Interactions of caerulein and morphine on gastrointestinal propulsion in the mouse

Summary The effects of subcutaneously administered caerulein (ceruletide) and morphine hydrochloride on gastric emptying and gastrointestinal propulsion were studied in male mice. Drug effects were evaluated by the movement of Indian ink administered directly into the stomach after drug injection. Morphine inhibited both gastrointestinal propulsion (ED₅₀=2.1 mol/kg) and gastric emptying (ED₅₀=43 mol/kg). Caerulein enhanced gastrointestinal propulsion (ED₅₀=0.93 nmol/kg) but inhibited gastric emptying (ED₅₀=17 nmol/kg). Inhibition of gastric emptying was further potentiated by the combined administration of caerulein and morphine. Naloxone reversed both effects of morphine but not those of caerulein. Morphine antagonized the propulsion-enhancing effect of caerulein.     

Capsaicin research as a new tool to approach of the human gastrointestinal physiology,pathology and pharmacology

Background: Capsaicin has been found to act on the capsaicin sensitive afferent nerves in animal experiments. Aim: The specific action of capsaicin on sensory afferent nerves affecting gastrointestinal (GI) functions was investigated in human GI physiology and pathology using pharmacological approaches. Materials and Methods: Observations were carried out in 98 normal healthy human subjects and in 178 patients with different gastrointestinal diseases (gastritis, erosions, ulcer, polyps, cancer, inflammatory bowel diseases, colorectal polyps, cancers). The gastric secretory responses and their chemical composition, gastric emptying, sugar loading test, gastric transmucosal potential difference (GTPD) were investigated following with administration of (a) capsaicin alone, (b) ethanol alone or with capsaicin, and (c) indomethacin-induced gastric mucosal microbleeding with or without capsaicin, both before and after 2 weeks capsaicin treatment. Immunohistochemical investigations were performed to establish the presence of the capsaicin (vanillinoid) receptor (TRVP1), CGRP and SP in the whole GI tract. Conventional molecular pharmacological methods were applied to study the effects of capsaicin and other drugs for their inhibitory effects on the gastric basal acid output. Results: Capsaicin decreased the gastric basal output, enhanced the “non parietal” (buffering) component of gastric secretory responses, gastric emptying, release of glucagon. Capsaicin prevents the indomethacin- and ethanol-induced gastric mucosal injury, while capsaicin itself enhanced the gastric transmucosal potential difference (GTPD). The capsaicin reactive receptors, TRVP1, CGRP, SP were detected in the GI mucosa in patients with different GI disorders, but their presence varied in acute and chronic GI disorders. Conclusion: Application of capsaicin offers a new research tool for understanding the vanilloid-related events of human GI functions in relation to normal physiology and in disease states and the use of pharmacological agents affecting these receptor mediated changes. This paper was part of the Proceedings of the International Mini-Symposium on Gastrointestinal Pharmacology – Tissue Injury, Protection and Healing (10^th July 2006) Kyoto Received 2 September 2006; accepted (after revision) 22 December 2006     

Gastric motility changes in capsaicin-induced cytoprotection in the rat stomach.

We have examined the effect of orally administered capsaicin on gastric motility in the rat to investigate a possible relationship between motility change and cytoprotection induced by this agent. Capsaicin, given orally (1-30 mg/kg), dose-dependently inhibited hemorrhagic band-like lesions induced by ethanol (60% in 150 mM HCl). This protection was significantly mitigated by desensitization of afferent neurons following capsaicin pretreatment 2 weeks before the experiment, and it was also significantly attenuated by prior administration of indomethacin, but not by spantide. Intragastric administration of capsaicin (30 mg/kg) significantly inhibited gastric motility and increased the mucosal blood flow, but had no effect on the transmucosal potential difference of the stomach. These functional changes induced by capsaicin were also less marked in the afferent neuronal desensitized rat, and they were significantly attenuated by indomethacin but not by spantide. These results suggest that the mucosal protection by intragastric capsaicin may be associated with the inhibition of gastric motility and the increase of mucosal blood flow. These responses may be induced by activation of primary afferent neurons which are probably sensitized by endogenous prostaglandins.     

