Increase in gastric intramucosal hydrogen ion concentration following endotoxin challenge in the rat and the actions of nitric oxide synthase inhibitors

1. Cardiovascular events and outcome in septic shock may be predicted by mo nitoring the fall in intramural pH (pHi), as an index of splanchnic perfusi on and mucosal ischaemia, In the present study, a small animal model for mo nitoring the changes of gastric pHi or intramucosal [H+] following challeng e with the endotoxin lipopolysaccharide (LPS) was developed in the rat. The role of nitric oxide (NO) in these events in this model was evaluated usin g the non-selective NO synthase (NOS) inhibitors N-G-nitro-L-arginine methy l ester (L-NAME) and N-G-monomethyl-L-arginine (L-NMMA). 2. The pHi and intramucosal [H+] were evaluated in omeprazole-pretreated ra ts (30 mg/kg, i.p.) using the Henderson equation after estimating the Pco(2 ) and the bicarbonate concentration in gastric wall. To measure gastric wal l Pco(2), the oesophagus was intubated and the pylorus ligated. The Pco(2) was measured by a blood gas analyser in 2 mL saline instilled for 30 min in the gastric lumen to equilibrate with the gastric wall. The pHi was measur ed under basal conditions and 3 and 5 h after LPS (3 mg/kg) administration. Separate groups received treatment with L-NMMA (25-50 mg/kg) or L-NAME con comitantly or 2.5 h after administration of LPS. 3. Intravenous administration of Escherichia coli LPS provoked a significan t fall in gastric pHi from 7.37 to 7.18 (median values; n=10-19) determined after 5 h. In groups treated concurrently with LPS and L-NAME (5 mg/kg; n = 19), there was a similar increase in intramucosal [H+] as that induced by LPS alone (n = 15) in those animals that survived. In contrast, L-NAME (5 mg/kg; n = 12), given 2.5 h after LPS challenge, at a time at which inducib le NOS is known to be significantly expressed, prevented the increase in in tramucosal [H+] at 3 and 5 h after LPS challenge. Similarly, L-NMMA (25-50 mg/kg; n=23), given 2.5 h after LPS challenge, dose-dependently inhibited t he increase in intramucosal [H+] at 3 and 5 h, 4. In conclusion, these findings indicate that this rat model could be usef ul in exploring the pathophysiology of acute endotoxin shock. Delayed admin istration of L-NAME and L-NMMA abolished the increase in gastric intramucos al [H+], supporting the involvement of excess NO in the tissue dysfunction associated with endotoxin shock. This suggests the potential value of this small animal model in evaluating the therapeutic activity of novel agents f or use in septic shock.