Gastric Hyperemic Response Research Articles

Regulatory mechanism of the gastric hyperemic response following barrier disruption: roles of cyclooxygenase-1, the prostaglandin E2/EP1 receptor and sensory neurons.

We herein reviewed the mechanism underlying the gastric hyperemic response following barrier disruption, with a focus on cyclooxygenase (COX) isozymes, prostaglandin (PG) E2, and capsaicin-sensitive afferent neurons. Mucosal damage was induced by exposing the stomach to 20 mM taurocholate (TC) with 50 mM HCl. The TC treatment disrupted surface epithelial cells, and then increased acid back-diffusion and mucosal blood flow (GMBF) in the stomachs of rats or wild-type mice. This hyperemic response in the rat stomach was inhibited by indomethacin without affecting acid back-diffusion, which resulted in the aggravation of lesions. The effect of indomethacin was mimicked by loxoprofen and the selective COX-1 inhibitor, SC-560, but not by the selective COX-2 inhibitor, celecoxib. The GMBF responses induced by TC were similarly observed in the stomachs of wild-type mice and EP3 receptor knockout mice, but not in mice lacking the EP1 receptor or pretreated with an EP1 antagonist. The increase in the GMBF response associated with acid back-diffusion after the TC treatment was also inhibited by the chemical ablation of capsaicin-sensitive afferent neurons, but not capsazepine, a TRPV1 antagonist. Thus, endogenous PGE2 produced by COX-1 plays a role in the gastric hyperemic response following barrier disruption of the stomach by interacting with capsaicin-sensitive afferent neurons, mainly through EP1 receptors, and facilitating the GMBF response to acid back-diffusion. These findings have also contributed to a deeper understanding of mucosal defensive mechanisms following barrier disruption and the development of new strategies for the treatment of gastrointestinal diseases.

Neuronal Nitric Oxide Synthase-Derived Nitric Oxide Is Involved in Gastric Mucosal Hyperemic Response to Capsaicin in Rats

Background and Aims: Activation of transient receptor potential vanilloid type 1 (TRPV1) by capsaicin leads to gastric hyperemic response through capsaicin-sensitive sensory nerves and nitric oxide (NO). The aim of the present study is to examine which isoform of nitric oxide synthase (NOS)/NO is involved in the hyperemic response to capsaicin in the rat stomach. Methods: Gastric mucosal blood flow (GMBF) was measured by laser Doppler flowmetry in rats. The localizations of TRPV1 and neuronal NOS (nNOS) in the rat gastric mucosa were detected by immunohistochemical staining. Results: The nNOS inhibitor N⁵-[imino(propylamino)methyl]-<smlcap>L</smlcap>-ornithine substantially reduced GMBF during capsaicin application, whereas the endothelial NOS (eNOS) inhibitor N⁵-(1-iminomethyl)-<smlcap>L</smlcap>-ornithine did not affect the effect of capsaicin during the application. The nonselective NOS inhibitor N^G-nitro-<smlcap>L</smlcap>-arginine methyl ester apparently inhibited the capsaicin-induced GMBF, while the inducible NOS inhibitor 1400W did not affect GMBF response to capsaicin. The immunohistochemical studies revealed nerve fibers coexpressing TRPV1 and nNOS around blood vessels in the gastric submucosa. Conclusion: We demonstrated for the first time that nNOS/NO is involved in gastric hyperemic responses to capsaicin.

W1554 Interaction of Nitric Oxide/Neuronal Nitric Oxide Synthase and CGRP/TRPV1-Expressing Neurons in Gastric Hyperemic Response to Intragastric Capsaicin in Rats

W1554 Interaction of Nitric Oxide/Neuronal Nitric Oxide Synthase and CGRP/TRPV1-Expressing Neurons in Gastric Hyperemic Response to Intragastric Capsaicin in Rats

Ablation of primary afferent neurons by neonatal capsaicin treatment reduces the susceptibility of the portal hypertensive gastric mucosa to ethanol-induced injury in cirrhotic rats