Role of central and peripheral ghrelin in the mechanism of gastric mucosal defence

Ghrelin, identified in the gastric mucosa, has been involved in the control of food intake and growth hormone (GH) release, but whether this hormone influences the gastric secretion and gastric mucosal integrity has been little elucidated. We compared the effects of intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) administration of ghrelin on gastric secretion and gastric lesions induced in rats by 75% ethanol or 3.5 h of water immersion and restraint stress (WRS) with or without suppression of nitric oxide (NO)-synthase or functional ablation of afferent sensory nerves by capsaicin. The number and the area of gastric lesions was measured by planimetry, the GBF was assessed by the H₂-gas clearance method and blood was withdrawn for the determination of the plasma ghrelin and gastrin levels. In addition, the gastric mucosal expression of mRNA for CGRP, the most potent neuropeptide released from the sensory afferent nerves, was analyzed in rats exposed to WRS with or without ghrelin pre-treatment. Ghrelin (5–80 μg/kg i.p. or 0.6–5 μg/kg i.c.v.) increased gastric acid secretion and attenuated gastric lesions induced by ethanol and WRS. This protective effect was accompanied by a significant rise in the gastric mucosal blood flow (GBF), luminal NO concentration and plasma ghrelin and gastrin levels. Ghrelin-induced protection was abolished by vagotomy and significantly attenuated by L-NNA and deactivation of afferent nerves with neurotoxic dose of capsaicin. The signal for CGRP mRNA was significantly increased in gastric mucosa exposed to WRS as compared to that in the intact gastric mucosa and this was further enhanced in animals treated with ghrelin. We conclude that central and peripheral ghrelin exerts a potent protective action on the stomach of rats exposed to ethanol or WRS, and these effects depend upon vagal activity and hyperemia mediated by the NOS-NO system and CGRP released from sensory afferent nerves.     

Stimulation of capsaicin-sensitive sensory peripheral nerves with topically applied resiniferatoxin decreases salicylate-induced gastric H+ back-diffusion in the rat

Capsaicin-sensitive sensory nerves (CSSN) exert local protective functions in the stomach and have been proposed to regulate gastric H⁺ back-diffusion. The present study aimed to evaluate the possible influence of stimulation of CSSN with the intragastrically (ig) applied capsaicin analogue, resiniferatoxin (RTX), on gastric H⁺ back-diffusion and mucosal injury caused by ig application of HCl (2 ml 0.15 mol/L) or acidified salicylate (200 mg/kg in 2 ml 0.15 mol/L HCl) after 1 or 2 h in the pylorus-ligated rat. Stimulation of CSSN with a low concentration (0.04 μg/ml) of RTX markedly decreased H⁺ back-diffusion caused by acidified salicylate. After acute bilateral truncal vagotomy or treatment with atropine sulphate, RTX did not inhibit gastric acid back-diffusion. Surgical vagotomy alone increased, while RTX or atropine markedly diminished, the development of gastric mucosal injury in these models. In saline-treated rats, RTX significantly reduced gastric secretory volume and acid output. The inhibitory effect lasted for 1 h. These data suggest an essential role for CSSN in regulation of gastric acid secretion and in maintaining the integrity of the gastric mucosa that appear to depend on intact vagal nerves.     

Acute studies on safety index of nonsteroidal anti-inflammatory drugs in rats

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat pain and inflammation. Their use is frequently limited by gastrointestinal side effects, ranging from dyspeptic symptoms to life threatening bleeding or perforations of gastroduodenal ulcers. The present study mainly aimed to establish a safety index of NSAIDs in experimental animals. Safety index is based on the ratio of ulcerogenic dose (UD₅₀) and anti-inflammatory dose (ED₅₀). The safety index of preferential COX-2 inhibitor (nimesulide, meloxicam) was investigated using carrageenan-induced paw oedema and acute ulcerogenic model in rats, compared with the classical NSAIDs (naproxen, indomethacin). Meloxicam was found to be the most potent NSAID (ED₅₀ 1.07 mg/kg, p.o.) followed by nimesulide (2.42 mg/kg, p.o.), indomethacin (2.72 mg/kg, p.o.) and naproxen (6.82 mg/kg, p.o.) after 240 min of carrageenan challenge. In acute ulcerogenic study naproxen, indomethacin and meloxicam were found to be ulcerogenic at lower doses (UD₅₀ 14.0, 3.80 and 3.21 mg/kg, p.o.) in comparison to nimesulide (UD₅₀ 24.52 mg/kg, p.o.). Meloxicam, naproxen and indomethacin also produced damage to gastric epithelium (disruption of mucus layer and damage to parietal cells) at ED₅₀ dose level when it was viewed under scanning electron microscope, but nimesulide did not distrub gastric mucosal integrity at ED₅₀ dose. Based on the safety index (Ulcerogenic dose₅₀ /Effective anti-inflammatory dose₅₀) the order of safety of these agents was nimesulide > meloxicam > naproxen > indomethacin.     

