Increase In Gastric Mucosal Blood Flow Research Articles

Daikenchuto, a Traditional Kampo Medicine, Facilitates Mucosal Hyperemic Responses through Activation of TRPA1- and TRPV1-Expressing Sensory Nerves in Rat Stomach

AbstractDaikenchuto is a traditional Kampo medicine used to treat cold sensations and dysmotility in the abdomen. This study investigated the roles of transient receptor potential ankyrin 1- and transient reporter potential vanilloid 1-expressing sensory nerves in daikenchuto-induced gastric mucosal blood flow by pharmacological and immunohistochemical analyses using male Sprague-Dawley rats. Gastric mucosal blood flow was measured in ex vivo stomachs using a laser Doppler flowmeter. Transient receptor potential ankyrin 1 activator allyl isothiocyanate or transient reporter potential vanilloid 1 activator capsaicin were applied for 10 min, and daikenchuto was applied for 10 or 30 min to the rat stomach. Transient reporter potential vanilloid 1 blocker N-(4-t-butylphenyl)-4-(3-chlopyridin-2-yl) tetrahydropyrazine-1(2H)-carboxamide and transient receptor potential ankyrin 1 blocker A-967079 were also administered intragastrically. Capsaicin and allyl isothiocyanate increased gastric mucosal blood flow immediately after the intragastric application, which was almost completely inhibited by N-(4-t-butylphenyl)-4-(3-chlopyridin-2-yl) tetrahydropyrazine-1(2H)-carboxamide and A-967079, respectively. Daikenchuto increased gastric mucosal blood flow in a concentration-dependent manner. A-967079 significantly inhibited the increase in gastric mucosal blood flow induced by daikenchuto. In contrast, N-(4-t-butylphenyl)-4-(3-chlopyridin-2-yl) tetrahydropyrazine-1(2H)-carboxamide inhibited the responses to daikenchuto only in the late phase but not in the initial phase. Interestingly, in the deafferentation of capsaicin-sensitive sensory fiber in rats, the increased gastric mucosal blood flow induced by daikenchuto was only decreased in the late phase. Although transient receptor potential ankyrin 1- and transient reporter potential vanilloid 1-immunoreactive fibers were observed around the submucosal blood vessels of normal subjects, they were completely absent in the deafferentation of capsaicin-sensitive sensory fibers. Thus, daikenchuto increases gastric mucosal blood flow via transient receptor potential ankyrin 1- and transient reporter potential vanilloid 1-co-expressing sensory nerves in rat stomachs.

Nitric oxide released from luminal s-nitroso-N-acetylcysteine increases gastric mucosal blood flow.

Nitric oxide (NO)-mediated vasodilation plays a key role in gastric mucosal defense, and NO-donor drugs may protect against diseases associated with gastric mucosal blood flow (GMBF) deficiencies. In this study, we used the ex vivo gastric chamber method and Laser Doppler Flowmetry to characterize the effects of luminal aqueous NO-donor drug S-nitroso-N-acetylcysteine (SNAC) solution administration compared to aqueous NaNO2 and NaNO3 solutions (pH 7.4) on GMBF in Sprague-Dawley rats. SNAC solutions (600 μM and 12 mM) led to a rapid threefold increase in GMBF, which was maintained during the incubation of the solutions with the gastric mucosa, while NaNO2 or NaNO3 solutions (12 mM) did not affect GMBF. SNAC solutions (600 μM and 12 mM) spontaneously released NO at 37 °C at a constant rate of 0.3 or 14 nmol·mL−1·min−1, respectively, while NaNO2 (12 mM) released NO at a rate of 0.06 nmol·mL−1·min−1 and NaNO3 (12 mM) did not release NO. These results suggest that the SNAC-induced GMBF increase is due to their higher rates of spontaneous NO release compared to equimolar NaNO2 solutions. Taken together, our data indicate that oral SNAC administration is a potential approach for gastric acid-peptic disorder prevention and treatment.

