was only slightly elevated for not more than 1–2 days.Mice treated on the 2nd day of life had normal reaction times on the hot plate and a small and inconsistent prolongation of the tail withdrawal latency. In contrast, mice treated on day 7, 10 or as adults had greatly prolonged latencies in both tests for at least 3 months. The changes in latencies were not affected by naloxone or methysergide.Responses to noxious chemical stimuli were moderately inhibited in mice treated on the 2nd day of life, but almost abolished in mice treated on day 7, 10 or as adults.Neonatal capsaicin treatment of rats resulted in a depletion of I-SP in spinal cord and sciatic nerve for 20 months. Capsaicin-evoked release of I-SP from rat spinal cord was reduced by 93% after neonatal treatment, but only by 69% 2 weeks after adult treatment.Treatment of mice on day 2 caused a similar decrease of the I-SP content in spinal cord and of the capsaicin-evoked I-SP release (88%) as treatment on day 4 or 7 although behavioural changes were different. After treatment of adult mice release of I-SP was reduced by 93%.Capsaicin administered intrathecally to rats or mice depleted I-SP in the spinal cord but not in the sciatic nerve. The animals were almost insensitive to noxious heat (tail withdrawal test) and to local application of mustard oil or capsaicin to the hindpaw. Chemosensitivity of the eye, however, remained unchanged.The experiments indicate that systemic or intrathecal capsaicin treatment of rats or mice affects thermo- and chemonociception but species differences were found. It appears, furthermore, that changes in substance P alone cannot explain all the observed behavioral effects after capsaicin treatment.     

Effects of cimetidine on stress ulcer and gastric acid secretion in the rat

Cimetidine at 25, 50, and 100 mg/kg significantly inhibited gastric acid secretion in rats with chronic gastric cannulas. Rats receiving either 50 or 100 mg/kg of cimetidine secreted significantly less gastric acid 3 hr after injection. Cimetidine failed to reduce the number of size of gastric lesions in rats lesions in rats subjected to a supine restraint procedure.     

Modulation by peripheral opioids of basal and distension-stimulated gastric acid secretion in the rat.

1. The influence of opioids in modulating gastric acid secretory responses has been investigated in the continuously perfused stomach of the anaesthetized rat. 2. Intravenous administration of morphine (0.75-3 mg kg-1) or the peripherally acting enkephalin analogue, BW443C (0.75-3 mg kg-1), substantially augmented acid secretion in basal conditions. These effects were significantly inhibited by the opioid antagonists naloxone (1 mg kg-1) and the peripherally acting N-methylnalorphine (2 mg kg-1). When administered alone, neither opioid antagonist influenced basal acid output. 3. Acid secretory responses to different levels of gastric distension (5-20 cmH2O) were significantly and dose-dependently reduced in rats pretreated with morphine (3 mg kg-1) or BW443C (1.5 mg kg-1). Previous administration of either naloxone or N-methyl nalorphine reversed the inhibitory effects of opioids on gastric acid secretion stimulated by distension. Likewise, blockade of opioid receptors with naloxone or N-methylnalorphine significantly increased acid output induced by distension. 4. Levels of serum gastrin in control animals were not increased after intragastric distension (20 cmH2O). Pretreatment with BW443C (1.5 mg kg-1) did not modify the levels of gastrin present during basal or distension stimulated conditions. 5. Pretreatment with morphine or BW443C did not influence the acid responses to i.v. injection of pentagastrin (100 micrograms kg-1), histamine (5 mg kg-1) or carbachol (4 micrograms kg-1). Acid secretion induced by i.v. administration of 2-deoxy-D-glucose (150 mg kg-1) was reduced in rats pretreated with morphine but not with BW443C. Gastric secretory responses to insulin (0.3 i.u. kg-1) were not modified by i.v. morphine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Relationship between the prevention of rat gastric erosions and the inhibition of acid secretion by prostaglandins

The formation of gastric mucosal erosions induced by indomethacin in the rat was inhibited in a time- and dose-dependent manner by antisecretory prostaglandins, the methyl analogues of PGE₂ being 400 times as active as the parent prostaglandin. PGA₂, a methyl analogue of PGF₂, and the H₂-receptor antagonist metiamide, also inhibited erosiol formation. There was a variable relationship between the doses required to inhibit erosions and to inhibit gastric acid secretion. In the anaesthetised rat, the low incidence of erosions with indomethacin was markedly increased by concurrent gastric perfusion with acid saline and taurocholate. This mucosal damage was inhibited by the methyl analogues of PGE₂, suggesting protective actions on the mucosa other than inhibition of acid secretion.     