Primary sensory afferent neurons modulate the hyperdynamic circulation in cirrhotic rats with portal hypertension. The stomach of cirrhotic rats is prone to damage induced by ethanol, a phenomenon associated with reduced gastric hyperemic response to acid-back diffusion. The aim of this study was to examine the impact of ablation of capsaicin-sensitive neurons and the tachykinin NK1 receptor antagonist A5330 on the susceptibility of the portal hypertensive gastric mucosa to ethanol-induced injury and its effects on gastric cyclooxygenase (COX) and nitric oxide synthase (NOS) mRNA expression. Capsaicin was administered to neonatal, male, Wistar rats and the animals were allowed to grow. Cirrhosis was then induced by bile duct ligation in adult rats while controls had sham operation. Ethanol-induced gastric damage was assessed using ex vivo gastric chamber experiments. Gastric blood flow was measured as well as COX/NOS mRNA expression. Topical application of ethanol produced significant gastric damage in cirrhotic rats compared to controls, which was reversed in capsaicin- and A5330-treated animals. Mean arterial and portal pressure was normalized in capsaicin-treated cirrhotic rats. Capsaicin and A5330 administration restored gastric blood flow responses to topical application of ethanol followed by acid in cirrhotic rats. Differential COX and NOS mRNA expression was noted in bile duct ligated rats relative to controls. Capsaicin treatment significantly modified gastric eNOS/iNOS/COX-2 mRNA expression in cirrhotic rats. Capsaicin-sensitive neurons modulate the susceptibility of the portal hypertensive gastric mucosa to injury induced by ethanol via tachykinin NK1 receptors and signalling of prostaglandin and NO production/release.

Gastric ulcerogenic responses following barrier disruption in knockout mice lacking prostaglandin EP1 receptors.

Endogenous prostaglandins (PGs) are considered to play a pivotal role in maintaining the mucosal integrity of the stomach after injury. In the present study, we evaluated the mucosal ulcerogenic and mucosal blood flow (GMBF) responses in the stomach after damage by taurocholate (TC) in knockout mice lacking EP1 or EP3 receptors. Under urethane anaesthesia, a mouse stomach was mounted in an ex vivo chamber, exposed to 20 mmol/L TC for 20 min and treated with 20 mmol/L HCl before and after TC. GMBF was measured with a laser Doppler flowmeter. Mucosal exposure to TC in wild-type mice caused a marked decrease in potential difference (PD), followed by an increase in H+ loss and GMBF. The decreased PD was gradually normalized after removal of TC from the chamber, with minimal damage in the mucosa 1 h after TC treatment. This hyperaemic response was inhibited by indomethacin, resulting in severe lesions in the mucosa without any change in PD or H+ loss. None of these responses induced by TC were altered in EP3-/- mice. However, in mice lacking EP1 receptors, TC treatment did not increase GMBF, despite causing PD reduction and acid loss, and resulted in severe damage in the mucosa. These responses were closely similar to those observed in animals pretreated with ONO-8711, a EP1 receptor antagonist. Mucosal PGE2 content was significantly increased after TC, similarly in all groups of mice. These results confirm a mediator role for PGE2 in gastric hyperaemic response following mucosal exposure to TC and suggest that endogenous PGs may contribute to maintaining mucosal integrity after barrier disruption, mainly through activation of the EP1 receptor subtype.

Mast cells are involved in the gastric hyperemic response to acid back diffusion via release of histamine.

Acid back diffusion into the rat stomach mucosa leads to gastric vasodilation. We hypothesized that histamine, if released from the rat mucosa under such conditions, is mast cell derived and involved in the vasodilator response. Gastric blood flow (GBF) and luminal histamine were measured in an ex vivo chamber. Venous histamine was measured from totally isolated stomachs. Mucosal mast cells (MMC), submucosal connective tissue mast cells (CTMC), and chromogranin A-immunoreactive cells (CgA IR) were assessed morphometrically. After mucosal exposure to 1.5 M NaCl, the mucosa was subjected to saline at pH 5.5 (control) or pH 1.0 (H(+) back diffusion) for 60 min. H(+) back diffusion evoked a marked gastric hyperemia, increase of luminal and venous histamine, and decreased numbers of MMC and CTMC. CgA IR cells were not influenced. Depletion of mast cells with dexamethasone abolished (and stabilization of mast cells with ketotifen attenuated) both hyperemia and histamine release in response to H(+) back diffusion. GBF responses to H(+) back diffusion were attenuated by H(1) and abolished by H(3) but not H(2) receptor blockers. Our data conform to the idea that mast cells are involved in the gastric hyperemic response to acid back diffusion via release of histamine.

