M. Dolores Barrachina

Nitric oxide mediates the inhibition by interleukin-1β of pentagastrin-stimulated rat gastric acid secretion

Bolus injection of interleukin‐1β (2 μg kg−1, i.v.) inhibited acid secretion induced by intravenous infusion of pentagastrin (8 μg kg−1 h−1) in the continuously perfused stomach of the anaesthetized rat. Administration of interleukin‐1β did not modify mean systemic arterial blood pressure. Pretreatment with NG‐nitro‐l‐arginine methyl ester (l‐NAME, 2 −10 mg kg−1, i.v.), but not dexamethasone (5 mg kg−1, s.c. twice over 16 h), restored the acid secretory responses to pentagastrin. The actions of l‐NAME were reversed by the prior administration of l‐arginine (100 mg kg−1, i.v.), but not by its enantiomer d‐arginine (100 mg kg−1, i.v.). l‐NAME (5 mg kg−1, i.v.) increased blood pressure but this was not the mechanism by which interleukin‐induced acid inhibition was prevented, since similar systemic pressor responses induced by phenylephrine (10 μg kg−1 min−1, i.v.), had no such effect. These findings suggest that interleukin‐induced inhibition of acid responses to pentagastrin involves synthesis of NO from l‐arginine.

Role of central glutamate receptors, nitric oxide and soluble guanylyl cyclase in the inhibition by endotoxin of rat gastric acid secretion

This study examines the role of a central pathway involving glutamate receptors, nitric oxide (NO) and cyclic GMP in the acute inhibitory effects of low doses of peripheral endotoxin on pentagastrin‐stimulated acid production. Vagotomy or intracisternal (i.c.) microinjections of the NO‐inhibitor, NG‐nitro‐L‐arginine methyl esther (L‐NAME; 200 μg rat−1) restored acid secretory responses in endotoxin (10 μg kg−1, i.v.)‐treated rats. The acid‐inhibitory effect of i.v. endotoxin (10 μg kg−1, i.v.) was prevented by prior i.c. administration of the NMDA receptor antagonists, dizocilpine maleate (MK‐801; 10 nmol rat−1) and D‐2‐amino‐5‐phosphono‐valeric acid (AP‐5; 20 nmol rat−1), or the AMPA/kainate antagonist 6,7‐dinitroquinoxaline‐2,3‐dione (DNQX; 10 nmol rat−1). However, the competitive metabotropic glutamate receptor antagonist (+)‐α‐methyl‐4‐carboxyphenylglycine (MCPG; 20–1000 nmol rat−1) did not antagonize the effects of endotoxin. I.c. administration of L‐glutamate (0.1 nmol rat−1) inhibited pentagastrin‐stimulated gastric acid secretion. Coadministration with L‐NAME (200 μg rat−1) prevented the inhibition of gastric acid secretion by the aminoacid. I.c. administration of 1H‐[1,2,4]Oxazodiolo[4,3‐a]quinoxalin‐1‐one (ODQ; 100 nmol rat−1), a soluble guanylyl cyclase (sGC) blocker, reversed the hyposecretory effect of endotoxin. I.c. administration of the cyclic GMP analogue 8‐Bromoguanosine‐3,5‐cyclic monophosphate (8‐Br‐cGMP; 100–300 nmol rat−1) reduced gastric acid production in a dose‐dependent manner. We conclude that central NMDA and AMPA/kainate receptors are involved in the acid inhibitory effect of peripherally administered endotoxin. This central pathway involves synthesis of NO, which acts on the enzyme sGC.

Involvement of neuronal processes and nitric oxide in the inhibition by endotoxin of pentagastrin-stimulated sastric acid secretion