Gastrointestinal cytoprotection: from basic science to clinical perspectives

An essential point of cytoprotection is that the prostaglandins are able to prevent chemical-induced gastric mucosal damage without affecting gastric acid secretion, this being originally suggested as a property specific to prostaglandins. Since then gastrointestinal cytoprotection has been shown with various agents (anticholinergic agents, H₂RA, growth factors) and retinoids the latter differing from the actions of vitamin A. In examining the various components of gastrointestinal cytoprotection we have performed studies in isolated cells, stable cell lines, animal experiments, healthy human subjects, and in patients with gastrointestinal diseases. Our attention has focused on the effects of cytoprotective agents on cellular viability, mitochondrial and DNA damage, oxygen free radicals, natural antioxidant systems, mucosal biochemistry, vascular events, gastrointestinal mucosal protection as well as in their prevention of different human diseases. This paper gives a short overview on the different approaches for the exploring gastrointestinal cytoprotection. Received 28 August 2006; revised version 27 October 2006; accepted 27 October 2006     

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.     

Gastroprotections of escins Ia, Ib, IIa, and IIb on ethanol-induced gastric mucosal lesions in rats.

Effects of escins Ia, Ib, IIa, and IIb isolated from horse chestnuts on ethanol-induced gastric mucosal lesions and the roles of capsaicin-sensitive afferent neurons, endogenous nitric oxide (NO), sulfhydryls, prostaglandins, as well as gastric secretion and the sympathetic nervous system, were investigated in rats. Test samples were given orally to fasted rats 1 h before ethanol (1.5 ml/rat, p.o.) treatment or ligation of the pylorus. Escins Ia-IIb (10-50 mg/kg) potently inhibited ethanol-induced gastric mucosal lesions, whereas desacylescins I and II (50 mg/kg) showed no such effect. These active saponins (10 and 20 mg/kg) did not decrease the gastric secretion. The gastroprotections of escins Ia-IIb were attenuated by the pretreatment with capsaicin, N(G)-nitro-L-arginine methyl ester, and indomethacin, but not by N-ethylmaleimide. The effects of escins Ia-IIb were also attenuated in streptozotocin-induced diabetic rats, in which the activity of the sympathetic nervous system was abnormal. These results suggest that the gastroprotections of escins Ia-IIb on ethanol-induced gastric mucosal lesions are acid-independent, whereas endogenous prostaglandins, NO, capsaicin-sensitive afferent neurons, and the sympathetic nervous system participate.     

The role of capsaicin-sensitive afferent nerves in protective effect of capsaicin against absolute ethanol-induced gastric lesions in rats

The role of capsaicin-sensitive afferent nerves in gastroprotection by capsaicin was investigated in the absolute ethanol-induced gastric lesion model in rats. Capsaicin (0.1 and 0.5 mg/kg, p.o.) inhibited the lesion formation dose-dependently. The protective effect of capsaicin was attenuated by indomethacin-pretreatment and disappeared in capsaicin-sensitive nerve degenerated rats. Capsaicin did not induce the distension of gastric mucosal folds. These results suggested that stimulation of capsaicin-sensitive afferent nerves by capsaicin would enhance the prostaglandin formation, leading to an inhibition of gastric lesions.     

