Lipopolysaccharide-induced gastroprotection is independent of the vagus nerve.

This study was done to examine the role of the vagus nerve in a model of gastric injury during endotoxemia. In conscious rats, lipopolysaccharide (LPS; 20 mg/kg i.p.) treatment for 5 hr prevented macroscopic gastric injury caused by acidified ethanol (150 mM HCl/50% ethanol). In addition, LPS enhanced gastric luminal fluid accumulation, decreased gastric mucosal blood flow (laser Doppler), and increased plasma gastrin levels (radioimmunoassay). Subdiaphragmatic truncal vagotomy, performed 7 days prior to LPS inhibited LPS-induced fluid accumulation, further reduced gastric mucosal blood flow following LPS, and augmented LPS-induced gastrin release compared to those in pyloroplasty controls. Atropine (1 mg/kg i.p.) prevented LPS-induced fluid accumulation but did not influence the effects of LPS on blood flow or gastrin release. Neither vagotomy nor atropine negated LPS-induced gastroprotection. This is the first report to examine the role of cholinergic nerves in the stomach during endotoxemia. The data indicate that LPS causes accumulation of gastric luminal fluid in part through its effects on cholinergic nerves. In contrast, the effects of vagotomy on blood flow and gastrin release following LPS involve a noncholinergic pathway. However, LPS-induced gastroprotection is independent of the vagus nerve.

Patient evaluation and management with selective use of magnetic resonance cholangiography and endoscopic retrograde cholangiopancreatography before laparoscopic cholecystectomy.

OBJECTIVE: To assess the utility of triage guidelines for patients with cholelithiasis and suspected choledocholithiasis, incorporating selective use of magnetic resonance cholangiography (MRC) and endoscopic retrograde cholangiopancreatography (ERCP) before laparoscopic cholecystectomy (LC). SUMMARY BACKGROUND DATA: ERCP is the most frequently used modality for the diagnosis and resolution of choledocholithiasis before LC. MRC has recently emerged as an accurate, noninvasive modality for the detection of choledocholithiasis. However, useful strategies for implementing this diagnostic modality for patient evaluation before LC have not been investigated. METHODS: During a 16-month period, the authors prospectively evaluated all patients before LC using triage guidelines incorporating patient information obtained from clinical evaluation, serum chemistry analysis, and abdominal ultrasonography. Patients were then assigned to one of four groups based on the level of suspicion for choledocholithiasis (group I, extremely high; group 2, high; group 3, moderate; group 4, low). Group 1 patients underwent ERCP and clearance of common bile duct stones; group 2 patients underwent MRC; group 3 patients underwent LC with intraoperative cholangiography; and group 4 patients underwent LC without intraoperative cholangiography. RESULTS: Choledocholithiasis was detected in 43 of 440 patients (9.8%). The occurrence of choledocholithiasis among patients in the four groups were 92.6% (25/27), 32.4% (12/37), 3.8% (2/52), and 0.9% (3/324) for groups 1, 2, 3, and 4, respectively (P <.001). MRC was used for 8.4% (37/440) of patients. Patient triage resulted in the identification of common bile duct stones during preoperative ERCP in 92.3% (36/39) of the patients. Unsuspected common bile duct stones occurred in six patients (1.4%). CONCLUSIONS: The probability of choledocholithiasis can be accurately assessed based on information obtained during the initial noninvasive evaluation. Stratification of risks for choledocholithiasis facilitates patient management with the most appropriate diagnostic studies and interventions, thereby improving patient care and resource utilization.

Inducible nitric oxide synthase mediates gut ischemia/reperfusion-induced ileus only after severe insults.

