Gastric Mucosal Blood Flow Research Articles

Proteinase-activated receptors in the gastrointestinal system: a functional linkage to prostanoids

Proteinase-activated receptors (PARs), G protein-coupled receptors, play critical roles in the alimentary system. Increasing evidence suggests that endogenous prostaglandins (PGs) mediate some of PARs' gastrointestinal functions. Systemic administration of the PAR1 agonist protects against gastric mucosal injury through PG formation in rats. PGs also appear to contribute, at least in part, to enhancement of gastric mucosal blood flow and suppression of gastric acid secretion by PAR1 activation. There is also evidence for involvement of PGs in modulation of gastrointestinal motility by PAR1 or PAR2. Importantly, modulation of ion transport by PAR1 or PAR2 in the intestinal mucosal epithelium is largely mediated by PGs. Studies using gastric and intestinal mucosal epithelial cell lines imply that the PAR1-triggered formation of PGs involves multiple signaling pathways including Src, EGF receptor trans-activation and activation of MAP kinases. Collectively, a functional linkage of PAR1 and/or PAR2 to PGs is considered important in the gastrointestinal system.

Dual modulation of the tension of isolated gastric artery and gastric mucosal circulation by hydrogen sulfide in rats

To clarify roles of H2S in regulation of gastric circulation, we investigated effects of NaHS, a H2S donor, on tension of isolated rat gastric artery and gastric mucosal blood flow in rats. In the precontracted ring preparations, NaHS caused contraction and relaxation at low and high concentrations, respectively. The NaHS-induced vasorelaxation was only partially blocked by glibenclamide, a K+ (ATP) channel inhibitor. The contractile activity of NaHS disappeared by removal of the endothelium or by inhibition of nitric oxide synthase and the endothelium-derived hyperpolarizing factor (EDHF) pathways. Intravenous injection of NaHS caused transient increase followed by decrease in gastric mucosal blood flow in rats. Collectively, in the gastric artery, NaHS appears to cause relaxation through both K+ (ATP) channel-dependent and -independent pathways and contraction through inhibition of NO and EDHF pathways. Together with the in vivo results, our study implies that H2S plays multiple complex roles in regulation of gastric circulation.

Prophylactic effect of lafutidine against the adverse reaction induced in rat stomach by repeated administration of 5-fluorouracil

We examined the prophylactic effect of lafutidine, a histamine H2 receptor antagonist, on the morphological and functional derangement of the rat stomach after the administration of 5-fluorouracil (5-FU) in the absence or presence of taurocholate Na (TC). Rats were given 5-FU p. o. once daily for 5 days. After 18 hr fasting, the animals were given omeprazole to inhibit acid secretion. Under urethane anesthesia, the stomach was mounted on an ex-vivo chamber, perfused with 100 mM HCl, and both the transmucosal potential difference (PD) and gastric mucosal blood flow (GMBF) were simultaneously measured before and after exposure of the mucosa to 20 mM TC for 30 min. The 5-FU treatment lowered the basal PD with a decrease in the mucosal height and caused few haemorrhagic lesions in the stomach when perfused with 100 mM HCl for 2 hr. The 5-FU treatment had no influence on the reduced PD response caused by TC, but significantly impaired the increase in GMBF after exposure to TC, resulting a marked aggravation of gastric lesions. Lafutidine, given together with 5-FU for 5 days, significantly antagonized the deleterious effect of 5-FU on the basal PD and the GMBF response to TC, and prevented the aggravation of gastric lesions. These effects of lafutidine were not mimicked by cimetidine and disappeared due to the chemical ablation of capsaicin-sensitive afferent neurons. We conclude that 1) 5-FU treatment caused the morphological and functional derangement of the stomach and increased the mucosal vulnerability against acid, and 2) lafutidine prevents such changes caused by 5-FU treatment, probably mediated through capsaicin-sensitive afferent neurons.