Capsaicin sensitive nerves in the jejunum of Nippostrongylus brasiliensis-sensitized rats participate in a cardiovascular depressor reflex

Summary Superfusion of capsaicin onto the serosal surface of jejunum of Nippostrongylus brasiliensis-sensitized rats induces a short-lasting (1–3 min), dose-dependent (2 to 20 g) decrease in blood pressure which ranges from –5.3±1.40% to –22.6±2.20%. The hypotension evoked by capsaicin was more marked in sensitized rats than in unsensitized animals, which responded only to the highest dose (20 mg) of capsaicin tested. The hypotensive effects of capsaicin were not affected by intravenous injections of mepyramine (10 mg/kg), a histamine receptor antagonist, or by the cycloxygenase inhibitor indomethacin (10 mg/kg). However, an intravenous injection of a platelet-activating factor (PAT) antagonist, BN 52021 (20 mg/kg), or an intraperitoneal injection of guanethidine (8 mg/kg) 18 h prior to experimentation, to functionally impair the sympathetic nerves, abolished the capsaicin-induced drop in blood pressure. Treatment of neonatal rats with capsaicin reduced by 75% the hypotensive effects of capsaicin, whereas the capsaicin antagonist, ruthenium red, reduced non-significantly the hypotensive action of capsaicin. It is concluded that the activation of jejunal sensory nerves in N. brasiliensis-sensitized rats by capsaicin induced a reflex hypotension that is dependent upon PAF release from mast cells and functional sympathetic nerves. In addition, the afferent function of the sensory nerves are not totally blocked by ruthenium red as capsaicin elicits the reflex hypotension in the presence of this blocker of sensory nerve efferent function.Correspondence to: R. Mathison     

Nabumetone,in contrast to etodolac,lacks gastrointestinal irritancy in the rat: Assessment by the inflammatory marker,haptoglobin, and blood loss

The aim of the present study was to compare the effects of the non-acidic anti-inflammatory drug, nabumetone, with those of etodolac on gastrointestinal mucosal integrity and blood loss in the rat. Gastrointestinal damage was absent in nabumetone-treated animals even at a high anti-inflammatory dose (79 mg/kg). Plasma haptoglobin, a marker of mucosal integrity, and caecal haemoglobin, a measure of blood loss, were also unchanged compared with controls. In contrast, etodolac induced both gastric (ED₅₀ 30 mg/kg) and ileal (ED₅₀ 4.5 mg/kg) ulceration in a dose-related manner. Accompany-ing these changes were increases in haptoglobin concentration and blood loss. It is suggested that nabumetone’s lack of gastrointestinal irritancy may relate, in part, to its non-acidic nature and to its active metabolite’s (6MNA) differential effects on prostanoid production and lack of enterohepatic circulation.     

Angiotensin AT1 receptor blockers suppress ischemia/reperfusion-induced gastric injury in rats

Ischemia/reperfusion (I/R) damages gastric mucosa via reactive oxygen species (ROS) activity. ROS was reportedly produced through angiotensin II stimulation in tissues such as kidney, heart and brain. To determine whether AT1 receptor plays a role in gastric mucosal damage, we examined the effect of AT1 receptor blocker (ARB; losartan, candesartan, valsartan) on I/R-induced gastric injury in rats. I/R produced microscopic gastric hemorrhagic injury, and increased gastric microvascular permeability and H₂O₂ production in rats. The mucosal lesions induced by I/R were attenuated by pretreatment of each ARB. The increase in microvascular permeability was suppressed by losartan pretreatment. Additionally, I/R-caused H₂O₂ activation was not observed by pretreatment of losartan, candesartan and valsartan. These results suggest that angiotensin II stimulation via AT1 receptor and following ROS production in the stomach contribute to the pathogenesis of the gastric I/R injury. Received 31 July 2006; revised 29 August 2006; accepted 21 August 2006     

Pulmonary Mechanical Responses to Intravenously Administered Capsaicin in Guinea-pigs: Effect of Peptidase Inhibitors

Summary: In order to examine the role of peptidases in modulating bronchoconstrictor responses to iv administered capsaicin, a potent C-fiber stimulant, we measured changes in pulmonary conductance (G_L) and dynamic compliance (C_dyn) in anesthetized mechanically ventilated guinea-pigs. Control guinea-pigs, and guinea-pigs treated with the neutral endopeptidase (NEP) inhibitors thiorphan (1.7 mg/kg) or SCH32615 (1 mg/kg), the angiotensin converting enzyme (ACE) inhibitor captopril (5.7 mg/kg), or combinations of NEP and ACE inhibitors, were given increasing doses of capsaicin by rapid iv injection. The doses of capsaicin required to cause a 50% decrease in G_L and C_dyn (ED₅₀G_L and ED₅₀C_dyn respectively) were computed for each animal. None of the peptidase inhibitors, when given alone, had any effect on the changes in pulmonary mechanics induced by capsaicin. However, combined administration of thiorphan and captopril, or SCH32615 and captopril, caused a decrease in ED₅₀C_dyn for capsaicin, and prolonged the time during which the peak changes in G_L induced by capsaicin persisted. These data support the hypothesis that substances whose degradation is inhibited by combined NEP and ACE inhibitors contribute to the bronchoconstriction induced by iv administered capsaicin. This profile of enzymatic degradation is consistent with the tachykinin, substance P.     