Effects of centrally injected glucagon-like peptide-2 on gastric mucosal blood flow in rats: Possible mechanisms

“Glucagon-like peptide-2” (GLP-2) is a peptide that is released from the enteroendocrine L cells in response to food in the gastrointestinal tract. Peripheral injection of GLP-2 has been shown to increase gastrointestinal blood flow, but effects of central GLP-2 on any vascular bed has not been studied yet. The aim of this study is to investigate the effects of various doses of intracerebroventricularly (i.c.v.)-injected GLP-2 on gastric mucosal blood flow (GMBF) and contribution of calcitonin gene related peptide (CGRP), nitric oxide synthase-nitric oxide (NOS-NO) and cyclooxygenase-prostaglandin (COX-PG) systems to the possible effect. The gastric chamber technique was used to determine GMBF. Urethane anesthesia was used throughout the recording procedure. Male Wistar rats were treated with GLP-2 (100, 150 ve 200ng/10μl; i.c.v.) or saline (10μl; i.c.v.) in order to find out the effective dose of i.c.v. GLP-2 on GMBF. Then, CGRP receptor antagonist CGRP-(8-37) (10μg/kg; s.c.), NOS inhibitor NG-nitro-l-arginine methyl ester (l-NAME; 30mg/kg; s.c.) or COX inhibitor indomethacin (5mg/kg; i.p.) was injected before the effective dose of i.c.v. GLP-2. GMBF was measured continuously for 35min following GLP-2 and recorded every fifth minute. Non-parametric Kruskal–Wallis test was used for statistical analysis. Differences were considered to be significant at p<0.05. GMBF increased rapidly following 100ng GLP-2 injection and did not fall to the basal levels during 35min. Other doses of i.c.v. GLP-2 did not produce any significant difference in GMBF. CGRP receptor antagonist, CGRP-(8-37) (10μg/kg; s.c.) and COX inhibitor indomethacin (5mg/kg; i.p.) significantly prevented the increase in GMBF due to GLP-2 (100ng; i.c.v.), while l-NAME (30mg/kg; s.c.) was ineffective. None of the drugs produced a significant change in GMBF when administered alone. Thus we suggest that, i.c.v. GLP-2 increases GMBF and CGRP and endogenous prostaglandins but not NO, contribute to this effect.

Gastroprotective mechanism of lafutidine, a novel anti-ulcer drug with histamine H2-receptor antagonistic activity.

Lafutidine (CAS 118288-08-7, FRG-8813) is a novel histamine H2-receptor antagonist with gastroprotective activity. The aim of this study was to investigate the property of the gastro-protective activity of lafutidine by examining the effect on ammonia-induced change in transmucosal potential difference (PD), basal gastric mucosal blood flow (GMBF) and noxious agent-induced cell damage. Intragastrical application of lafutidine accelerated the recovery of the PD reduction after exposure of the mucosa to 0.25% ammonia solution and the accelerating effect was abolished by chemical deafferentation, but not with indometacin, a cyclooxygenase inhibitor. The application of capsaicin, as a reference compound, significantly promoted the recovery of the ammonia-induced PD reduction and this effect was not altered with indometacin. Lafutidine given intragastrically caused a sustained increase in GMBF in a dose-dependent fashion, which was also completely inhibited in the deafferentated rats. In vitro studies revealed that, in contrast to 16,16-dimethyl prostaglandin E2, lafutidine did not protect isolated gastric superficial epithelial cells from ethanol- or ammonia-induced damage. In conclusion, the gastroprotection of lafutidine is induced by promoting the restitution of the damaged mucosa after a noxious agent, not by directly protecting the epithelial cells and this effect may be caused through the mechanism of capsaicin-sensitive afferent nerves.