Gastric acid secretion in conscious miniature pigs

Summary Gastric acid secretion was studied in 5 miniature pigs provided with a chronic gastric fistula. Basal secretion did not change during the growth of the animals. Histamine, carbachol, and pentagastrin produced a dose-dependent volume and acid response. The highest peak acid output (PAO) was achieved with histamine. The maximal peak volume output after histamine was only exceeded by carbachol which was due to an excessive salivation. The maximal PAO after carbachol and pentagastrin as well as the maximal peak volume output after pentagastrin were very low. The poor secretory responses to carbachol and pentagastrin are discussed in the light of possible inhibitory mechanisms or of drug-receptor-interactions.Supported by a grant from the Deutsche Forschungsgemeinschaft.     

Stimulation by capsaicin of gastric alkaline secretion in anesthetized rats.

Effects of mucosal application of capsaicin on alkaline secretion were examined in the stomachs of anesthetized rats and compared with those in the duodenum. The stomach (acid secretion was inhibited by omeprazole given i.p.) or the duodenum was perfused with saline (pH 4.5); both the pH of the perfusate and transmucosal potential difference (PD) were continuously monitored; and the HCO3- output was determined by the pH change. Under these conditions, the mucosal application of capsaicin (0.3-6 mg/ml for 30 min) caused significantly increased pH and HCO3- output in a concentration-related manner in both tissues, while PD increased in the duodenum and decreased in the stomach. The HCO3- stimulatory action of capsaicin was markedly attenuated by sensory deafferentation, significantly mitigated by prior administration of indomethacin, and exhibited a marked tachyphylaxis after the repeated exposure at a high concentration (6 mg/ml). None of these treatments had any effect on the pH, PD and HCO3- responses induced by prostaglandin E2 (300 micrograms/kg, i.v.) in these tissues. These results indicate that mucosal application of capsaicin increased the gastroduodenal HCO3- output by stimulation of capsaicin-sensitive sensory neurons. This action may be in part mediated by endogenous prostaglandins.     

Role of central oxytocin in the inhibition by endotoxin of distension-stimulated gastric acid secretion

The gastric acid hyposecretory state associated with endotoxemia is mediated by a nervous reflex involving the central nervous system. The aim of the present study was to analyse the central effects of different peptides on distension-stimulated gastric acid secretion and the endogenous role of such peptides on the hyposecretory effects of endotoxin. The effect of an intracisternal (i.c.) administration of oxytocin, vasopressin, corticotropin releasing factor (CRF), bombesin, somatostatin and the opioid receptor agonist BW443C or an intravenous (i.v.) injection of a small dose of endotoxin on distension-stimulated gastric acid secretion was studied in the continuously perfused stomach of anaesthetised rats. In some animals, specific receptor antagonists for oxytocin (Compound VI [d(CH2)5, Tyr(Me)2, Thr4, Tyr-NH2(9)]-OVT, 0.01-1 microg/rat), vasopressin (des-Gly9-[beta-Mercapto-beta,beta-cyclopentamethylene-propiony l1, O-Et-Tyr2, Val4, Arg8]-VP, 20 microg/rat), CRF (alpha-helical CRF [9-41], 50 microg/rat) or bombesin (D-Phe12-Bombesin, 20 microg/rat) were administered i.c. before endotoxin. Distension-stimulated acid secretion was significantly inhibited by central oxytocin (0.2, 2 or 4 nmol/rat, 45+/-16%, 69+/-10% and 79+/-5% reduction, respectively), CRF (0.5, 1 or 2 nmol/rat, 52.2+/-15.6%, 74.3+/-9.1% and 93.2+/-1.6% reduction, respectively) and bombesin (2 nmol/rat, 79.1+/-5.8% reduction). The hyposecretory effect induced by endotoxin (5 microg/kg, 60.2+/-2.3% reduction) was reversed in a dose-dependent manner by pretreatment with the oxytocin receptor antagonist (0.01, 0.1 and 1 microg/rat, 65.2+/-14.4%, 88.0+/-22.5% and 112.4+/-25.2% of control response, respectively) while the vasopressin (20 microg/rat), CRF (50 microg/rat) or bombesin (20 microg/rat) receptor antagonists had no effect. The present results support a role for the endogenous release and action in the central nervous system of oxytocin in the inhibitory effect of endotoxin on gastric acid secretion.     