Gastric mucosal preventive effects of prostacyclin and β-carotene,and their biochemical effects in rats treated with ethanol and HCl at different doses and time intervals after administration of necrotizing agents

Aims

The aims of these studies were to evaluate the biochemical mechanisms involving energy metabolism of:

1. Gastric mucosal damage affected by oral administration of 0.6 mol/L HCl (representing an acid-dependent model) and 96% ethanol (EtOH) (as a non-acid-dependent model);
2. PGI₂-induced (ED₅₀=5 μg/kg po) and β-carotene-induced (ED₅₀=1 mg/kg po) gastroprotection on the gastric mucosal damage produced by HCl and EtOH at different times and doses.

Methods

Sprague-Dawley rats were used. After 24 h starvation (with tap water ad libitum), gastric mucosal damage was induced by oral administration of 1 ml 0.6 mol/L HCl or 96% EtOH. Rats were pretreated with oral saline, PGI₂ (5 and 50 μg/kg) and β-carotene (1 and 10 mg/kg) and killed at 0, 1, 5, 15, 30 and 60 min after administration of the necrotizing agents. The number and severity of gastric mucosal lesions, measurement of adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), lactate (enzymatically), and cyclic adenosine monophosphate (cAMP) by RIA were carried out at different time intervals, after the necrotizing agents were administered. The ratio of ATP/ADP, adenylate pool (ATP+ADP+AMP) and ‘energy charge’ [(ATP+0.5 ADP)/(ATP+ADP+AMP)] were calculated.

Results

The results showed that:

1. The mucosal damage (number and severity) reached about 50% of that obtained 60 min after administration of the necrotizing agents in both models;
2. PGI₂ prevented in the early period (0–15 min), while β-carotene inhibited in the later period (15–60 min) the gastric mucosal damage produced by EtOH and HCl;
3. The ATP-ADP transformation was decreased in the first (early; 0–15 min) by PGI₂ and in the late period (15–60 min) by β-carotene;
4. ATP-cAMP transformation was increased in the early period by PGI₂ and in the late phase by β-carotene;
5. No significant change was obtained in the ‘energy charge’ and lactate by PGI₂ or β-carotene administration;
6. The changes in adenine nucleotides were the same in the EtOH or HCl models with and without treatment with PGI₂ and β-carotene; however, the mucosal protective action of PGI₂ and β-carotene, and the energy metabolism, differed significantly dependent on dose and time after

administration of EtOH and HCl.

Conclusions

1. The development of gastric mucosal damage and its prevention can be discriminated into early and late phases;
2. The early phase of gastric mucosal damage can be prevented by PGI₂, and the late phase by β-carotene;
3. The β-carotene effect only partly depends on its presumptive scavenging properties; and
4. PGI₂ prevents the development of gastric mucosal damage, while β-carotene stimulates the repair mechanisms.

     

Antinociceptive and anti-hyperalgesic effects of bis(4-methylbenzoyl) diselenide in mice: Evidence for the mechanism of action

Abstract

Context: The organoselenium compounds have been described to demonstrate several biological activities, including pain management.

Objective: This study investigated the antinociceptive, hyperalgesic, and toxic effects of oral administration of bis(4-methylbenzoyl) diselenide (BMD) in mice.

Materials and methods: The antinociceptive and anti-hyperalgesic effects of BMD (1, 5, 10, 25, and 50?mg/kg, p.o.) were evaluated using models of nociception: formalin, capsaicin, bradykinin (BK), cinnamaldehyde, phorbol myristate acetate (PMA), 8-bromo-cAM, and glutamate-induced nociception; and mechanical hyperalgesia induced by carrageenan (Cg) or complete Freund's adjuvant (CFA). The acute toxicity was evaluated by biochemical markers for hepatic and renal damages.