Effect of capsazepine, the capsaicin antagonist, on gastric hyperemic response induced by acid back-diffusion in rats

Effect of capsazepine, the capsaicin antagonist, on gastric hyperemic response induced by acid back-diffusion in rats

Effect of capsazepine, the capsaicin antagonist, on gastric hyperemic response induced by acid back-diffusion in rats

Effect of capsazepine, the capsaicin antagonist, on gastric hyperemic response induced by acid back-diffusion in rats

Monochloramine impairs mucosal blood flow response and healing of gastric lesions in rats: relation to capsaicin-sensitive sensory neurons.

We examined the effects of monochloramine (NH2Cl) on the gastric mucosal blood flow (GMBF) response and the healing of ethanol-induced gastric lesions in rats. Rats fasted for 18 h were given the 99% ethanol p.o. for induction of gastric lesions, and were fed normally from 1 h later onwards. Monochloramine, at non-ulcerogenic doses (5 to approximately 20 mmol/L), was given p.o. twice daily for 7 days, starting 2 h after ethanol treatment. Gastric lesions caused by ethanol healed almost completely within 7 days with re-epithelialization. The repeated administration of NH2Cl significantly delayed the healing of ethanol-induced gastric lesions in a dose-dependent manner. The damaged mucosa showed a marked rise in H+ permeability, resulting in luminal acid loss, but this process was accompanied by an increase of mucosal blood flow. Monochloramine did not affect the increased mucosal H+ permeability observed in the stomach after damage by ethanol, but significantly inhibited the mucosal hyperemic response associated with luminal acid loss. Prior exposure of the mucosa to NH2Cl (20 mmol/L) did not affect the gastric hyperemic response caused by mucosal application of misoprostol (a prostaglandin E1 derivative) or NOR-3 (a nitric oxide donor), but totally attenuated the increase of GMBF in response to intragastric capsaicin. Impaired healing and GMBF responses were also observed in rats following chemical ablation of capsaicin-sensitive sensory neurons. These results suggest that NH2Cl impaired the healing of acute gastric mucosal lesions at low concentrations, and this action may be attributable, at least partly, to the impairment of gastric hyperemic response caused by the dysfunction of capsaicin-sensitive sensory neurons.

Mast cells are involved in the gastric hyperemic response to acid back-diffusion via release of histamine

280: G1061–G1069,2001.—Acid back diffusion into the rat stomach mucosa leadsto gastric vasodilation. We hypothesized that histamine, ifreleased from the rat mucosa under such conditions, is mastcell derived and involved in the vasodilator response. Gastricblood flow (GBF) and luminal histamine were measured in anex vivo chamber. Venous histamine was measured from to-tally isolated stomachs. Mucosal mast cells (MMC), submu-cosal connective tissue mast cells (CTMC), and chromograninA-immunoreactive cells (CgA IR) were assessed morpho-metrically. After mucosal exposure to 1.5 M NaCl, the mu-cosa was subjected to saline at pH 5.5 (control) or pH 1.0 (H

Effect of monochloramine on recovery of gastric mucosal integrity and blood flow response in rat stomachs — Relation to capsaicin-sensitive sensory neurons