Nitric oxide and sensory afferent neurones modulate the protective effects of low-dose endotoxin on rat gastric mucosal damage

Pretreatment (1 h) with low doses (5–40 μg/kg i.p.) of Escherichia coli endotoxin dose dependently reduced the gastric mucosal damage induced by a 10 min challenge with 1 ml ethanol (50% and 100%) in conscious rats. Treatment with the nitric oxide synthesis inhibitor, oxide synthesis inhibitor, N^G-nitro- -arginine methyl ester (L-NAME, 5 and 10 mg/kg i.p.), significantly inhibited the protective effects of endotoxin (40 μg/kg i.p.). The actions of L-NAME were reversed by the prior administration of -arginine (100 mg/kg i.p.). The protective effects of endotoxin were not influenced by pretreatment with dexamethasone (5 mg/kg s.c. twice) or indomethacin (5 mg/kg s.c.). However, ablation of sensory afferent neurones by capsaicin pretreatment (20, 30 and 50 mg/kg s.c.) abolished the mucosa protective effects of endotoxin (40 μg/kg). These findings suggest that the protection elicited by low doses of endotoxin against ethanol-induced mucosal damage involves synthesis of nitric oxide and activation of sensory neurones.     

The effects of capsaicin upon electrogenic ion transport in rat descending colon

Summary Preparations of rat descending colon mucosa have been used to record changes in short circuit current (SCC) under voltage clamp conditions. When added to the basolateral compartment capsaicin (8-methyl-N-vanillyl-6-nonenamide, 0.1-3 M) caused an initial transient increase in SCC, followed by a more prolonged reduction in SCC, that lasted for 20–30 min.Repeated applications of 3 M capsaicin caused desensitisation of the initial secretory response. The antisecretory effects (i. e. reduction in SCC from the original baseline) remained, although they were significantly reduced. In some preparations described as non-responders, 3 M capsaicin did not elicit a secretory response. No desensitisation of the remaining antisecretory responses was observed in these tissues; in fact these reductions in SCC were consistently larger than those from tissues which responded with a secretory response.Tetrodotoxin (100 nM), hexamethonium (10 M), and yohimbine (50 M) had no significant effect upon either secretory or antisecretory responses. Ruthenium red (10 M) abolished the secretory response to 3 M capsaicin, but had no effect upon the antisecretory responses. Pretreatment of the tissues with 1 M substance P(SP) resulted in significant desensitisation to the peptide and abolished the secretory response to 3 M capsaicin. The antisecretory responses remained, and were significantly larger compared with responses from control tissues. Send offprint requests to H. M. Cox at present address     

Differential effects of calcium channel antagonists on histamine and pentagastrin-stimulated gastric acid secretion in the rat

Different calcium channel antagonists have been assessed for their ability to inhibit gastric acid secretion in rats. Whereas verapamil, diltiazem and cinnarizine inhibited pentagastrin-induced gastric acid secretion but not histamine-induced secretion, nifedipine selectively inhibited the stimulant effect of histamine. In contrast, the vasodilator hydralazine had non-selective effects. These findings indicate that calcium-antagonists may have differential effects against different secretagogues and these effects are not simply related to hypotensive effects.     