Inducible nitric oxide synthase (NOS 2) is thought to play a role in gut motility disorders that occur under proinflammatory conditions. Clinically, ileus occurs after sepsis and shock-induced gut ischemia/reperfusion (I/R). The purpose of this study was to determine if NOS 2 mediates impaired intestinal transit in well-established models of both moderate and severe gut ischemia/reperfusion. At laparotomy, Sprague-Dawley rats had duodenal catheters placed. Small intestinal transit was determined by quantitating the percentage tracer (FITC-dextran) in 10 equal segments of intestine 30 min after catheter injection [expressed as the mean geometric center (MGC) of distribution]. Transit was assessed at 6 and 24 h after gut ischemia [45 or 75 min of superior mesenteric artery occlusion (SMAO) with sham laparotomy as control]. In a separate set of experiments, N(6)-(iminoethyl)-L-lysine (L-NIL), a selective NOS 2 antagonist, was administered 1 h prior to laparotomy and transit was determined after 6 h as described above. Ileal NOS 2 expression was assessed by Western immunoblot and quantitative "real-time" RT-PCR. We observed that both 45 and 75 min of SMAO decreased intestinal transit at 6 h of reperfusion compared to sham. Ileal NOS 2 mRNA and protein were increased after 75, but not 45, min of SMAO. In addition, L-NIL improved transit after 75, but not 45, min of SMAO. We conclude that (1) NOS 2 is upregulated in the gut only after more severe ischemic insults, and (2) ileus is mediated, at least in part, by NOS 2 under these conditions.

Post-injury multiple organ failure: the role of the gut.

Despite intensive investigation, the pathogenesis of post-injury multiple organ failure (MOF) remains elusive. Laboratory and clinical research strongly suggests that the gastrointestinal tract (i.e., the gut) plays a pivotal pathogenic role. Since its inception in 1988, the Trauma Research Center (TRC) at the University of Texas-Houston Medical School (UTHMS) has focused its efforts on elucidating the role of the gut in post-injury MOF. On the basis of our observations and those of others, we believe that 1) shock with resulting gut hypoperfusion is an important inciting event, 2) the reperfused gut is a source of proinflammatory mediators that can amplify the early systemic inflammatory response syndrome (SIRS) and thus contribute to early MOF, 3) early gut hypoperfusion causes an ileus in both the stomach and small bowel that sets the stage for progressive gut dysfunction so that the proximal gut becomes a reservoir for pathogens and toxins that contribute to late sepsis-associated MOF, and 4) late infections cause further worsening of this gut dysfunction. Thus, the gut can be both an instigator and a victim of MOF. The purpose of this article is to provide the rationale behind these beliefs and to provide a brief overview of the ongoing research projects in the TRC at UTHMS.

Nitric oxide synthase inhibition negates bombesin-induced gastroprotection.

BACKGROUND: Bombesin prevents gastric injury primarily by the release of endogenous gastrin. Gastroprotection by exogenous gastrin is negated by nitric oxide synthase inhibition, which implicates a role for nitric oxide as a protective mediator. Because both endothelial and inducible isoforms of this enzyme can play a role in mucosal defense, this study was done to examine the contrasting effects of 2 nitric oxide synthase inhibitors on bombesin-induced gastroprotection. METHODS: Rats were given subcutaneous saline or bombesin (10-100 microg/kg) 30 minutes before they received a 1-mL orogastric bolus of acidified ethanol (150 mmol/L of hydrochloric acid/50% ethanol) and rats were killed 5 minutes later for assessment of macroscopic injury (mm(2)). Gastric mucosal blood flow was measured by laser Doppler. Endothelial, neural, and inducible nitric oxide synthase were assessed by using Western immunoblot. RESULTS: Bombesin decreased gastric mucosal damage, and dose-dependently increased blood flow when compared with saline-treated rats. Endothelial but not neural or inducible nitric oxide synthase immunoreactivity was increased by bombesin. In additional studies, intraperitoneal administration of N(G)-nitro-l-arginine methyl ester (l-NAME, 5-10 mg/kg), a nonselective nitric oxide synthase inhibitor, negated bombesin-induced gastroprotection and hyperemia, whereas the selective inducible inhibitor aminoguanidine (45 mg/kg) did not. Subcutaneous (SC) l-arginine (300 mg/kg), but not d-arginine, abolished the effects of l-NAME. CONCLUSIONS: Taken together, these data suggest that nitric oxide produced by the endothelial isoform of nitric oxide synthase plays an important role in mediating the gastroprotective and hyperemic actions associated with bombesin.

Effects of intestinal ischemia/reperfusion injury on gastric acid secretion.