Gastric mucosal blood flow (GMBF) response and the recovery of gastric mucosal integrity were investigated in anesthetized rat stomachs after damage by monochloramine (NH2C1), in comparison with 20 mM taurocholate Na (TC). A rat stomach was mounted in an ex-vivo chamber, and the mucosa was exposed to 50 mM HCl during a test period. Mucosal application of 20 mM TC for 10 min caused a marked reduction of transmucosal potential difference (PD), but the PD recovered rapidly without development of gross lesions 90 min later. In contrast, the exposure of the mucosa to NH 2Cl (5~20 mM) produced a concentration-dependent decrease in gastric PD, and the values remained lowered even 90 min after removal of the agent, resulting in severe hemorrhagic damage in the stomach. TC caused a considerable H + back-diffusion, followed by an increase in the GMBF. In the mucosa damaged by NH 2Cl, such GMBF responses were not observed, except for the temporal increase during the exposure, although similar degrees of H + back-diffusion were observed following NH 2Cl treatment. In addition, the prior exposure of the mucosa to NH 2Cl significantly attenuated gastric hyperemic response induced by capsaicin but not by misoprostol (a PGE 1 derivative) or NOR-3 (a NO donor). Chemical ablation of capsaicin-sensitive sensory neurons had no effect on the PD reduction caused by TC but totally attenuated the GMBF response, resulting in hemorrhagic damage in the stomach. These results suggest that NH 2Cl delayed the recovery of the mucosal integrity in the stomach after damage, and this effect may be attributable, at least partly, to the impairment of gastric hyperemic response associated with H + back-diffusion, probably due to dysfunction of capsaicin-sensitive sensory neurons.

Neural emergency system in the stomach

The maintenance of gastric mucosal integrity depends on the rapid alarm of protective mechanisms in the face of pending injury. Afferent neurons of extrinsic origin constitute an emergency system that is called into operation when the gastric mucosa is endangered by acid and other noxious chemicals. The function of these chemoceptive afferents can be manipulated selectively and explored with the excitotoxin capsaicin. Most of the homeostatic actions of capsaicin-sensitive afferents are brought about by peptides released from their peripheral endings in the gastric wall. When stimulated, chemoceptive afferents enhance gastric blood flow and activate hyperemia-dependent and hyperemia-independent mechanisms of protection and repair. In the rodent stomach, these local regulatory roles of sensory neurons are mediated by calcitonin gene-related peptide acting via calcitonin gene-related peptide 1 receptors and neurokinin A acting via neurokinin 2 receptors, with both peptides using nitric oxide as their common messenger. In addition, capsaicin-sensitive neurons form the afferent arc of autonomic reflexes that control secretory and motor functions of the stomach. The pathophysiological potential of the neural emergency system is best portrayed by the gastric hyperemic response to acid backdiffusion, which is signaled by afferent nerve fibers. This mechanism limits damage to the surface of the mucosa and creates favorable conditions for rapid restitution and healing of the wounded mucosa. GASTROENTEROLOGY 1998;114:823-839

Inhibition of acid-induced hyperaemia in the rat stomach by endogenous NK 2 receptor ligands

Since exogenously applied tachykinins (substance P and neurokinin A) prevent the neurogenic hyperaemia which is elicited by acid back-diffusion in the rat stomach, we investigated whether endogenous tachykinins would act in a similar manner. Acid back-diffusion, induced by perfusing the stomach with 15% ethanol in the presence of 0.05 M HCl, increased gastric mucosal blood flow (GMBF) by 60–100% as determined by hydrogen clearance in urethane-anaesthetized rats. This response remained unchanged after pretreatment with the tachykinin NK 1 receptor antagonist SR 140,333 (300 nmol/kg) but tended to be enhanced by the NK 2 receptor antagonist MEN 10,627 (200 nmol/kg). When given during ongoing acid back-diffusion, MEN 10,627 significantly enhanced the acid-evoked vasodilatation as compared with vehicle or SR 140,333. We conclude that endogenously released tachykinins, acting via NK 2 receptors, limit the gastric hyperaemic response to acid.

Cyclo-oxygenase isozymes in mucosal ulcergenic and functional responses following barrier disruption in rat stomachs.