Stimulatory effects of nitric oxide donors on gastric acid secretion in isolated mouse stomach

We previously reported on the stimulatory role of endogenous nitric oxide (NO) in gastric acid secretion. In the present study, we investigated the effects of NO donors on acid secretion in isolated mouse stomach. Nitroprusside (100 μM–1 mM) inhibited the gastric acid secretion induced by histamine (500 μM) in a concentration-dependent manner. In addition, nitroprusside abolished the acid secretion induced by bethanechol (100 μM) and by electrical stimulation (10 Hz) of the vagus nerve. On the other hand, nitroprusside, 75 μM, which did not affect the acid secretion induced by histamine, itself elicited an increase in acid secretion. The acid secretion induced by 75 μM nitroprusside was inhibited by 10 μM famotidine, a histamine H₂ receptor antagonist. These results suggest that NO donors at high doses act on gastric parietal cells, resulting in inhibition of the stimulated acid secretion, and, at lower doses, facilitate histamine release from histamine-containing cells, leading to the increased acid secretion.     

Endotoxin inhibition of distension-stimulated gastric acid secretion in rat: mediation by NO in the central nervous system.

1. The involvement of nitric oxide in the acute inhibitory effects of low doses of endotoxin, following intracerebroventricular (i.c.v.) or intravenous (i.v.) administration, on gastric acid secretion stimulated by distension or i.v. infusion of pentagastrin has been investigated in the continuously perfused stomach of the anaesthetized rat. 2. The i.c.v. administration of E. coli endotoxin (800 ng kg-1) abolished the acid secretory response induced by gastric distension (20 cm water intragastric pressure) within 30 min of administration. 3. By contrast, submaximal rates of acid secretion induced by i.v. infusion of pentagastrin (8 micrograms kg-1 h-1) were not inhibited by i.c.v. administration of endotoxin (800 ng kg-1). 4. Prior i.c.v. administration of the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 800 micrograms kg-1) restored the acid secretory responses to distension in rats treated with endotoxin (i.c.v.). 5. Likewise, i.v. administration of endotoxin (5 micrograms kg-1) abolished the acid secretory response induced by gastric distension within 30 min of administration. Prior i.c.v. injection of L-NAME (800 micrograms kg-1) or its i.v. administration (10 mg kg-1) restored acid secretory responses in rats receiving i.v. endotoxin. 6. The reversal by L-NAME (i.v.) of the acid inhibitory effects of endotoxin (i.v.) was prevented by L-arginine (12 mg kg-1, i.c.v. or 100 mg kg-1, i.v.), but not by its enantiomer D-arginine. 7. The present results imply the existence of an acute response to endotoxin involving NO synthesis in the brain.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cyclic GMP and acid production in isolated gastric cells of the rat

Summary Just as cAMP is regarded as an intracellular mediator of histamine, so has cGMP been connected with cholinergic stimulation of gastric acid secretion. The object of the present investigation was to study the possible role of cellular cGMP on ¹⁴C-aminopyrine uptake, an indirect measure of parietal cell H⁺-production, by using mixtures of isolated rat gastric cells and fractions with different parietal cell content. Cellular cAMP and cGMP. The phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) enhanced the cAMP and cGMP of gastric cells in a time- and concentration-dependent manner, by 98 and 124% (1 mmol/l) and was included in all further studies. In parietal cell enriched fractions, histamine elevated cAMP by 109% (100 mol/l) without changing cGMP while carbachol did not influence either nucleotide. Various thiols and nitrogen compounds strongly enhanced cellular cGMP, e. g. hydroxylamine and l-cysteine (1 mmol/l) by 527 and 656%, whereas changes in cAMP were minimal. The hydroxylamine response occurred in parietal cell depleted and enriched fractions. ¹⁴ C-aminopyrine (AP) uptake. IBMX alone reduced the basal AP uptake, potentiated the effect of histamine and inhibited the effect of carbachol, which alone stimulated basal accumulation by 302%. The most efficacious stimulant of parietal cell H⁺-production was dibutyryl cAMP (582%, 100 mol/l), whereas dibutyryl cGMP was without effect. However, this latter compound (1 mmol/l) reduced AP accumulation due to dibutyryl cAMP almost completely. Thiols and nitrogen compounds all more or less reduced AP uptake.The data contraindicate the theory of a second messenger function for cGMP in cholinergic acid stimulation of the rat stomach. They show, that an increase in cGMP is associated with low H⁺-production, even if cAMP levels are raised above their resting state. Thus, the results suggest that cGMP rather mediates inhibition of acid secretion, possibly by counteracting the messenger function of cAMP.This study was supported by the Deutsche Forschungsgemeinschaft     