BACKGROUND: The mechanism responsible for gastric colonization in critically injured ICU patients remains to be fully elucidated. Moreover, the effects of gut ischemia/reperfusion (I/R) injury on gastric function are unclear. It was our hypothesis that gut I/R injury would cause gastric dysfunction. MATERIALS AND METHODS: Rats were anesthetized and, via laparotomy, the superior mesenteric artery (SMA) was clamped at its aortic origin for 45 min followed by clamp removal. Rats were allowed to awaken and then killed after 6 h of reperfusion. Control rats underwent laparotomy with SMA isolation. Stomachs were removed, gastric fluid was aspirated, and the volume, pH, and protein, bicarbonate, and glucose contents were determined. Serum and antral mucosa were prepared for gastrin radioimmunoassay and the glandular mucosa was assessed for morphologic injury. RESULTS: SMA I/R injury caused significant accumulation of gastric luminal fluid that was alkaline and rich in protein, glucose, and bicarbonate content when compared with sham controls. SMA I/R injury also caused gastric surface epithelial cell injury and significantly increased serum and antral gastrin levels. In additional rats, gut I/R injury inhibited basal acid secretion and blunted the acid secretory response to pentagastrin. CONCLUSIONS: This study demonstrated for the first time that small intestinal I/R injury causes significant gastric dysfunction. The findings suggest that this type of injury, a frequent occurrence in critically injured ICU patients, may predispose patients to gastric colonization due to stasis and loss of the natural bactericidal effects of gastric acid.

Does upregulation of inducible nitric oxide synthase (iNOS) render the stomach more susceptible to damage?

Nitric oxide from constitutive nitric oxide synthase (NOS) augments gastric mucosal blood flow and is important in mucosal defense. However, the function of the inducible isoform of NOS (iNOS) in the gastric mucosa remains to be fully elucidated. This study was done to examine the role of iNOS in gastric mucosal blood flow and gastric injury following endotoxemia. Conscious rats were given intraperitoneal saline or lipopolysaccharide (LPS, 5 or 20 mg/kg). Five hours later, rats were anesthetized, a laparotomy made, gastric fluid aspirated, and 3 ml of 20% ethanol introduced into the forestomach. Rats were sacrificed 10 min later for assessment of macroscopic injury (mm2) to the gastric mucosa. Other rats did not receive 20% ethanol, but instead, gastric mucosal blood flow was determined with laser Doppler, followed by sacrifice and removal of stomachs for determination of gastric mucosal iNOS immunoreactivity (Western immunoblot). Lipopolysaccharide dose dependently increased gastric injury, decreased gastric mucosal blood flow, and increased gastric mucosal iNOS immunoreactivity compared to rats receiving saline. In additional experiments and using a similar protocol, intraperitoneal administration of aminoguanidine (45 mg/kg), an iNOS inhibitor, reversed lipopolysaccharide-induced gastric injury and restored gastric mucosal blood flow to baseline, whereas the nonselective NOS inhibitor, NG-nitro-l-arginine methyl ester (5 mg/kg) did not. Taken together, these data suggest that upregulation of iNOS is in part responsible for the detrimental effects of LPS on the gastric mucosa, possibly from a reduction in gastric mucosal blood flow.

The efficacy of magnetic resonance cholangiography for the evaluation of patients with suspected choledocholithiasis before laparoscopic cholecystectomy.

BACKGROUND: Endoscopic retrograde cholangiography is the most commonly utilized tool for the identification of common bile duct stones (CBDS) before laparoscopic cholecystectomy, whereas the role of magnetic resonance cholangiography (MRC) for patient evaluation before laparoscopic cholecystectomy is currently undefined. METHODS: We prospectively evaluated the efficacy of MRC for the identification of CBDS among patients with high risk for choledocholithiasis. Patient selection was based on clinical, sonographic, and laboratory criteria. Standard cholangiograms were obtained when possible for verification of MRC results. RESULTS: Ninety-nine patients underwent evaluation with preoperative MRC. CBDS was visualized in 30% of patients. MRC sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 85%, 90%, 77%, 94%, and 89%, respectively. CONCLUSIONS: MRC is useful for the evaluation of patients with suspected choledocholithiasis. Advantages of MRC include its noninvasive nature, ease of application, and accuracy in identifying and estimating the size of CBDS. Application of MRC in this setting reduces the need for diagnostic endoscopic retrograde cholangiography. Future investigations should be directed at the development of cost-effective utilization strategies for MRC application.