1. We examined the effects of selective and nonselective cyclo-oxygenase (COX) inhibitors on various functional changes in the rat stomach induced by topical application of taurocholate (TC) and investigated the preferential role of COX isozymes in these responses. 2. Rat stomachs mounted in ex vivo chambers were perfused with 50 mM HCl and transmucosal potential difference (p.d.), mucosal blood flow (GMBF), luminal acid loss and luminal levels of prostaglandin E2 (PGE2) were measured before, during and after exposure to 20 mM TC. 3. Mucosal application of TC in control rats caused a reduction in p.d., followed by an increase of luminal acid loss and GMBF, and produced only minimal damage in the mucosa 2 h later. Pretreatment with indomethacin (10 mg kg[-1], s.c.), a nonselective COX-1 and COX-2 inhibitor, attenuated the gastric hyperaemic response caused by TC without affecting p.d. and acid loss, resulting in haemorrhagic lesions in the mucosa. In contrast, selective COX-2 inhibitors, such as NS-398 and nimesulide (10 mg kg[-1], s.c.), had no effect on any of the responses induced by TC and did not cause gross damage in the mucosa. 4. Luminal PGE2 levels were markedly increased during and after exposure to TC and this response was significantly inhibited by indomethacin but not by either NS-398 or nimesulide. The expression of COX-1-mRNA was consistently detected in the gastric mucosa before and after TC treatment, while a faint expression of COX-2-mRNA was detected only 2 h after TC treatment. 5. Both NS-398 and nimesulide significantly suppressed carrageenan-induced rat paw oedema, similar to indomethacin. 6. These results confirmed a mediator role for prostaglandins in the gastric hyperaemic response following TC-induced barrier disruption, and suggest that COX-1 but not COX-2 is a key enzyme in maintaining 'housekeeping' functions in the gastric mucosa under both normal and adverse conditions.

Mechanism of gastric hyperemic response during acid secretion in rats: relation to nitric oxide, prostaglandins, and sensory neurons.

The mechanism of gastric mucosal hyperemic response during pentagastrin-induced acid secretion was investigated in anesthetized rats in relation to prostaglandins (PGs), nitric oxide (NO), and sensory neurons. A rat stomach was mounted in an ex vivo chamber and perfused with saline or glycine (200 mM), and the mucosal blood flow (GMBF), determined by laser Doppler flowmetry, and acid secretion was measured simultaneously. Intravenous infusion with a submaximal dose of pentagastrin (60 micrograms/kg/h) caused a significant increase in GMBF as well as acid secretion. Such GMBF responses were totally attenuated when acid secretion was inhibited by omeprazole and cimetidine or when the luminal H+ was buffered by mucosal perfusion with glycine (200 mM). Tripelennamine, an H1 antagonist, did not have any affect on acid secretory and GMBF responses to pentagastrin. On the other hand, prior administration of NG-nitro-L-arginine methyl ester (L-NAME), the NO synthase inhibitor, significantly mitigated the increase of GMBF induced by pentagastrin without any influence on acid secretion, and this effect was antagonized by simultaneous administration of L-arginine. The gastric hyperemic response to pentagastrin was also significantly mitigated by indomethacin or sensory deafferentation after capsaicin pretreatment, with no effect on acid secretion, and was totally inhibited by combined treatments with indomethacin plus L-NAME in addition to sensory deafferentation. Pentagastrin infusion for 8 h did not by itself cause macroscopic damage in the stomach, but additional treatments with L-NAME and indomethacin plus sensory deafferentation provoked severe lesions in the gastric mucosa. These results suggest that the gastric hyperemic response to pentagastrin (submaximal dose) is totally dependent on H+ and that this process is mediated by endogenous NO and PGs as well as by capsaicin-sensitive sensory neurons and plays a pivotal role in maintaining mucosal integrity during acid secretion.

Tachykinin inhibition of acid-induced gastric hyperaemia in the rat.