Measurement of gastric acid secretion by conductivity

Gastric acid secretion in the anaesthetized rat has been measured by continuously recording the conductivity of the effluent in the reperfusion system previously developed by the authors. (H⁺) and (Na⁺) were measured by titration and flame photometry respectively and compared with the total conductivity of the effluent. The differences between the calculated and measured conductance were within the experimental error of the observations. There was no clear relationship between rates of secretion of hydrogen ions and sodium ions in this preparation. Conductance was used to measure acid concentration and to assay inhibitors and stimulants of gastric acid secretion.A conductivity meter has been designed and used to measure gastric acid secretion in the perfused rat stomach preparation. Measurements of conductivity were shown to be a measure of the hydrogen ion concentration of the effluent. The quality and linearity of the response was superior to that achieved with pH methods. The sensitivity of the system has been increased which has enabled 10 ng of gastrin I to give a significant effect. It was possible to monitor six preparations with one meter during assays of urogastrone and gastrin.     

Role of voltage-gated cation channels and axon reflexes in the release of sensory neuropeptides by capsaicin from isolated rat trachea

In order to reveal the role of axon reflexes and sensory receptors in sensory neuropeptide release in response to capsaicin, liberation of substance P, calcitonin gene-related peptide and somatostatin from isolated rat tracheae was investigated in the presence of voltage-sensitive Na(+) and Ca(2+) channel blocking agents. Neuropeptide release induced by capsaicin (10 nM) remained unchanged in the presence of 25 mM lidocaine, 1 microM tetrodotoxin or the N-type Ca(2+) channel inhibitor, omega-conotoxin GVIA (100-300 nM). Peptide release by 100 pulses of 2 Hz field stimulation was prevented by lidocaine or tetrodotoxin. Omega-agatoxin TK (250 nM) significantly inhibited and Cd(2+) (200 microM) prevented capsaicin-induced neuropeptide release. These results suggest that chemical stimulation-induced neuropeptide release does not involve activation of fast Na(+) channels or N- and P-type voltage-dependent Ca(2+) channels, but contribution of Q-type Ca(2+) channels is possible. Sensory neuropeptides are released by capsaicin from sensory receptors without axon reflexes.     

硝酸钇对大鼠胃粘膜和胃酸分泌的影响

本文研究硝酸钇对饥饿大鼠和幽门结扎大鼠的胃粘膜和胃酸分泌的影响。硝酸钇ig对饥饿大鼠的胃粘膜有严重损伤,但硝酸钇ip对幽门结扎大鼠胃粘膜的损伤却有预防作用。硝酸钇在8～32mg/kg范围内,无论是ig还是ip对胃酸分泌均有抑制作用,且呈明显的剂量效应关系,但4mg/kg对胃酸分泌影响不大。硝酸钇ig可减少胃壁结合粘液的分泌,ip途径则无影响。     

Cholinergic control of gastric acid secretion

Summary In the perfused stomach preparation of the anaesthetized rat the cholinergic agonists acetylcholine (ACh) and bethanechol stimulated gastric acid secretion. Both agonists produced similar maximal acid output (70 mol/15 min) when infused intravenously. However, bethanechol was more potent, eliciting half maximal stimulation at 1.98 mol/kg/h. Secretory responses to either agonist were antagonized in a dose related fashion by blockade of muscarinic receptors with atropine. In contrast, inhibition of nicotinic receptors with hexamethonium produced a striking potentiation of ACh stimulated secretion whilst the bethanechol elicited secretion remained unaffected. In the presence of full nicotinic receptor blockade the ACh response curve was shifted to the left sixfold, half maximal stimulation being produced at 1.79 mol/kg/h. Cimetidine partially inhibited the secretory responses elicited by either ACh or bethanechol while blockade of adrenoceptors ( and ) did not affect acid output induced by cholinergic agonists. Secretion elicited by ACh is interpreted as being the composite effect of prosecretory action and an inhibitory mechanism due to the activation of nicotinic receptors. Hexamethonium, through nicotinic receptor blockade, inhibits the restricting mechanism and thus reveals the full stimulatory action of ACh.