Prophylactic effect of rebamipide against the irritative and healing impairment actions of alendronate in rat stomachs

We examined the effect of rebamipide, an antiulcer drug, on the mucosal irritative and the healing impairment action of alendronate in rat stomachs. Male SD rats were used to examine the effect of rebamipide in the following 3 experiments. 1) Alendronate applied topically to the chambered stomach under urethane anaesthesia produced a decrease in the transmucosal potential difference and an increase of gastric mucosal blood flow and luminal acid loss, resulting in slight damage to the mucosa. Pretreatment with rebamipide for 3 days had no effect on the changes induced by alendronate. 2) Oral administration of alendronate caused non-haemorrhagic lesions in the stomach within 4 hr. Rebamipide, given either as a single p. o. injection or repeatedly for 7 days, did not significantly affect the lesions induced by alendronate. 3) Alendronate, given p. o. once daily for 1 week, markedly delayed the healing of acetic acid-induced gastric ulcers with the suppression of basic fibroblast growth factor (bFGF) expression. Rebamipide, given twice daily for 7 days, significantly promoted the delayed ulcer healing caused by alendronate, with the concomitant recovery of bFGF expression. These results suggest that rebamipide does not affect the direct irritating action of alendronate in the gastric mucosa, but this agent antagonizes the healing impairment action of alendronate by counteracting the downregulation of bFGF expression in the ulcerated mucosa.

Aging Gastropathy—Novel Mechanisms: Hypoxia, Up-regulation of Multifunctional Phosphatase PTEN, and Proapoptotic Factors

Aging gastric mucosa has impaired mucosal defense and increased susceptibility to injury. Our aims were to determine the mechanisms responsible for above abnormalities. We used Fisher F-344 rats, 3 and 24 months of age. We measured gastric mucosal blood flow; visualized mucosal hypoxia; examined expression of early growth response-1 transcription factor and phosphatase and tensin homologue deleted on chromosome 10 (PTEN); assessed apoptosis; and determined expression of caspase-3, caspase-9, and survivin. We also examined susceptibility of gastric mucosa of young and aging rats to ethanol injury and whether down-regulation of PTEN affects susceptibility of aging gastric mucosa to injury. To determine human relevance, we examined expression of PTEN and survivin in human gastric specimens of young and aging individuals. Gastric mucosa of aging (vs young) rats has a 60% reduction in mucosal blood flow; prominent hypoxia; and increased early growth response-1 transcription factor and PTEN messenger RNAs, and proteins. It also has increased expression of proapoptotic proteins caspase-3 and capase-9, reduced survivin, and a 6-fold increased apoptosis vs mucosa of young rats. Ethanol-induced gastric mucosal injury in aging (vs young) rats was significantly increased. The down-regulation of PTEN in gastric mucosa of aging rats completely reversed its increased susceptibility to ethanol injury. In aging human gastric mucosa, PTEN expression was significantly increased, whereas survivin was significantly reduced. (1) Gastric mucosa of aging rats has significantly reduced blood flow, tissue hypoxia, activation of Egr-1, PTEN; increased caspases; and reduced survivin. (2) These changes increase susceptibility of aging gastric mucosa to injury.

Preventive Effects of Rebamipide on NSAID-Induced Gastric Mucosal Injury and Reduction of Gastric Mucosal Blood Flow in Healthy Volunteers

The precise mechanisms of acute damage and the role of gastric mucosal blood flow in gastric mucosal injury induced by nonsteroidal anti-inflammatory drugs (NSAIDs) remain uncertain. The aim of this study was to evaluate the preventive effect of rebamipide on gastric mucosal injury and reduction of gastric mucosal blood flow (GMBF) after ibuprofen administration. Twenty healthy volunteers were randomized two groups. The rebamipide group took ibuprofen, 1800 mg/day, and rebamipide, 100 mg t.i.d., for 7 days. The placebo group took ibuprofen, 1800 mg/day. The numbers of gastric ulcer subjects were three in the placebo group and zero in the rebamipide group. The mean modified Lanza score after ibuprofen administration was significantly higher in the placebo group than the rebamipide group (2.9+/-1.7 vs. 1.3+/-1.0, respectively; P=0.032). The GMBF of the placebo group was significantly decreased at antrum from baseline, from 2.8+/-0.5 to 2.0+/-0.5 tissue perfusion units (P=0.005). There was no difference in GMBF change in the rebamipide group. Gastric mucosal injury was correlated with GMBF reduction in antrum (r=-0.677, P=0.001). In conclusion, it is suggested that the decrease in GMBF may have been associated with NSAID-induced gastric mucosal injury, and rebamipide may have prevented NSIAD-induced gastric mucosal injury by maintaining GMBF in healthy subjects.