Impairment by 5-Fluorouracil of the Healing of Gastric Lesions in Rats: Effect of Lafutidine, a Histamine H2 Receptor Antagonist, Mediated by Capsaicin-Sensitive Afferent Neurons

We investigated the influence of 5-fluorouracil (5-FU), an anti-tumor agent, on the healing of gastric lesions generated by 0.6 M HCl in rats and the effect of lafutidine, a histamine H(2) receptor antagonist, on the impaired healing. Animals fasted for 18 h were given 1 ml of 0.6 M HCl p.o., fed normally from 1 h later, and killed 1-96 h thereafter. 5-FU was given i.v. twice, 1 h and 24 h after the HCl. The gastric lesions healed spontaneously within 96 h. Although it decreased acid secretion, 5-FU markedly delayed the healing. Lafutidine, but not cimetidine, given p.o. immediately after each dosing of 5-FU significantly reversed the delay in healing by 5-FU, and this effect was attenuated by the chemical ablation of capsaicin-sensitive afferent neurons. Capsaicin also significantly reversed the delay in healing. The mucosal application of 50 mM HCl did not affect gastric mucosal blood flow (GMBF) in the normal stomach, but significantly increased it in the stomach damaged by 0.6 M HCl. The increases in GMBF were attenuated by 5-FU; however, the co-administration of lafutidine significantly restored the response. In addition, 5-FU inhibited both cell proliferation and migration in rat gastric epithelial cells (RGM1) in vitro. These results suggest that 5-FU delayed the healing of gastric lesions generated by 0.6 M HCl, probably through the inhibition of cell migration and proliferation, as well as the impairment of GMBF, and lafutidine reversed the delay in healing, mainly through the amelioration of the GMBF response mediated by capsaicin-sensitive afferent neurons.

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.

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.

Cyclooxygenase isozymes involved in adaptive functional responses in rat stomach after barrier disruption.

We investigated the preferential role of cyclooxygenase (COX) isozymes in various functional changes of the rat stomach after exposure to taurocholate (TC) as a mild irritant. Under urethane anesthesia, a rat stomach mounted in an ex vivo chamber was perfused with saline or acid (50 mM HCl), and transmucosal potential difference (PD), gastric mucosal blood flow (GMBF), and acid secretion were measured before and after exposure of the stomach to 20 mM TC for 30 min. Indomethacin, 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole (SC-560) (a selective COX-1 inhibitor), or rofecoxib (a selective COX-2 inhibitor) was given intraduodenally 30 min before the TC treatment. Mucosal application of TC caused a marked reduction in PD, followed by a decrease of acid secretion and an increase of GMBF. Previous administration of indomethacin did not affect the reduction in PD but significantly mitigated the two other responses induced by TC, resulting in a delay in the recovery in PD. These effects were mimicked by SC-560 but not rofecoxib, although neither of these drugs had any effect on the reduction in PD. Perfusion of TC-treated stomachs with 50 mM HCl caused only minimal damage, yet this treatment produced gross lesions in the presence of indomethacin or SC-560. Mucosal exposure to TC increased prostaglandin E2 production, but the response was inhibited by both indomethacin and SC-560 but not rofecoxib. These results suggested that COX-1 but not COX-2 is a key enzyme for regulating the functional alterations of the stomach and for maintaining the mucosal integrity after barrier disruption.

Involvement of EDHF in the hypotension and increased gastric mucosal blood flow caused by PAR-2 activation in rats.

1. Agonists for protease-activated receptor-2 (PAR-2) cause hypotension and an increase in gastric mucosal blood flow (GMBF) in vivo. We thus studied the mechanisms underlying the circulatory modulation by PAR-2 activation in vivo, especially with respect to involvement of endothelium-derived hyperpolarizing factor (EDHF). 2. Arterial blood pressure and GMBF were measured in anesthetized rats in vivo. Vascular relaxation was assessed in the precontracted rat gastric arterial rings in vitro. 3. The PAR-2-activating peptide SLIGRL-NH2 and/or trypsin, administered i.v., produced largely NO-independent hypotension and increase in GMBF accompanied by decreased gastric mucosal vascular resistance (GMVR) in rats. 4. Combined administration of apamin and charybdotoxin, but not each of them, specifically abolished the hypotension, increased GMBF and decreased GMVR caused by the PAR-2 agonists. 5. In the isolated rat gastric artery, SLIGRL-NH2 elicited endothelium-dependent relaxation even in the presence of an NO synthase inhibitor and indomethacin, which was abolished by apamin plus charybdotoxin. 6. Our data suggest involvement of apamin/charybdotoxin-sensitive K+ channels in the PAR-2-triggered hypotension and increased GMBF, predicting a role of EDHF-like factors.