1. Primary afferent neurones releasing the vasodilator, calcitonin gene-related peptide, mediate the gastric hyperaemic response to acid back-diffusion. The tachykinins neurokinin A (NKA) and substance P (SP) are located in the same neurones and are co-released with calcitonin gene-related peptide. In this study we investigated the effect and possible role of tachykinins in the acid-evoked gastric vasodilatation in urethane-anaesthetized rats. 2. Gastric acid back-diffusion, induced by perfusing the stomach with 15% ethanol in the presence of 0.05 M HCl, increased gastric mucosal blood flow by 60-90%, as determined by the hydrogen clearance technique. NKA and SP (0.14-3.78 nmol min-1 kg-1, infused intra-aortically) inhibited the gastric mucosal hyperaemic response to acid back-diffusion in a dose-dependent manner, an effect that was accompanied by aggravation of ethanol/acid-induced macroscopic haemorrhagic lesions. 3. The inhibitory effect of NKA (1.26 nmol min-1 kg-1) on the acid-induced gastric mucosal vasodilatation was prevented by the tachykinin NK2 receptor antagonists, MEN 10,627 (200 nmol kg-1) but left unaltered by the NK1 receptor antagonist, SR 140,333 (300 nmol kg-1) and the mast-cell stabilizer, ketotifen (4.6 mumol kg-1). 4. Under basal conditions, with 0.05 M HCl being perfused through the stomach, NKA (1.26 nmol min-1 kg-1) reduced gastric mucosal blood flow by about 25%, an effect that was abolished by SR 140,333 but not MEN 10,627 or ketotifen. 5. SR 140,333, MEN 10,627 or ketotifen had no significant effect on basal gastric mucosal blood flow nor did they modify the gastric mucosal hyperaemic reaction to acid back-diffusion. 6. The effect of NKA (1.26 nmol min-1 kg-1) in causing vasoconstriction and inhibiting the vasodilator response to acid back-diffusion was also seen when blood flow in the left gastric artery was measured with the ultrasonic transit time shift technique. 7. Arginine vasopressin (AVP, 0.1 nmol min-1 kg-1) induced gastric mucosal vasoconstriction under basal conditions but was unable to inhibit the dilator response to acid back-diffusion. 8. These data show that NKA has two fundamentally different effects on the gastric circulation. Firstly, NKA reduces gastric blood flow by activation of NK1 receptors. Secondly, NKA inhibits the gastric hyperaemic response to acid back-diffusion through an NK2 receptor-mediated mechanism. These two tachykinin effects appear to take place independently of each other since they are mediated by different receptors. This concept is further supported by the inability of AVP to mimic tachykinin inhibition of the gastric vasodilator response to acid back-diffusion.

Changes in gastric HCO-3 secretory response to NG-nitro-L-arginine methyl ester in rats following repeated administration.

The effect of repeated administration of the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) on gastric HCO-3 secretion was examined using ex vivo chambered stomachs of anaesthetized rats. Intravenous administration of L-NAME (5 mg/kg) increased gastric HCO-3 secretion with a concomitant rise in arterial blood pressure (BP). The HCO-3 stimulatory action of L-NAME diminished when rats were pretreated with L-NAME (20 mg/kg, p.o., twice daily) for 1 or 3 days and an inverse relationship was found between the degree of secretory stimulation and the period of pretreatment. The increased BP response to L-NAME was also significantly lessened following repeated pretreatment; basal BP showed a stepwise increase during repeated pretreatment and did not change at all in response to i.v. L-NAME after 3 days pretreatment. When delta HCO-3 output induced by i.v. L-NAME was plotted against delta BP (from basal values) during repeated pretreatment with L-NAME, a significant relationship was found between these two factors. The reduction in the HCO3 secretory response to L-NAME was restored when animals were pretreated with L-arginine (500 mg/kg, i.p., twice daily) together with L-NAME. However, prostaglandin E2 (300 micrograms/kg, i.v.) caused a gastric HCO-3 secretory response similar to L-NAME, regardless of whether rats had been pretreated with L-NAME or not. In contrast, the attenuation by L-NAME of the acid (0.2 nmol/L HCl)-induced gastric hyperaemic response was not influenced by repeated pretreatment with L-NAME. We conclude that repeated p.o. pretreatment with L-NAME reduces the HCO-3 stimulatory action of i.v. L-NAME and that this phenomenon may be explained by the lack of further elevation of BP in response to i.v. L-NAME following repeated pretreatment with this agent. Thus, the stimulation of HCO-3 secretion by i.v. L-NAME may be causally related with increased BP in response to this agent.