Effects of cholecystokinin on gastric injury and gastric mucosal blood flow.

Cholecystokinin (CCK) is a vasodilator and prevents gastric injury from ethanol. Its effects against other irritants are unknown. This study was conducted to (1) assess whether CCK or oleate, a CCK secretagogue, could prevent gastric injury from other damaging agents and (2) examine the role of blood flow in CCK-induced gastroprotection. Conscious rats were pretreated for 10 minutes with intravenous saline solution or CCK (5 nmol/kg) or were given 1 ml of orogastric water or oleate (100 mmol/L) 30 minutes before a 1 ml orogastric bolus of acidified ethanol (150 mmol/L hydrochloric acid/50% ethanol), 0.75N hydrochloric acid, or 0.2N sodium hydroxide. Rats were killed 5 minutes after receiving an irritant and the total area (mm2) of macroscopic injury was quantified. The duration of CCK-induced gastroprotection against acidified ethanol was examined at 5, 10, 30, and 60 minutes after its administration. Other rats had gastric mucosal blood flow determined (fluorescent microspheres) at identical time points. CCK and oleate decreased gastric injury from all three luminal irritants. CCK-induced gastroprotection was present for 30 minutes but only enhanced gastric mucosal blood flow at 5 and 10 minutes. These data suggest that endogenous CCK may play a role in gastric mucosal defense and that blood flow alone does not fully explain CCK gastroprotection.

Gastroprotective actions of bombesin, L-DOPA, and mild irritants: roles of prostaglandins and sensory neurons.

BACKGROUND: Bombesin and dopamine prevent gastric injury by an unknown mechanism. Sensory neurons and endogenous prostaglandins play an important role in gastric mucosal defense. This study was designed to assess the role of these two local defense mechanisms in bombesin and dopamine-induced gastroprotection, as well as mild irritant-induced adaptive cytoprotection. METHODS: Conscious, fasted rats were given either capsaicin (125 mg/kg subcutaneously) to ablate sensory neurons or indomethacin (5 mg/kg intraperitoneally) to inhibit prostaglandin synthesis, 2 weeks and 30 minutes, respectively, before administration of bombesin (100 micrograms/kg subcutaneously), the dopamine precursor L-DOPA (25 mg/kg intraperitoneally), or the mild irritant 25% ethanol (1 mL orogastric). A 1-mL orogastric bolus of acidified ethanol (150 mmol/L HCl/50% ethanol) was given 30 minutes after pretreatment with these peptides and 15 minutes after administration of the mild irritant. Rats were killed 5 minutes later and the total area of macroscopic gastric injury quantified. RESULTS: Ablation of sensory neurons with capsaicin negated the protective actions of bombesin but failed to reverse gastroprotection by L-DOPA or 25% ethanol. Cyclooxygenase inhibition with indomethacin partially reversed bombesin and mild irritant-induced gastroprotection but did not diminish the protective actions of L-DOPA. CONCLUSIONS: Bombesin requires intact sensory neurons to exert its protective actions through a mechanism mediated, at least in part, by endogenous prostaglandins. Adaptive cytoprotection by the mild irritant 25% ethanol requires the presence of endogenous prostaglandins but not sensory neurons. L-DOPA-induced gastroprotection is independent of both local defense mechanisms.

Effects of endotoxin on gastric injury from luminal irritants in rats: potential roles of nitric oxide.