Effect of thoracic epidural analgesia on gastric blood flow after oesophagectomy

The oesophagectomy procedure includes the formation of a gastric tube to re-establish the continuity of the gastrointestinal tract. The effect of thoracic epidural analgesia (TEA) on gastric mucosal blood flow (GMBF) remains unknown in clinical practice. The aim of this prospective observational study was to assess the microcirculatory changes induced by TEA in the early post-operative course. Eighteen consecutive patients who underwent radical oesophagectomy with en-bloc resection and two-field lymphadenectomy for oesophageal cancer, and benefited from TEA during the post-operative course, were studied prospectively, and compared with nine patients who declined the use of TEA in the same period (control group). GMBF was measured using a laser Doppler flowmeter in three consecutive time periods (before and after 1 and 18 h of TEA infusion). Post-operative monitoring also included the measurement of arterial pressure, cardiac output, gas exchange and intrathoracic blood volume index. After the first and 18th hour of infusion, TEA induced an increase in GMBF compared with baseline and the control group. The mean arterial pressure and intrathoracic blood volume index decreased after the first hour of TEA infusion with no influence on the cardiac index. This clinical study demonstrates that TEA improves the microcirculation of the gastric tube in the early post-oesophagectomy period. The clinical relevance of TEA in this setting should be validated in larger studies focusing on the clinical outcome following oesophagectomy.

New method of evaluating gastric mucosal blood flow by ultrasound

Objective. Evaluation of gastrointestinal blood flow is important. However, a non-invasive measurement method has not yet been established. The aim of this study was to compare measurement of normal gastric mucosal blood flow by advanced dynamic flow (ADF) flash echo imaging (FEI) with intravenous Levovist with measurement by laser Doppler flowmetry (LDF) to clarify the usefulness of ADF-FEI and thereby consider its feasibility as a non-invasive gastric mucosal blood flow measurement method. Material and methods. Measurements were obtained in 25 beagle dogs (8-month-old males, body-weight, 10.6±1.3 kg, mean±SD). After insertion of a gastrointestinal endoscope, gastric mucosal blood flow at the greater curvature of the corpus was measured by LDF, and images of gastric mucosal blood flow were obtained by ADF-FEI (frequency; 4.7 MHz) with intravenous injection of Levovist (30 mg/kg). ADF-FEI images were transferred to a personal computer. A region of interest was set on the mucosa of the greater curvature of the corpus, and a time intensity curve (TIC) was plotted from the measured echo intensities. The area under the curve (AUC) calculated from the TIC and the median flow determined by LDF were analyzed and compared. Results. Evaluation of normal gastric mucosal blood flow by ADF-FEI was possible in all animals. There was a strong, significant correlation between gastric mucosal blood flow measured by LDF and the AUC obtained by ADF-FEI (r=0.869, p<0.0001). Conclusions. Gastric mucosal blood flow can be accurately measured by ADF-FEI with intravenous Levovist injection.

Effect of acupuncture at Foot-Yangming Meridian on gastric mucosal blood flow, gastric motility and brain-gut peptide