Increased susceptibility of gastric mucosa to ulcerogenic stimulation in diabetic rats--role of capsaicin-sensitive sensory neurons.

1. We examined the gastric mucosal blood flow (GMBF) and ulcerogenic responses following barrier disruption induced by sodium taurocholate (TC) in diabetic rats and investigated the role of capsaicin-sensitive sensory neurons in these responses. 2. Animals were injected streptozotocin (STZ: 70 mg kg(-1), i.p.) and used after 5, 10 and 15 weeks of diabetes with blood glucose levels of > 350 mg dl(-1). The stomach was mounted on an ex-vivo chamber under urethane anaesthesia and exposed to 20 mM TC plus 50 mM HCl for 30 min in the presence of omeprazole. Gastric transmucosal potential difference (PD), GMBF, and luminal acid loss (H+ back-diffusion) were measured before and after exposure to 20 mM TC, and the mucosa was examined for lesions 90 min after TC treatment. 3. Mucosal application of TC caused PD reduction in all groups; the degree of PD reduction was similar between normal and diabetic rats, although basal PD values were lower in diabetic rats. In normal rats, TC treatment caused luminal acid loss, followed by an increase of GMBF, resulting in minimal damage in the mucosa. 4. The increased GMBF responses associated with H+ back-diffusion were mitigated in STZ-treated rats, depending on the duration of diabetes, and severe haemorrhagic lesions occurred in the stomach after 10 weeks of diabetes. 5. Intragastric application of capsaicin increased GMBF in normal rats, but such responses were mitigated in STZ diabetic rats. The amount of CGRP released in the isolated stomach in response to capsaicin was significantly lower in diabetic rats when compared to controls. 6. The deleterious influences on GMBF and mucosal ulcerogenic responses in STZ-diabetic rats were partially but significantly antagonized by daily insulin (4 units rat(-1)) treatment. 7. These results suggest that the gastric mucosa of diabetic rats is more vulnerable to acid injury following barrier disruption, and this change is insulin-sensitive and may be partly accounted for by the impairment of GMBF response associated with acid back-diffusion and mediated by capsaicin-sensitive sensory neurons.

Peripheral mediators involved in gastric hyperemia to vagal activation by central TRH analog in rats

Mechanisms mediating the increase in gastric mucosal blood flow (GMBF) induced by the stable thyrotropin-releasing hormone (TRH) analog RX-77368 injected intracisternally at a gastric acid secretory dose (30 ng) were investigated using hydrogen gas clearance in urethan-anesthetized rats. The histamine H1 receptor antagonist pyrilamine (intravenously), capsaicin (subcutaneously, 10 days), and NG-nitro-L-arginine methyl ester (L-NAME, intracisternally) failed to impair the 150% rise in GMBF induced by intracisternal injection of RX-77368. By contrast, atropine (subcutaneously) and NG-monomethyl-L-arginine (intravenously) completely inhibited the increase in GMBF evoked by intracisternal RX-77368. L-NAME (intravenously) blocked the intracisternal RX-77368-induced increase in GMBF in capsaicin-pretreated rats, and the L-NAME effect was reversed by intravenous L- but not D-arginine. These findings indicate that vagal efferent activation induced by TRH analog injected intracisternally at a gastric acid secretory dose increases GMBF through atropine-sensitive mechanisms stimulating L-arginine-nitric oxide pathways, whereas H1 receptors and capsaicin-sensitive afferent fibers do not play a role.