Results: BMD significantly inhibited the licking time of the injected paw in the early and late phases of a formalin test with ED₅₀ values of 14.2 and 10.8?mg/kg, respectively. This compound reduced nociception produced by capsaicin (ED₅₀ of 32.5?mg/kg), BK (ED₅₀ of 24.6?mg/kg), glutamate (ED₅₀ of 28.7?mg/kg), cinnamaldehyde (ED₅₀ of 18.9?mg/kg), PMA (ED₅₀ of 9.6?mg/kg), and 8-bromo-cAMP (ED₅₀ of 24.8?mg/kg). In the glutamate test, the pretreatment with nitric oxide (NO) precursor, l-arginine, reversed antinociception caused by BMD or N^ω-nitro-l-arginine (_L-NOARG), but the effect of BMD was not abolished by naloxone. Mechanical hyperalgesia induced by Cg and CFA was attenuated by BMD, 70?±?4% and 65?±?4%, respectively. Furthermore, a single oral dose of BMD did not change plasma aspartate (AST) and alanine aminotransferase (ALT) activities or urea and creatinine levels.

Conclusion: BMD demonstrated as a promising compound because of the antinociceptive and anti-hyperalgesic properties in mice.     

MEN 11,420, a peptide tachykinin NK2 receptor antagonist, reduces motor responses induced by the intravesical administration of capsaicin in vivo

This study investigates the role of tachykinin NK₁ and NK₂ receptors in motor responses induced by the intravesical instillation of capsaicin in urethane-anaesthetized rats. SR 140,333 (1 μmol/kg, i.v.), a non-peptide NK₁ receptor antagonist, abolished urinary bladder contractions induced by the selective NK₁ receptor agonist [Sar⁹]SP-sulfone (0.1-100 nmol/kg, i.v.) without affecting those induced by the NK₂ receptor agonist [?Ala⁸]NKA(4-10). MEN 11,420 (100 nmol/kg, i.v.), a cyclic peptide NK₂ receptor antagonist, abolished bladder contractions induced by [?Ala⁸]NKA(4-10) (0.3-300 nmol/kg, i.v.) without modifying those induced by [Sar⁹]SP-sulfone. Intravesical instillation of capsaicin (6 nmol/0.6 ml/rat) produced a motor response consisting in a primary contraction followed by a series of high amplitude phasic contractions. The intravesical instillation of saline (0.6 ml/rat) produced a primary contraction of lower amplitude with respect to that induced by capsaicin and the total area under the curve was also lower in saline-instilled rats, however the number and the amplitude of phasic contractions was similar to that induced by capsaicin. MEN 11,420 (100 nmol/kg, i.v.) did not modify motor responses induced by the intravesical administration of saline. In contrast, in capsaicin-instilled rats, MEN 11,420 (100 nmol/kg, i.v.) reduced the primary contraction, the area under the curve and also the number of phasic contractions. SR 140,333 (1 μmol/kg, i.v.) reduced the primary contraction but not other parameters. The combination of SR 140,333 (1 μmol/kg, i.v.) and MEN 11,420 (100 nmol/kg, i.v.) produced an additive inhibitory effect on the primary contraction but not a further inhibition on other parameters with respect to that observed with MEN 11,420 alone. In hexamethonium (110 μmol/kg, i.v.)-pretreated animals the intravesical instillation of capsaicin produced a tonic contraction having greater amplitude and area than that induced by saline. MEN 11,420, but not SR 140,333, significantly reduced the bladder response to capsaicin in hexamethonium-pretreated rats. Again, the combined administration of MEN 11,420 and SR 140,333 did not produce further inhibitory effect in comparison to MEN 11,420 alone. It is concluded that the motor responses induced by the intravesical instillation of capsaicin are mediated by the activation of peripheral tachykinin NK₂ receptors. Received: 11 February 1997 / Accepted: 17 April 1997     

