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Hildebrand et al reported data suggesting that gastrin releasing peptide (GRP) may be a physiological regulator of pre- and postprandial gastric acid secretion (Gut 2001;49:23–8). Interestingly, these effects were independent of gastrin and the authors appropriately questioned the physiological role of gastrin in regulating gastric secretion. Several aspects of the authors' conclusions deserve further clarification and discussion.
The authors concluded that alteration of somatostatin secretion is unlikely to explain the acid inhibitory action of BIM26226 because the GRP antagonist did not alter somatostatin mRNA levels. They also argued that the lack of change of gastrin mRNA supported the physiological data showing no alteration in gastrin secretion with BIM26226. In short term experiments such as these, it is incorrect to assume mRNA levels reflect peptide secretion rates. In longer term studies this may be true, but it is clear that neuropeptide translation, synthesis, and secretion are all regulated independently and changes may not occur in parallel.1,2 Indeed, previous studies with GRP infusion in humans have shown that although secretion of gastrin peptide was enhanced, gastrin mRNA levels were actually decreased.3 Thus it would be unwise to exclude the possibility of any peptide having a role in this dynamic system on the basis of unchanged mRNA levels.
The authors also state that muscarinic receptor activation inhibits somatostatin secretion from D cells. This is correct for fundic but incorrect for antral D cells. Muscarinic activation actually stimulates somatostatin release from antral D cells.4–6 This would be more compatible with the mechanisms suggested by the authors: GRP enhanced neuronal acetylcholine release and this reduced fundic somatostatin mediated inhibition of histamine and acid secretion; in the antrum, stimulation of somatostatin release would then impair the gastrin response and could contribute to the lack of gastrin response seen in the current experiments.
The authors felt that previous in vitro studies of G cells were difficult to assess but they appear to have overlooked detailed studies of cultured human G cells. Squires et al demonstrated two receptors of the GRP family in antral tissue, namely GRPR (BB1) and BRS-3 (BB3).7 BRS-3 is an orphan receptor that does not functionally respond to bombesin/GRP except at very high concentrations.8 Single cell microfluorometry clearly showed antral G cells responding to bombesin with an increase in intracellular calcium, thus suggesting that human antral G cells express physiologically functional GRP receptors.7 In the light of these data, the results of Hildebrand et al are very interesting and the current study should stimulate interest in the ever evolving understanding of gastric secretory function. Further studies with BIM26226 under different conditions, to more fully describe the pathophysiological role of GRP, are awaited with interest.
We appreciate Dr Beales's interest in our study describing the effects of gastrin releasing peptide (GRP) and its antagonist BIM26226 on gastric acid secretion in healthy male subjects. One can only speculate on the mechanisms of GRP stimulated acid secretion. The points raised by Dr Beales are interesting and valid. However, a word of caution is necessary for some of his conclusions: data from rats and dogs cannot be used to explain the mechanisms of GRP on acid secretion as the effects of endogenous GRP on acid output were independent of plasma gastrin in humans. These results are clearly in contrast with findings in animals and suggest species differences. Thus the molecular mechanism of GRP stimulated acid production has not directly been substantiated in humans. This is not likely to be investigated in the near future because the antagonist BIM26226 is no longer available for human use.
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