To observe the effect of acupuncture at Foot-Yangming Meridian on gastric mucosal blood flow (GMBF), gastric motility and brain-gut peptide. Sixty SD rats were randomly divided into 6 groups: normal control group, model group (group with gastric mucosal damage, GMD), Sibai group (with acupuncture at Sibai point + GMD), Tianshu group (with acupuncture at Tianshu point + GMD), Zusanli group (with acupuncture at Zusanli point + GMD) and non-acupoint group (with acupuncture at non-acupoint + GMD). The GMD model group was induced by infusing pure alcohol into gastric cavity. H(2) Gas Clearance Test (HGCT) was used to measure GMBF, the frequency and amplitude of gastric motility were measured by the method of aerocyst, the content of brain-gut peptide in sinus ventriculi and bulbus medullae were detected by radioimmunoassay. Inhibitory effect of the frequency and amplitude of gastric motility were shown in model group, and the rates of frequency and amplitude changes were remarkably different from the normal control group (-19.41 +/- 17.21 vs -4.71 +/- 10.32, P < 0.05; -51.61 +/- 29.02 vs 1.81 +/- 14.12, P < 0.01). In comparison with control group, the GMBF was 0.52 +/- 0.161 mL vs 1.03 +/- 0.255 mL per 100g tissue/min, P < 0.01, the content of motilin in sinus ventriculi and bulbus medullae was 63.04 +/- 7.77 pg/mL vs 72.91 +/- 8.42 pg/mL, P < 0.05 and 50.96 +/- 8.77 pg/mL vs 60.76 +/- 8.05 pg/mL, P < 0.05, but the content of somatostatin in sinus ventriculi and bulbus medullae was 179.85 +/- 43.13 ng/g vs 90.54 +/- 40.42 ng/g, P < 0.01 and 532.86 +/- 122.58 ng/g vs 370.91 +/- 76.29 ng/g, P < 0.05,respectively. In comparison with model group, the amplitude of gastric motility was 1.52 +/- 20.13, -6.52 +/- 23.31, 6.92 +/- 25.21 vs -51.61 +/- 29.02, P < 0.01 and GMBF was 0.694 +/- 0.160 mL vs 0.893 +/- 0.210 mL, 1.038 +/- 0.301 mL vs 0.52 +/- 0.161 mL per 100g tissue/min, P < 0.01, respectively in Tianshu, Sibai and Zusanli groups, the content of motilin in sinus ventriculi and bulbus medullae was 71.64 +/- 9.35 pg/mL vs 63.04 +/- 7.77 pg/mL, P < 0.05; 58.96 +/- 6.69 pg/mL vs 50.96 +/- 8.77 pg/mL, P < 0.05 in Zusanli group and 72.84 +/- 8.62 pg/mL vs 63.04 +/- 7.77 pg/mL, P < 0.05 in Sibai group, while the content of somatostatin in bulbus medullae in Tianshu, Sibai and Zusanli groups was 480.62 +/- 151.69 ng/g, 388.53 +/- 155.04 ng/g, 365.76 +/- 143.93 ng/g vs 532.86 +/- 122.58 ng/g, P < 0.05, respectively. Electro-acupuncture at acupoints of Foot-Yangming Meridian could enhance the gastric motility, improve GMBF, and regulate the content of motilin and somatostatin in sinus ventriculi and bulbus. The effects of acupuncture on GMBF and gastric motility may be related to the content of brain-gut peptide.

Association of high expression in rat gastric mucosal heat shock protein 70 induced by moxibustion pretreatment with protection against stress injury

To study the effect of moxibustion on Zusanli or Liangmeng point on gastric mucosa injury in stress-induced ulcer rats and its correlation with the expression of heat shock protein 70 (HSP70). Sixty healthy SD rats (30 males, 30 females) were divided into control group, injury model group, Zushanli point group, Liangmeng point group. Stress gastric ulcer model was induced by binding cold stress method. Gastric mucosa ulcer injury (UI) index was calculated by Guth method. Gastric mucosa blood flow (GMBF) was recorded with a biological signal analyzer. Protein content and gene expression in gastric mucosal HSP70 were detected by immunohistochemistry (IHC) and reverse transcription polymerase chain reaction (RT-PCR). Thiobarbital method was used to determine malondialdehyde (MDA) content. Gastric mucosal endothelin (ET) and prostaglandin E(2) (PGE(2)) were analyzed by radioimmunoassay. High gastric mucosal UI index, high HSP70 expression, low GMBF and PGF(2), elevated MDA and ET were observed in gastric mucosa of rats subjected to cold stress. Moxibustion on Zusanli or Liangmeng point decreased rat gastric mucosal UI index, MDA and ET. Conversely, the expression of HSP70, GMBF, and PGE(2) was elevated in gastric mucosa after pretreatment with moxibustion on Zusanli or Liangmeng point. The observed parameters were significantly different between Zusanli and Liangmeng points. Pretreatment with moxibustion on Zusanli or Liangmeng point protects gastric mucosa against stress injury. This protection is associated with the higher expression of HSP70 mRNA and protein, leading to release of PGE(2) and inhibition of MDA and ET, impairment of gastric mucosal index.