Dimaprit stimulation of gastric acid secretion in rhesus monkeys and dogs

Tests were performed to characterize the gastric secretory effect of the H₂ agonist, dimaprit, in rhesus monkeys. Dose-response studies were performed. The monkeys were chaired, and increasing doses of dimaprit (0.03 to 3.0 mg/kg hr) were infused intravenously. Gastric secretions were collected continuously through a nasogastric tube and were measured at 15-min intervals. The completeness of collection was confirmed based on the recovery of an intragastric marker. Dimaprit dose dependently increased the total acid output (ED₅₀ = 0.198 mg/kg hr) and the volume of gastric secretion. Ranitidine (1 mg/kg hr, i.v.) shifted the dimaprit dose-response curve to the right in a parallel fashion causing a 13-fold increase in the ED₅₀ for acid output (2.54 mg/kg hr). Similarly, ranitidine competitively inhibited the secretory effect of dimaprit in the gastric fistula dog. In addition, when a single dose of dimaprit was infused over a 4-hr period, both the monkey and dog exhibited a secretory plateau followed by a secretory “fade.” We conclude that the secretory effects of dimaprit are qualitatively similiar for rhesus monkeys and dogs.     

Neuropeptides and gastric mucosal homeostasis

The role of central nervous system (CNS) in regulation of gastric function has long been known. The dorsal vagal complex (DVC) has an important role in regulation of gastric mucosal integrity; it is involved both in mucosal protection and in ulcer formation. Neuropeptides have been identified in DVC, the origin of these peptides are both intrinsic and extrinsic. Neuropeptides are localized also in the periphery, in afferent neurons. The afferent neurons also have efferent-like function in the gastroinetestinal tract, and neuropeptides released from the peripheral nerve endings of primary afferent neurons can induce gastric mucosal protection. Centrally and /or peripherally injected neuropeptides, such as amylin, adrenomedullin, bombesin, cholecystokinin, neurotensin, opioid peptides, thyreotropin releasing hormone and vasoactive intestinal peptide, influence both the acid secretion and the gastric mucosal lesions induced by different ulcerogens. The centrally induced gastroprotective effect of neuropeptides may be partly due to a vagal dependent increase of gastric mucosal resistance to injury; activation of vagal cholinergic pathway is resulted in stimulation of the release of mucosal prostaglandin and nitric oxide. Furthermore, release of sensory neuropeptides (calcitonin gene-related peptide, tachykinins) from capsaicin sensitive afferent fibers are also involved in the centrally induced gastroprotective effect of neuropeptides.     

Capsaicin-sensitive nerves modulate resting blood flow and vascular tone in rat gut

Summary Acute and chronic treatments with capsaicin were used to evaluate the role of afferent neurons in the regulation of intestinal blood flow. Experiments were performed on anesthetized rats, in which mean intestinal blood flow was determined with a pulsed Doppler flowmeter mean systemic arterial pressure was determined with a transducer, and intenstinal vascular conductance (C) was calculated from these measurements. Acute administration of periarterial capsaicin (0.5 mg) induced biphasic intestinal vascular responses. An early hyperemic response occurred with a maximal increase in blood flow of 31 % at 5 min, followed by a decrease in blood flow of 17% at 30 min. Arterial pressure was decreased by the application of capsaicin, initially by 10%. There was an early increase of 49% in conductance, followed by a 15% decrease, compared with control values. When 1 or 4 mg capsaicin was instilled into the lumen of the jejunum there was a response pattern similar to that observed after periarterial application of capsaicin. Intrajejunal capsaicin (4 mg) increased blood flow by 51%, followed by a decrease of 16%. Mean mesenteric artery conductance was increased by 32% initially and subsequently was decreased by 21%, in response to acute intrajejunal administration of capsaicin. Both mean blood flow and conductance were increased (44% and 76%, respectively) in adult rats chronically pretreated with capsaicin (170 mg total dose) when compared with vehicle-treated controls.However, in rats pretreated neonatally with capsaicin (50 mg/kg) and allowed to mature, basal flood flow was lower than in control animals but C was not different from control littermates. These findings suggest that the hyperemic effect of acute administration of capsaicin may be related to the stimulation of afferent sensory nerves and release of vasodilatory peptides. The late vasoconstrictor effect could be due to neuronal depletion of vasodilator peptides in perivascular nerves. However, changes observed in the intestinal circulation after chronic pretreatment with capsaicin in the adult rat, in contrast to the observations in the neonatally treated rat, cannot be explained entirely by simple depletion of peptides from the sensory nerves. We conclude that capsaicin-sensitive, afferent nerves in the small intestine modulate the resting vascular tone in rat gut. Send offprint requests to O. D. Hottenstein at the above address