The expression and function of inducible nitric oxide synthase (iNOS) in the stomach is unclear. This study assessed the effects of endotoxin on rat gastric iNOS expression and its role in gastric injury from luminal irritants. In conscious rats, a 5-h treatment with intraperitoneal lipopolysaccharide (LPS; 1-20 mg/kg) dose dependently increased gastric mucosal iNOS immunoreactivity and increased gastric luminal nitrate and nitrite accumulation (Griess reaction). LPS also increased gastric luminal fluid accumulation and reduced macroscopic gastric injury from orogastric acidified ethanol. Aminoguanidine (45 mg/kg) did not prevent LPS-induced gastroprotection or gastric fluid accumulation. NG-nitro-L-arginine methyl ester increased gastric luminal fluid and caused macroscopic gastric injury when given with LPS. Using an anesthetized preparation followed by removal of luminal fluid, LPS reduced gastric mucosal blood flow and exacerbated gastric injury from either acidified ethanol or acidified taurocholate, an effect that was negated by aminoguanidine. These data indicate that in conscious rats, the gastroprotective effect of endotoxin is dependent on constitutive NOS but not iNOS activity. However, the inducible isoform participates in the ability of endotoxin to exacerbate gastric injury from luminal irritants in the anesthetized rat.

Bombesin prevents gastric injury in the rat: role of gastrin.

Bombesin or gastrin-releasing peptide prevents gastric injury by an unknown mechanism. Since exogenous gastrin is a gastroprotective agent, this study was undertaken to test the hypothesis that gastroprotection by bombesin involves release of endogenous gastrin. Subcutaneous bombesin (10-100 microg/kg) dose dependently reduced macroscopic injury to the acid-secreting portion of the stomach caused by 1 ml of orogastric acidified ethanol (150 mM hydrochloric acid-50% ethanol). Blockade of type A cholecystokinin receptors with intraperitoneal MK-329 (1 mg/kg) reversed intravenous cholecystokinin (5 nmol/kg)-induced gastroprotection, but not that of bombesin. In contrast, intraperitoneal type B cholecystokinin (gastrin) receptor blockade with L-365,260 (25 mg/kg) diminished the protective actions of both subcutaneous bombesin (100 microg/kg) and intravenous gastrin (25 pmol/kg). In additional studies, subcutaneous bombesin (10-100 microg/kg) dose dependently increased serum gastrin levels (radioimmunoassay). Both the gastroprotective actions of bombesin and bombesin-induced gastrin release were enhanced following immunoneutralization of endogenous somatostatin with intraperitoneal somatostatin antibody (2 mg). These data indicate that bombesin prevents gastric injury primarily by release of endogenous gastrin and both effects are modified by endogenous somatostatin.

Cyclooxygenase inhibition attenuates cholecystokinin-induced gastroprotection.

Cholecystokinin prevents gastric injury by an unknown mechanism. This study was conducted in conscious, fasted female rats in order to assess the role of endogenous prostaglandins as a potential protective mechanism for cholecystokinin-induced gastroprotection. Intravenous administration of cholecystokinin (0.05-5 nmol/kg) dose-dependently reduced macroscopic injury to the glandular portion of the stomach caused by 1 ml of orally administered acidified ethanol (150 mM hydrochloric acid-50% ethanol), an effect corroborated by histologic analysis. In time course studies, this protective action occurred as early as 10 min following cholecystokinin injection (5 nmol/kg intravenously), but was absent at 1 hr. Cyclooxygenase inhibition with either indomethacin (5 mg/kg intraperitoneally) or aspirin (100 mg/kg intraperitoneally) resulted in a partial reversal in cholecystokinin-induced gastroprotection, effects that were similar in magnitude. However, while indomethacin reduced gastric mucosal prostaglandin synthesis (enzyme-linked immunoassay) by 60%, aspirin almost totally abolished prostaglandin synthesis (95% reduction). Cholecystokinin (5 nmol/kg intravenously) did not significantly enhance gastric mucosal prostaglandin synthesis in the absence of cyclooxygenase inhibition. These data indicate that cholecystokinin requires the presence of endogenous prostaglandins in order to fully exert its gastroprotective actions. However, release of endogenous prostaglandins does not entirely explain the protective response, and additional factors likely participate in this action.

Role of cardiac markers in evaluation of suspected myocardial infarction. Selecting the most clinically useful indicators.