Aspirin Can Elicit The Recurrence of Gastric Ulcer Induced with Acetic Acid in Rats

This study was supported by grants of New Ideas Capability for Backbone Teachers in Universities of Heilongjiang and of Scientific Research foundation in Qiqihar Medical College. Background/ Aims: Ulcer recurrence and poor healing may be critically important to the development of serious gastrointestinal complications in patients with long-term non-steroid anti-inflammatory drugs (NSAIDs). The present study is to investigate the effects of aspirin on ulcer recurrence and healing quality and to explore the mechanism. Methods: Gastric ulcers were induced with acetic acid in rats; aspirin was administrated by gavage from day 25 to day 54 after ulcer induction. The gastric juice volume, pH, gastric mucus, gastric mucosal blood flow (GMBF) and prostaglandin E₂ (PGE₂) were measured. The mRNA transcription of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) were analyzed with RT-PCR and protein expression with Western blot. Results: The gastric juice volume was significantly increased in aspirin group compared with those of fasting or saline control groups (P<0.01); while the pH, mucus, GMBF and PGE₂ were significantly decreased in aspirin treated rats compared with those of other two groups (P<0.01). COX-2, evaluated with mRNA and protein expression, was significantly augmented in aspirin group compared with others. The quality of ulcer healing (QOUH) in Aspirin group was poorer than that of fasting or saline control groups. Conclusions: Aspirin enhance the recurrence of gastric ulcer. The inhibition of cycloxygenase, mucus secretion and mucosal blood flow may be involved. Aspirin also impair the quality of ulcer healing.

Genetic Evidence for a Protective Role of Heat Shock Factor 1 against Irritant-Induced Gastric Lesions

Gastric lesions result from an imbalance between aggressive and defensive factors. Indirect lines of evidence suggest that heat shock proteins (HSPs) induced by various aggressive factors provide a major protective mechanism. In this study, we compared gastric ulcerogenic response in wild-type mice and in those lacking heat shock factor 1 (HSF1), a transcription factor for hsp genes. The severity of gastric lesions induced by ethanol or hydrochloric acid was worsened in HSF1-null mice. Immunoblotting, real-time reverse transcription-polymerase chain reaction, immunohistochemical analysis, and terminal deoxynucleotidyl transferase dUTP nick-end labeling assay revealed that the ethanol administration up-regulated gastric mucosal HSPs, in particular HSP70, in an HSF1-dependent manner, and more apoptotic cells were observed in the gastric mucosa of HSF1-null mice than in wild-type mice. In contrast, other parameters governing the gastric ulcerogenic response, including gastric acid secretion, gastric mucosal blood flow, and prostaglandin E(2) levels, were not significantly affected by the absence of the hsf1 gene. Geranylgeranylacetone (GGA), a clinically used antiulcer drug with HSP-inducing activity, suppressed ethanol-induced gastric lesions in wild-type mice but not in heat shock factor 1 (HSF1)-null mice. The results suggest that the aggravation of irritant-induced gastric lesions in HSF1-null mice is due to their inability to up-regulate HSPs, leading to apoptosis. It is also suggested that the HSP-inducing activity of GGA contributes to the drug's antiulcer activity. This study provides direct genetic evidence that HSPs, after their HSF1-dependent up-regulation, confer gastric protection against the irritant-induced lesions.

Effects of early enteral arginine supplementation on resuscitation of severe burn patients

Objectives To investigate the effects of dietary supplementation of l-arginine ( l-Arg) on shock in severely burned patients. Methods This was a prospective, randomized, single blind, controlled study. Forty-seven severely burned patients due to various causes with a total burn surface area (TBSA) more than 50% each admitted in early postburn phase (within 10 h postburn) were included in this study. All patients were treated by the traditional resuscitation program of our institute. After the nasogastric feeding tube was placed, they were randomly divided into three groups—(1) group A400 ( n = 16): giving gastrointestinal feeding with 500 ml 5% GNS, containing l-Arg (400 mg/kg day) at equal pace with fluid resuscitation; (2) group A200 ( n = 16): giving gastrointestinal feeding with 500 ml 5% GNS containing l-Arg (200 mg/kg day); (3) group C ( n = 15): giving gastrointestinal feeding with 500 ml 5% GNS without any supplementation. The feeding started within 12 h after burn and lasted for 72 h, the feeding rate was controlled by an enteral feeding pump. The following parameters were observed on days (PBD) 1–4: serum nitric oxide content (NO), mean arterial blood pressure (MAP), oxygenation index (PO 2/FiO 2), and arterial blood content of lactic acid (LA). Gastric mucosal blood flow was measured by laser Doppler flow-metry on PBD1 and PBD2. Results (1) Enteral feeding of l-Arg did not change MAP of severely burned patients, with no difference in MAP between the l-Arg supplemented and control groups. (2) There were significant changes of the l-Arg supplemented groups (A400 and A200), with an increased gastric mucosa blood flow, oxygenation index, and a decreased LA content in arterial blood, compared with the control group. (3) The serous NO content was significantly decreased in the A400 group on PBD2–4 ( P < 0.01), and in the A200 group on PBD4 ( P < 0.05) compared with the control group. Conclusions Enteral feeding with l-arginine supplementation on early stage of burn decreases NO production to a relatively normal level and exerts beneficial effects on the resuscitation of burned shock.