Calcitonin gene-related peptide affords gastric mucosal protection by activating potassium channel in Wistar rat

Background & Aims: Calcitonin gene-related peptide (CGRP) protects the gastric mucosa against injurious stimuli in various experimental models. The underlying mechanism could be the increase in gastric mucosal blood flow (GMBF). A number of endogenous vasodilators exert their effects through the activation of adenosine triphosphate (ATP)-sensitive potassium (K ATP) channels on vascular smooth muscle. The present experiments were performed to elucidate whether CGRP increases GMBF through the activation of K ATP channels and whether the channels are involved in the protection by CGRP of gastric mucosa. Methods: GMBF was determined by the hydrogen-clearance technique in male Wistar rats. Mucosal lesions were produced by intragastric superfusion with 0.15N HCl and 15% ethanol for 40 minutes. Effects of an agonist (Y-26763, intra-arterially) and an inhibitor (glibenclamide, intravenously) of K ATP channels were tested. Results: Y-26763 increased GMBF, which was abolished by glibenclamide, and a CGRP-induced increase in GMBF was attenuated by glibenclamide. Macroscopic and microscopic lesions were exacerbated by human CGRP-(8-37) (a CGRP-1 receptor antagonist; intra-arterially) and glibenclamide but were ameliorated by exogenous CGRP (intra-arterially). Conclusions: CGRP protects the gastric mucosa against ulcerogenic stimuli, at least in part, through the activation of K ATP channels in rats. GASTROENTEROLOGY 1998;114:71-76

Central vagal activation by TRH induces gastric hyperemia: role of CGRP in capsaicin-sensitive afferents in rats.

The role of calcitonin gene-related peptide (CGRP) in the vagal cholinergic-mediated increase in gastric mucosal blood flow (GMBF) induced by the stable thyrotropin-releasing hormone (TRH) analogue RX-77368 injected intracisternally (ic, 30 ng) was investigated in urethan-anesthetized rats using the hydrogen gas clearance technique. alpha-CGRP (14 micrograms.kg-1.h-1) or bethanechol (150 micrograms.kg-1.h-1) infused close intra-arterially to the stomach or RX-77368 injected intracisternally increased GMBF by 76, 102, and 131%, respectively, 30 min after administration. The CGRP antagonist, human CGRP-(8-37) [hCGRP-(8-37)], injected intravenously (15 micrograms/kg bolus and 3 micrograms.kg-1.h-1) inhibited by 100, 97, and 73% the gastric hyperemic response to alpha-CGRP, TRH analogue, and bethanechol, respectively, whereas the substance P antagonist CP-96,345 (3 mg/kg iv) had no effect. In capsaicin-pretreated rats, hCGRP-(8-37) no longer blocked the increase in GMBF induced by intracisternal RX-77368. These results suggest that the gastric hyperemic response to central vagal activation induced by intracisternal TRH analogue at 30 ng is mediated by local effector function of capsaicin-sensitive afferent fibers releasing CGRP.

Effect of Local Acid-Base Status on Gastric Mucosal Blood Flow and Surface Cell Injury by Bile Acid

Topical application of 5 m M sodium taurocholate (5 TC, pH 1.2) to canine gastric mucosa results in luminal hydrogen ion (H +) loss and surface epithelial cell (SEC) injury. However, gross mucosal injury does not occur because of a protective increase in gastric mucosal blood flow (GMBF). The mechanism of this blood flow response is unknown. To test the hypothesis that mucosal acid-base status influences mucosal blood flow and surface cell injury, three groups of dogs with vascularized chambered gastric mucosae were studied during two sequential 30-min periods. Mucosae were exposed during period 1 to topical acidified isotonic saline (ATS, pH 1.2), and during period II to topical 5 TC. During both periods, group A ( n = 5) received close intraarterial (ia) NaCl (0,15 M), group B ( n = 5) close ia HCO 3 (0.32 M), and group C ( n = 4) close ia HCl (0.2 N ). Parameters evaluated during both ATS and 5 TC periods included the luminal accumulation of DNA (DNAE, a sensitive marker of SEC exfoliation), luminal H + loss, and GMBF measured using radiolabeled microspheres. Gastric venous pH was also measured. It was found that, compared to the NaCl group, the HCO 3 group had no increase in GMBF after 5 TC exposure. Simultaneously, however, SEC loss was reduced by 48%, 604 ± 72 with NaCl versus 314 ± 59 μg/30 min DNA with HCO 3, P < 0.025. Infusion of ia HCl generated a large increase in GMBF without an increase in SEC injury compared to ia NaCl. Thus, mucosal acid-base status is an important modulator of mucosal blood flow which is itself critically important to gastric mucosal protection during bile acid induced injury.

