Institutionen för medicin / Department of Medicine
Abstract
The regulation of gastric acid secretion is complex and involves
endocrine, paracrine, and neurocrine mechanisms. Among these, the
interconnecting cross-talk between different gut peptides is an important
part in the control of acid secretion. The aims of this thesis were (1)
to develop a new method of measuring intragastric pH for prolonged
periods of time, and (2) apply developed and in-use methods using
different substances and their impact on gastric acid secretion in vivo
experiments on rats. (3) To study the changes in acid output and the
migrating motor complex (MMC) when subjected to different substances, and
(4) to further study the alterations in expression of different gut
peptides in tissue samples in vitro, and the impact of inflammation in
the gut.
The novel Bravo model developed gave reliable recordings compared to the
chronic fistula model. The pH rose during treatment with esomeprazole and
the acid output in the fistula model decreased accordingly. Gut peptides
ghrelin and somatostatin increased in plasma when subjected to
esomeprazole treatment, while gastrin remained unchanged. Ghrelin
administered in bolus doses increased the intragastric pH in accordance
with previous experiments.
The gut peptides somatostatin, neurotensin, and vasoactive intestinal
peptide increased during pentagastrin-stimulated infusion and challenge
with hydrochloric acid and polyethylene glycol both in plasma and
intestinal perfusate, though the most pronounced elevation was seen in
perfusate and with somatostatin. Gastrazole gave the most extensive
inhibitory effect on acid secretion compared to ranitidine and
esomeprazole.
The CCK2-receptor antagonist YF476 inhibited acid secretion long-term and
increased concentrations of ghrelin and somatostatin in plasma, but
gastrin remained low. Tissue mRNA content of the peptides and their
receptors were unchanged except for the ghrelin receptor. When subdued to
NSAID gastrin, CCK2-receptor and iNOS increased in mRNA expression while
other peptides and receptors were unchanged.
Administration of NPS evoked a response in the MMC pattern with irregular
spiking and prolonged cycle length of the activity fronts, and the mRNA
expression of iNOS, TNF, and IL-1ß increased in the tissue.
In conclusion, The Bravo model can be used as a complement to the chronic
fistula model for measurements of pH. The regulation of gastric acid
secretion is not only limited to the stomach, but also present in the
smaller intestine where release of somatostatin seems to be most
important. Different mechanisms are involved in the blockage of acid
secretion when subjected to YF476, but under NSAID treatment the
expression of gastrin and its receptor CCK2 increase and COX- 2 is
activated which demonstrates a novel pathway for the study of gastric
ulcerations. NPS, a novel neuropeptide influences the gastric motility
and could have a role in inflammatory responses seen in the changes in
the migrating motor complex and inflammatory markers iNOS, TNF, and
IL-1ß