Dietary nitrate increases gastric mucosal blood flow and mucosal defense

Salivary nitrate from dietary or endogenous sources is reduced to nitrite by oral bacteria. In the acidic stomach, nitrite is further reduced to bioactive nitrogen oxides, including nitric oxide (NO). In this study, we investigated the gastroprotective role of nitrate intake and of luminally applied nitrite against provocation with diclofenac and taurocholate. Mucosal permeability ((51)Cr-EDTA clearance) and gastric mucosal blood flow (laser-Doppler flowmetry) were measured in anesthetized rats, either pretreated with nitrate in the drinking water or given acidified nitrite luminally. Diclofenac was given intravenously and taurocholate luminally to challenge the gastric mucosa. Luminal NO content and nitrite content in the gastric mucus were determined by chemiluminescence. The effect of luminal administration of acidified nitrite on the mucosal blood flow was also investigated in endothelial nitric oxide synthase-deficient mice. Rats pretreated with nitrate or given nitrite luminally had higher gastric mucosal blood flow than controls. Permeability increased more during the provocation in the controls than in the nitrate- and nitrite-treated animals. Dietary nitrate increased luminal NO levels 50 times compared with controls. Nitrate intake also resulted in nitrite accumulation in the loosely adherent mucous layer; after removal of this mucous layer, blood flow was reduced. Nitrite administrated luminally in endothelial nitric oxide synthase-deficient mice increased mucosal blood flow. We conclude that dietary nitrate and direct luminal application of acidified nitrite decrease diclofenac- and taurocholate-induced mucosal damage. The gastroprotective effect likely involves a higher mucosal blood flow caused by nonenzymatic NO production. These data suggest an important physiological role of nitrate in the diet.

Mucosal acid causes gastric mucosal microcirculatory disturbance in nonsteroidal anti-inflammatory drug-treated rats

The mechanism by which nonsteroidal anti-inflammatory drugs (NSAIDs) suppress gastric mucosal blood flow is not fully understood, although the depletion of mucosal prostaglandin E 2 has been proposed as one possible explanation. We investigated the role of gastric acid on gastric mucosal blood flow in NSAID-treated rats. A rat stomach was mounted in an ex vivo chamber, and gastric mucosal blood flow was measured sequentially in a 5-mm 2 area of the gastric corpus using a scanning laser Doppler perfusion image system. Results showed that diclofenac (5 mg/kg s.c.) and indomethacin (10 mg/kg s.c.) did not affect gastric mucosal blood flow, although both strongly decreased mucosal prostaglandin E 2 when saline was instilled into the gastric chamber. On replacement of the saline in the chamber with 100 mM hydrochloric acid, these drugs caused a decrease in gastric mucosal blood flow levels within 30 min. The specific cyclooxygenase (COX)-2 inhibitors celecoxib (50 mg/kg s.c.) and rofecoxib (25 mg/kg s.c.) did not affect mucosal prostaglandin E 2 level, nor did they decrease gastric mucosal blood flow, even when hydrochloric acid was added to the chamber. Furthermore, measurement of vasoconstrictive factors present in the mucosa showed that endothelin-1 levels increased after administration of diclofenac s.c. in the presence of intragastric hydrochloric acid. This indicates that the presence of mucosal hydrochloric acid plays an important role in the NSAID-induced decrease in gastric mucosal blood flow, while the COX-1-derived basal prostaglandin E 2, which is unlikely to control gastric mucosal blood flow itself, protects microcirculatory systems from mucosal hydrochloric acid.