Intracisternal thyrotropin‐releasing hormone‐induced vagally mediated gastric protection against ethanol lesions: Central and peripheral mechanisms

The vagus is involved in mediating gastric cytoprotection and adaptive cytoprotection. However, the central and peripheral mechanisms through which the vagus expresses its action are still poorly known. Medullary thyrotropin-releasing hormone (TRH) plays an important role in the vagal regulation of gastric function. The stable TRH analogue, RX 77368, micro-injected into the cisterna magna or the dorsal motor nucleus (DMN) of the vagus at a dose that did not influence gastric acid secretion prevented gastric injury induced by intragastric administration of 60% ethanol in conscious or urethane-anaesthetized rats. The cytoprotective action of TRH is mediated through vagal cholinergic release of prostaglandin E2 (PGE2). Prostaglandin E2 action is unrelated to changes in gastric mucosal blood flow (GMBF). In addition, other peripheral mechanisms involve calcitonin gene-related peptide (CGRP) contained in capsaicin sensitive afferent fibres and nitric oxide, both of which mediate the associated increase in GMBF induced by intracisternal injection of RX 77368. These data indicate that medullary TRH induces vagally mediated gastric protection against ethanol lesions. Its action is expressed through the muscarinic dependent release of PGE2 and nitric oxide, and efferent function of capsaicin-sensitive afferent fibres releasing CGRP.

Mechanism by which histamine increases gastric mucosal blood flow in the rat

The mechanism by which histamine increases gastric mucosal blood flow (GMBF) was investigated in the anesthetized rat. The experiment was performed in the presence of tripelennamine, an H1 antagonist, to focus on the relationship between acid secretion (H2-receptor-mediated response) and GMBF. The stomach was mounted on a Lucite chamber, perfused with saline, and GMBF was measured by laser Doppler flowmetry simultaneously with acid secretion. Under these conditions, histamine at the submaximal dose significantly increased GMBF as well as acid secretion, and this increase of GMBF was completely blocked when acid secretion was inhibited by cimetidine or omeprazole. The elevation of GMBF caused by histamine was also significantly attenuated when luminal H+ was removed by intraluminal perfusion with NaHCO3 or glycine. Glycine by itself did not affect the increase of acid secretion induced by histamine and the increase of GMBF caused by isoproterenol, yet significantly inhibited the GMBF response induced by pentagastrin. Intraluminal perfusion with HCl also produced an increase of GMBF in a concentration-related manner, even in the presence of omeprazole during histamine infusion. Pretreatment of the animals with indomethacin significantly blocked the GMBF responses induced by either histamine or luminal HCl. These results suggest that the increase of GMBF during acid secretion induced by histamine may be caused by luminal H+ and involve endogenous prostaglandins in its mechanism.

Role of nitric oxide in gastric hyperemia induced by central vagal stimulation.

The effects of N omega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthesis, on the vagal cholinergic increase in gastric mucosal blood flow (GMBF) and acid secretion induced by intracisternal injection of the thyrotropin-releasing hormone (TRH) analogue, RX 77368, were studied. GMBF and acid secretion were measured simultaneously by the hydrogen gas clearance technique and titration of gastric perfusate in urethan-anesthetized rats. RX 77368 (30 ng) injected intracisternally stimulated gastric acid secretion and GMBF for 90 and 180 min respectively. GMBF was increased from basal 63 +/- 4 to 166 +/- 14 ml.min-1.100 g-1 at 60 min postinjection. L-NAME (3 mg/kg) injected intravenously 15 min before RX 77368 completely prevented the increase in GMBF induced by the TRH analogue, whereas the acid response was not modified. The effect of L-NAME was reversed by L-arginine but not by the stereoisomer D-arginine. These results show that the increase in GMBF, but not the stimulation of acid secretion, induced by central vagal activation is mediated through a product of L-arginine-NO pathway.