In the workup of a patient with chest pain, knowing which cardiac marker or markers to measure is not always easy. Many factors affect the choice of the most clinically effective test: elapsed time after onset of pain, possible presence of skeletal muscle injury, potential delays in receiving test results, to name a few. In this review article, Dr Mercer compares the current cardiac markers, rates them according to the 10 characteristics of the ideal marker, and offers guidelines for selecting the appropriate marker in various clinical settings.

Protective action of gastrin-17 against alcohol-induced gastric injury in the rat: role in mucosal defense.

Exogenous cholecystokinin (CCK) or exposure of the stomach to the mild irritant 25% ethanol can prevent gastric injury. Ingestion of ethanol also elicits the release of CCK as well as gastrin, which is structurally similar to CCK. This study was undertaken in conscious rats to examine the gastroprotective actions of gastrin and to assess the effect of CCK-gastrin receptor blockade on adaptive cytoprotection with ethanol as the mild irritant. Intravenous (1-25 pmol/kg) administration of gastrin-17 dose dependently increased gastric mucosal blood flow (laser Doppler) and reduced gastric injury caused by 1 ml of orally administered acidified ethanol (150 mM HCl-50% ethanol). Similar gastroprotection was achieved with the gastrin secretagogue 5% peptone (1 ml orogastrically). The gastroprotective capabilities of gastrin-17 were attenuated by the type B CCK (gastrin) receptor antagonist L-365,260 (12.5-25 mg/kg i.p.) and by capsaicin desensitization (125 mg/kg s.c.). CCK octapeptide (5 nmol/kg i.v.)-induced protection was reversed by the type A CCK receptor antagonist MK-329 (1 mg/kg i.p.). Neither receptor antagonist, alone or in combination, reversed the protective effects of the mild irritant 25% ethanol (1 ml orogastrically). Thus, whereas gastrin may play a role in gastric mucosal defense, neither CCK nor gastrin appears to participate in the phenomenon of adaptive cytoprotection.

Hypotension during septic shock does not correlate with plasma levels of nitric oxide metabolites in the conscious rat.

Hypotension following administration of lipopolysaccharide may be due to excessive production of the potent vasodilator nitric oxide brought about by induction of nitric oxide synthase. The purpose of this study was to determine in conscious, fasted rats what role nitric oxide played in lipopolysaccharide-induced hypotension. When examined by Western immunoblot analysis, inducible nitric oxide synthase immunoreactivity was detected in the aorta at 3 hours and increased over time following administration of intraperitoneal lipopolysaccharide (20 mg/kg). When compared with saline-treated control rats, significant hypotension was observed at 2, 4, and 6 hours following lipopolysaccharide treatment. Blood pressure at 2 hours did not differ significantly from that at 6 hours. Using the Griess reaction to quantify plasma levels of nitrates and nitrites as an index of systemic nitric oxide production, an augmentation in the formation of these nitric oxide metabolites was demonstrated at 4 and 6 hours but not at 2 hours. Subcutaneous administration of the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (5 mg/kg) prevented lipopolysaccharide-induced hypotension, an effect reversed by subcutaneous L-arginine but not D-arginine (350 mg/kg). However, nitric oxide synthase inhibition did not attenuate the ability of lipopolysaccharide to increase plasma nitrate/nitrite levels. These data indicate that lipopolysaccharide-induced production of nitric oxide metabolites does not correlate with lipopolysaccharide-induced hypotension.

Effects of dopamine and alpha-2 adrenoreceptor blockade on L-dopa and cholecystokinin-induced gastroprotection.