Contribution of Sensory Neurons to Sex Difference in the Development of Stress-Induced Gastric Mucosal Injury in Mice

Sensory neurons play a critical role in reducing stress-induced gastric mucosal injury by releasing calcitonin gene-related peptide (CGRP) through an increase in gastric mucosal levels of prostacyclin (PGI(2)). Because estrogen enhances nerve growth factor-mediated CGRP production in sensory neurons, we hypothesized that stress-induced gastric mucosal injury occurs less in females than in males. Gastric ulcer index, gastric myeloperoxidase activity, and gastric tissue levels of CGRP and 6-keto-PGF(1alpha), a stable metabolite of PGI(2), were determined in male and female wild-type (CGRP(+/+)) mice and CGRP knockout (CGRP(-/-)) mice subjected to water-immersion restraint stress. In CGRP(+/+) mice, ulcer index and myeloperoxidase activities were lower and gastric tissue levels of CGRP and 6-keto-PGF(1alpha) were higher in female mice than in male mice, but there were no such sex differences in CGRP(-/-)mice. Sex differences in CGRP(+/+) mice were eliminated by pretreatment with SB366791 (500 microg/kg intraperitoneally), a vanilloid receptor antagonist, and by ovariectomy. Reversal of sex differences by ovariectomy was not observed in female CGRP(+/+) mice with estradiol replacement (1 mg . kg(-1). wk(-1) for 3 weeks). Levels of CGRP messenger RNA in dorsal root ganglion neurons isolated from female CGRP(+/+) mice were decreased by ovariectomy, and these decreases were reversed by estradiol replacement. Estrogen-mediated increases in CGRP levels in sensory neurons might contribute to reduce stress-induced gastric mucosal injury by attenuating inflammatory responses. This might at least partly explain the sex difference observed in the development of stress-induced gastric mucosal injury in mice.

Capsaicin and Gastric Ulcers

In recent years, infection of the stomach with the organism Helicobacter Pylori has been found to be the main cause of gastric ulcers, one of the common ailments afflicting humans. Excessive acid secretion in the stomach, reduction in gastric mucosal blood flow, constant intake of non-steroid anti-inflammatory drugs (NSAIDS), ethanol, smoking, stress etc. are also considered responsible for ulcer formation. The prevalent notion among sections of population in this country and perhaps in others is that “red pepper” popularly known as “Chilli,” a common spice consumed in excessive amounts leads to “gastric ulcers” in view of its irritant and likely acid secreting nature. Persons with ulcers are advised either to limit or avoid its use. However, investigations carried out in recent years have revealed that chilli or its active principle “capsaicin” is not the cause for ulcer formation but a “benefactor.” Capsaicin does not stimulate but inhibits acid secretion, stimulates alkali, mucus secretions and particularly gastric mucosal blood flow which help in prevention and healing of ulcers. Capsaicin acts by stimulating afferent neurons in the stomach and signals for protection against injury causing agents. Epidemiologic surveys in Singapore have shown that gastric ulcers are three times more common in the “Chinese” than among Malaysians and Indians who are in the habit of consuming more chillis. Ulcers are common among people who are in the habit of taking NSAIDS and are infected with the organism “Helicobacter Pylori,” responsible for excessive acid secretion and erosion of the mucosal layer. Eradication of the bacteria by antibiotic treatment and avoiding the NSAIDS eliminates ulcers and restores normal acid secretion.