Prostaglandins modulate the responsiveness of the gastric microcirculation of sodium nitroprusside in cirrhotic rats

Cirrhotic rats have an increased susceptibility to ethanol-induced gastric injury, related to an inability to mount a defensive gastric hyperemic response to luminal irritants, and associated with an impaired reactivity of the gastric microcirculation to nitric oxide (NO)/cyclic guanosine monophosphate (cGMP)-dependent vasodilators. Whether this hyporesponsiveness is in some way related to depressed prostaglandin synthesis by the stomach of cirrhotic rats is not clear. The aims of this study were to evaluate the role of NO and prostaglandins in the regulation of the gastric microcirculation under resting conditions and in response to administration of sodium nitroprusside, as well as to investigate the mechanisms of the hyporesponsiveness of the gastric microcirculation to nitrovasodilators. Cirrhosis was induced in rats by bile duct ligation, and controls had sham-operation. NG-nitro-L-arginine-methyl-ester (L-NAME) and indomethacin administration produced a greater reduction in gastric blood flow in cirrhotic rats than controls. Indomethacin pretreatment almost completely abolished the responsiveness to sodium nitroprusside (NaNP) in cirrhotic rats, while not affecting controls. Long-term administration of misoprostol to cirrhotic rats restored to normal the responsiveness to NaNP, whereas long-term administration of aspirin to healthy rats resulted in a hyporesponsiveness of the gastric microcirculation to NaNP similar to that seen in cirrhotic rats. We conclude that there are interactions between NO and prostaglandins in regulating gastric blood flow in both healthy and cirrhotic rats. The hyporesponsiveness of the gastric microcirculation of cirrhotic rats to a nitrovasodilator may occur as a consequence of prolonged depression of gastric prostaglandin synthesis.

Impairment of the gastric hyperemic response to luminal acid in cirrhotic rats.

Liver cirrhosis impairs gastric mucosal resistance to luminal acid in humans and in animal models. Because we have previously shown that pentagastrin enhances defensive as well as aggressive factors implicated in mucosal injury, we examined the hypothesis that the pentagastrin-mediated enhancement of mucosal defense mechanisms may be impaired in cirrhotic rats. Increased acid backdiffusion and susceptibility to gross mucosal injury, associated with an elimination of the hyperemic response to gastric barrier disruption, was observed in cirrhotic rats. In in vivo microscopic studies in anesthetized rats, cirrhosis had no effect on pentagastrin-associated enhancement of mucus gel thickness or baseline gastric mucosal blood flow, although baseline mucus gel thickness was decreased. Cirrhosis did, however, abolish the luminal acid-related hyperemic response to pentagastrin, which was associated with impaired intracellular pH homeostasis during acid superfusion. Cirrhosis did not alter submucosal calcitonin gene-related peptide immunoreactive nerves. We conclude that acid backdiffusion and pentagastrin-associated hyperemic responses are important mucosal defensive factors that are specifically impaired by cirrhosis.

Prostaglandins modulate the responsiveness of the gastric microcirculation of sodium nitroprusside in cirrhotic rats

Cirrhotic rats have an increased susceptibility to ethanol-induced gastric injury, related to an inability to mount a defensive gastric hyperemic response to luminal irritants, and associated with an impaired reactivity of the gastric microcirculation to nitric oxide (NO)/cyclic guanosine monophosphate (cGMP)-dependent vasodilators. Whether this hyporesponsiveness is in some way related to depressed prostaglandin synthesis by the stomach of cirrhotic rats is not clear. The aims of this study were to evaluate the role of NO and prostaglandins in the regulation of the gastric microcirculation under resting conditions and in response to administration of sodium nitroprusside, as well as to investigate the mechanisms of the hyporesponsiveness of the gastric microcirculation to nitrovasodilators. Cirrhosis was induced in rats by bile duct ligation, and controls had sham-operation. NG-nitro-L-arginine-methyl-ester (L- NAME) and indomethacin administration produced a greater reduction in gastric blood flow in cirrhotic rats than controls. Indomethacin pretreatment almost completely abolished the responsiveness to sodium nitroprusside (NaNP) in cirrhotic rats, while not affecting controls. Long-term administration of misoprostol to cirrhotic rats restored to normal the responsiveness to NaNP, whereas long-term administration of aspirin to healthy rats resulted in a hyporesponsiveness of the gastric microcirculation to NaNP similar to that seen in cirrhotic rats. We conclude that there are interactions between NO and prostaglandins in regulating gastric blood flow in both healthy and cirrhotic rats. The hyporesponsiveness of the gastric microcirculation of cirrhotic rats to a nitrovasodilator may occur as a consequence of prolonged depression of gastric prostaglandin synthesis. (Hepatology 1996 Jan;23(1):123-9)