Dopamine and cholecystokinin have been colocalized in neurons and represent endogenous enteric neurotransmitters. Both peptides possess potent protective actions against gastric injury when given exogenously. This study was undertaken in conscious female rats to test the hypothesis that cholecystokinin may exert its protective actions via release of dopamine. Experiments were designed to ascertain whether L-dopa, a dopamine precursor, could prevent gastric injury with the same degree of efficacy as cholecystokinin and to determine what role alpha-2 adrenoreceptors and dopamine receptors play in mediating the protective actions of these peptides. Intraperitoneal administration of L-dopa (1 to 25 mg/kg) in a dose-dependent manner prevented the type of macroscopic injury to the acid-secreting portion of the stomach that is caused by 1 ml of orogastric acidified ethanol (150 mmol/L hydrochloric acid/50% ethanol), an effect corroborated by histologic examination. Administration of either the alpha-2 adreno-receptor antagonist yohimbine (0.1 to 1.0 mg/kg) or the dopamine receptor antagonist haloperidol (1 to 5 mg/kg) caused a partial reversal of L-dopa-induced protection but not the protective actions of subcutaneous cholecystokinin (100 microg/kg). Simultaneous administration of both receptor antagonists had an additive effect and completely reversed the protective actions of L-dopa. The dopamine precursor L-dopa was just as effective in maintaining the integrity of the gastric epithelium in the face of a damaging insult as the gut peptide cholecystokinin. However, the data indicate that L-dopa initiates its protective actions through activation of both alpha-2 adrenoreceptors and dopamine receptors, whereas the protective effects of cholecystokinin are elicited by means of a different mechanism.

Cholecystokinin-induced protection against gastric injury is independent of endogenous somatostatin.

Cholecystokinin (CCK) prevents macroscopic injury to the stomach from luminal irritants by an unknown mechanism. The present study was undertaken in conscious rats to ascertain what role gastric mucosal blood flow, sensory neurons, and endogenous somatostatin play in CCK-induced gastric protection. Subcutaneous administration of CCK (10-100 micrograms/kg) significantly reduced macroscopic injury to the acid-secreting portion of the stomach caused by 1 ml of orally administered acidified ethanol (150 mM HCl, 50% ethanol) and augmented gastric mucosal blood flow (fluorescent microspheres) in a dose-dependent fashion. However, although the protective response to CCK (100 micrograms/kg) was still present at 2 h, the blood flow response had returned to baseline by 45 min. Ablation of capsaicin-sensitive afferent neurons with capsaicin (125 mg/kg sc) did not negate CCK-induced protection. Pretreatment with exogenous somatostatin (1 pmol-1 nmol/kg sc) failed to prevent the damaging effects of acidified ethanol to gastric mucosa. Immunoneutralization of endogenous somatostatin with somatostatin monoclonal antibody (2 mg ip) did not reverse the protective actions of CCK. Thus the data suggest that although CCK may prepare the gastric mucosa to withstand a damaging insult by augmenting gastric mucosal blood flow, its protective mechanism is independent of intact sensory neurons and endogenous somatostatin.

Gastric injury induced by ethanol and ischemia-reperfusion in the rat. Differing roles for lipid peroxidation and oxygen radicals.

This study determined the role that oxygen-derived free radicals played in the production of gastric injury in rats challenged orally with concentrated ethanol or subjected to vascular compromise. In the ethanol study, rats were pretreated with a variety of free radical scavengers or enzyme inhibitors prior to exposing the stomach to 100% ethanol. At sacrifice, the degree of macroscopic damage to the glandular gastric mucosa was quantified. In separate studies, the effects of ethanol on gastric mucosal levels of enaldehydes (malondialdehyde and 4-hydroxynonenal) were examined as an index of lipid peroxidation. Superoxide dismutase and catalase pretreatment were without benefit in reducing injury in our ethanol model, excluding potential contributory roles for the superoxide anion or hydrogen peroxide, respectively. Dimethyl sulfoxide and desferoxamine were likewise without protective capabilities, eliminating a role for the hydroxyl radical. Allopurinol, a xanthine oxidase inhibitor, provided no protection under acute conditions, even though partial protection was noted when administered chronically. Further, enaldehyde levels were not increased over control levels in alcohol-exposed mucosa, indicating no enhanced lipid peroxide formation. In contrast, in animals in which ischemia to the stomach was induced followed by reperfusion, marked gastric injury was observed in combination with enhanced enaldehyde levels. Prevention of enaldehyde formation by a 21-aminosteroid concomitantly prevented injury induced by ischemia-reperfusion. These findings support the conclusion that ischemia-reperfusion injury to the stomach is an oxygen-derived free radical process whereas ethanol-induced injury clearly involved some other process. Although allopurinal was partially protective against ethanol damage when administered chronically, observations in other models of injury suggest that this action is independent of its inhibitory effect on xanthine oxidase.