A novel use of methylene blue as a pharmacological tool

Introduction A new use of methylene blue as an ulcerogenic agent and the mechanisms involved were identified with an objective to exploit methylene blue as a pharmacological tool to study investigational antiulcer agents. Methods Ulcerogenic potential was assessed using electron microscopy and measurement of an ulcer index after administering methylene blue (5–125 mg kg − 1 , p.o.) or absolute ethanol (99%v/v, 2 ml, p.o.) to fasted rats. Estimation of thiobarbituric acid reactive substances, superoxide dismutase, reduced glutathione and catalase was used to assess oxidative stress. H +/K + ATPase activity, gastric mucosal blood flow and gastric acid secretion were measured to study the mechanism of methylene induced gastric ulcer. Results Methylene blue (100 mg kg − 1 , p.o.) produced marked ulceration of the gastric mucosa due to increased levels of thiobarbituric acid reactive substances, activities of the H +/K + ATPase and superoxide dismutase, and decreased blood flow to the gastric mucosa, activity of catalase combined with reduced glutathione levels. Discussion It may be concluded that methylene blue activates the H +/K + ATPase to increase gastric acid secretion and reduces blood supply to gastric mucosa to produce oxidative stress that subsequently causes ulceration of gastric mucosa. Methylene blue can be used as an ulcerogenic agent to study mechanisms of investigational antiulcer agents.

Real-time visualization and quantitation of canine gastric mucosal blood flow by contrast-enhanced ultrasonography

Objective. Contrast-enhanced ultrasonography has become a method of choice for evaluating gastric blood flow, but intermittent scanning techniques can sometimes distort the results. Low-mechanical index imaging using Definity as the injected contrast material has been advocated for real-time evaluation of microperfusion in other organs. We investigated the reliability of low-mechanical index imaging using Definity in the evaluation of gastric mucosal blood flow. Material and methods. Under general anesthesia, 10 beagle dogs weighing 9–10 kg underwent real-time harmonic imaging under low acoustic power (mechanical index = 0.2) after intravenous contrast injection using Definity (60 mg/kg). Laser Doppler flow measurement was also performed to evaluate gastric mucosal blood flow. After administration of a diclofenac sodium suppository, low-mechanical index imaging and laser Doppler flowmetry were repeated. Results. Real-time visualization of gastric mucosal blood flow was successful in all dogs undergoing low-mechanical index imaging with Definity. Quantitative assessment of gastric mucosal blood flow was successful in eight dogs. After diclofenac sodium administration, gastric mucosal blood flow measured by both laser Doppler flowmetry and contrast ultrasonography decreased in seven of eight dogs; in the other dog, gastric mucosal blood flow increased slightly. A strong positive correlation was evident between blood flow measured by laser Doppler flowmetry and low-mechanical index imaging (r=0.777, p<0.005). Conclusions. Low-mechanical index imaging with Definity is a non-invasive way to evaluate gastric mucosal blood flow in real-time, high-resolutional images, which may have additional important gastrointestinal tract applications.

Dopexamine and norepinephrine versus epinephrine on gastric perfusion in patients with septic shock: a randomized study [NCT00134212

IntroductionMicrocirculatory blood flow, and notably gut perfusion, is important in the development of multiple organ failure in septic shock. We compared the effects of dopexamine and norepinephrine (noradrenaline) with those of epinephrine (adrenaline) on gastric mucosal blood flow (GMBF) in patients with septic shock. The effects of these drugs on oxidative stress were also assessed.MethodsThis was a prospective randomized study performed in a surgical intensive care unit among adults fulfilling usual criteria for septic shock. Systemic and pulmonary hemodynamics, GMBF (laser-Doppler) and malondialdehyde were assessed just before catecholamine infusion (T0), as soon as mean arterial pressure (MAP) reached 70 to 80 mmHg (T1), and 2 hours (T2) and 6 hours (T3) after T1. Drugs were titrated from 0.2 μg kg-1 min-1 with 0.2 μg kg-1 min-1 increments every 3 minutes for epinephrine and norepinephrine, and from 0.5 μg kg-1 min-1 with 0.5 μg kg-1 min-1 increments every 3 minutes for dopexamine.ResultsTwenty-two patients were included (10 receiving epinephrine, 12 receiving dopexamine–norepinephrine). There was no significant difference between groups on MAP at T0, T1, T2, and T3. Heart rate and cardiac output increased significantly more with epinephrine than with dopexamine–norepinephrine, whereas. GMBF increased significantly more with dopexamine–norepinephrine than with epinephrine between T1 and T3 (median values 106, 137, 133, and 165 versus 76, 91, 90, and 125 units of relative flux at T0, T1, T2 and T3, respectively). Malondialdehyde similarly increased in both groups between T1 and T3.ConclusionIn septic shock, at doses that induced the same effect on MAP, dopexamine–norepinephrine enhanced GMBF more than epinephrine did. No difference was observed on oxidative stress.