Administration of E. coli endotoxin (1 mg kg−1, i.v.) abolished the acid response induced by the i.v. infusion of pentagastrin (8 μg kg−1, h-1) in the continuously perfused stomach of the anaesthetized rat. Local serosal application of tetrodotoxin (36 ng per rat) completely restored acid responses to pentagastrin in endotoxin-treated rats. However, pretreatment with atropine (0.5 mg kg−1, s.c.), capsaicin (20, 30, and 50 mg kg−1, s.c. 2 weeks before the study) or guanethidine (16 mg kg−1, s.c. 3 and 16h before) did not influence the inhibitory effects of endotoxin. Continuous i.v. infusion with NG-nitro arginine methyl ester (L-NAME, 10 mg kg−1, h−1) restored the secretory responses to pentagastrin in endotoxin treated rats. The effects of L-NAME were reversed by L-arginine (100 mg kg−1, h−1, i.v.), but not by its enantiomer D-arginine (100 mg kg−1, h−1, i.v.). The secretory responses elicited by pentagastrin (10−10–10−6 M) in the isolated lumen perfused stomach of the rat were not influenced by incubation (100 min) with endotoxin (10 μg ml −1). These observations with tetrodotoxin indicate that inhibition of acid secretion by endotoxin in vivo involves neuronal activity, while inhibition of NO synthesis had a comparable inhibitory action. Activation of a systemic non-adrenergic non-cholinergic neuronal pathway involving NO could thus mediate the acute acid inhibitory effects of endotoxin.

Low endotoxemia prevents the reduction of gastric blood flow induced by NSAIDs: role of nitric oxide

The role of nitric oxide (NO) in the effects of low endotoxemia on gastric damage and blood flow has been evaluated in indomethacin‐treated rats. Pretreatment (−1 h) with endotoxin (40 μg kg−1) reduced gastric damage induced by indomethacin (20 mg kg−1) in conscious rats. Endotoxin prevented the reduction in gastric blood flow (laser Doppler flowmetry) induced by indomethacin in pentobarbital‐anaesthetised rats. Pretreatment with an NO‐synthase (NOS) inhibitor (L‐NAME, 1 mg kg−1) reversed the protective effect of endotoxin on gastric blood perfusion. Endotoxin did not modify the expression of mRNA for endothelial NOS or inducible NOS in the gastric corpus when evaluated 1 h postinjection. However, a 3.8‐fold increase in inducible NOS mRNA and a 61% reduction in endothelial NOS mRNA were observed in the gastric corpus 4 h after endotoxin administration. Evaluation of both total and Ca2+‐dependent NOS activity by analysing the rate of conversion of L‐arginine to L‐citrulline in gastric corpus homogenates showed no differences between animals treated with endotoxin and those treated with saline 1 or 4 h beforehand. Ca2+‐independent NOS activity was almost non‐apparent in control as well as in endotoxin‐treated rats at all the time points analysed. Low endotoxemia preserves blood perfusion and protects the gastric mucosa against the deleterious effects of indomethacin through the endogenous NO release. NO synthesis in response to endotoxin does not involve the inducible NOS, but probably depends on the post‐translational/biochemical regulation in vivo of a Ca2+‐dependent NOS, most probably endothelial NOS.

Acute normovolaemic anaemia prevents ethanol-induced gastric damage in rats through a blood flow related mechanism

The aim of the study was to assess whether changes in gastric mucosal blood flow induced by acute normovolaemic anaemia influence the susceptibility of the gastric mucosa to ethanol-induced damage, and the relationship of these changes with nitric oxide biosynthesis. Acute normovolaemic anaemia, promoted by exchanging 3 ml of blood by a plasma expander, induced a significant increase in gastric mucosal blood flow measured by hydrogen gas clearance, without changes in arterial blood pressure. After intragastric 60% ethanol administration, gastric blood flow was still significantly higher in anaemic than in control rats, and this was associated with a lower macroscopic and microscopic gastric damage. Following ethanol administration, anaemic rats pretreated with an inhibitor of nitric oxide biosynthesis (l-NMMA, 50 mg/kg, i.v.) had a lower gastric blood flow and a higher macroscopic gastric damage than anaemic rats without pretreatment. Anaemic rats pretreated with vasopressin also had after ethanol administration a lower gastric blood flow and a higher macroscopic gastric damage. It is concluded that acute normovolaemic anaemia protects the gastric mucosa against damage induced by intragastric ethanol. The inhibition of nitric oxide biosynthesis reverts in part this protective effect, and this seems to be related with the capability of nitric oxide to increase gastric mucosal blood flow, since vasoconstriction by a nitric oxide-independent mechanism causes a similar effect.

Biopharmaceutics: Changes in Gastric Mucosal Permeability Induced by Haemorrhagic Shock in the Anaesthetized Rat: Modulation by Acid

Gastric mucosal damage induced by haemorrhagic shock in the anaesthetized rat has been evaluated by studying changes in capillary‐to‐lumen clearance of fluorescein isothiocyanate (FITC)‐labelled dextran.