Role of Nitric Oxide and Prostaglandins in Gastroprotection Induced by Capsaicin and Papaverine

Capsaicin and papaverine are potent vasorelaxants with strong gastroprotective activity against damage induced by absolute ethanol. This protection was originally attributed to the increase in gastric mucosal blood flow (GBF) and the present study was designed to determine the possible role of nitric oxide (NO) and prostaglandins (PG) in the protective and hyperemic effects of capsaicin and papaverine on rat gastric mucosa. We found that the pretreatment with capsaicin (0.1-0.5 mg/kg i.g.) or papaverine (0.1-2 mg/kg i.g.) reduced dose dependently the area of ethanol-induced lesions, the ED50 being 0.3 and 1 mg/kg, respectively. This protection was accompanied by a gradual increase in the GBF. Intravenous injection of N omega-nitro-L-arginine (L-NNA; 1.2-5 mg/kg), a selective blocker of NO synthase, which by itself caused only a small increase in ethanol lesions, reversed dose dependently the protective and hyperemic effects of capsaicin and papaverine against ethanol-induced damage and attenuated the increase in GBF induced by each of these agents alone. This deleterious effect of L-NNA on the gastric mucosa and the GBF was fully antagonized by L-arginine (200 mg/kg i.v.) but not by D-arginine. L-arginine partly restored the decrease in GBF induced by L-NNA. Pretreatment with indomethacin (5 mg/kg i.p.), which suppressed the generation of PG by 85%, slightly enhanced the mucosal lesions induced by ethanol but failed to affect the fall in GBF induced by this irritant. Gastroprotective and hyperemic effects of capsaicin and papaverine were partly reversed by indomethacin suggesting that endogenous PG are also implicated in these effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Antisecretory and cytoprotective doses of enprostil do not alter gastric mucosal blood flow

Prostaglandins of the E series are antisecretory and cytoprotective. Cytoprotection occurs in the deep but not superficial gastric mucosa. It has been hypothesized that the mechanism of cytoprotection involves increased gastric mucosal blood flow (GMBF). However, basal and stimulated gastric mucosal blood flow is greater in the deep than superficial corpus mucosa. The purpose of this study was to investigate the effect of a prostaglandin E 2 analog, enprostil, on GMBF in the deep mucosa, where cytoprotection is observed, in both antisecretory and cytoprotective doses. Gastric mucosal blood flow in the deep half of the mucosa was measured by the hydrogen gas clearance method before, during and after intragastric perfusion of enprostil, 0.1–100μg/kg, in urethane anesthetized rats. Enprostil did not alter GMBF in any of the doses tested. Therefore, the cytoprotective action of enprostil is mediated by factors other than a primary increase in GMBF.

Limitations of laser-Doppler velocimetry and reflectance spectrophotometry in estimating gastric mucosal blood flow.

This study investigated the accuracy of laser-Doppler flowmetry (LDV) and reflectance spectrophotometry (RS) measurements as an index of blood flow in the gastric mucosa of the rat, in experimental conditions such as pharmacologically induced vasoconstriction, hypoxia, hyperoxia, and acute normovolemic anemia. Hydrogen gas clearance was used as a reference method. After vasopressin infusion, LDV signal and indexes of hemoglobin (IHb) and oxygen (ISO2) content in the gastric mucosa estimated by RS significantly decreased in parallel with the reduction of gastric mucosal blood flow (GMBF). Neither hypoxia (5% O2 administration) nor hyperoxia (100% O2) affected GMBF or LDV signal. However, both IHb and ISO2 significantly decreased or increased after hypoxia or hyperoxia, respectively. Acute normovolemic anemia induced a significant increase in GMBF, while LDV signal and ISO2 remained unchanged. IHb significantly decreased in linear relationship with the decrements in the hematocrit. It is concluded that 1) in pharmacologically induced GMBF changes, LDV and RS correlate with GMBF; 2) when changes in hemoglobin saturation are induced, LDV but not RS reflects GMBF; and 3) in acute normovolemic anemia, neither LDV nor RS reflects changes in GMBF.