Cyclic AMP (adenosine 3',5'-monophosphate or cyclic adenylate) has now been established as a second messenger mediating many of the effects of a variety of hormones. Several of the metabolic effects mediated by cyclic AMP are discussed, and it is suggested that certain other ("functional" or "mechanical") hormonal effects may be similarly mediated. In particular, the evidence presented supports the hypothesis that the positive inotropic response to the catecholamines is mediated by cyclic AMP. Although knowledge of the biological role of cyclic AMP has not been widely applied clinically, sufficient knowledge has now accumulated to make research in this area desirable.

Some Aspects of the Biological Role of Adenosine 3',5'-monophosphate (Cyclic AMP)

Cyclic nucleotides and their role in gastrointestinal secretion.

Adenosine-3',5'-monophosphate: intracellular mediator for methyl xanthine stimulation of gastric secretion.

The relationship between cyclic AMP production and the response of isolated canine parietal cells to histamine has been examined. Histamine increased cyclic AMP generation, and this effect correlated with histamine stimulation of oxygen consumption and aminopyrine accumulation. Metiamide inhibited histamine-stimulated cyclic AMP generation and oxygen consumption in a parallel fashion. At concentrations below 100 microM, isobutyl AMP production and oxygen consumption in a similar fashion. However, with IMX above 100 microM, histamine caused no further increases in oxygen consumption, despite markedly enhanced cyclic AMP generation. Neither carbachol nor gastrin increased cyclic AMP production beyond that produced by IMX alone, and the combinations of histamine and carbachol and of histamine and gastrin produced no greater cyclic AMP generation than produced by histamine. These findings support a close relationship between cyclic AMP production and the action of histamine but not of carbachol or gastrin on isolated parietal cells. The mechanisms underlying the potentiating interactions between histamine, carbachol, and gastrin involve step(s) beyond stimulation of cyclic AMP generation.

Histamine and cyclic AMP in isolated canine parietal cells.

BIECK, P. R., J. A. OATES, G. A. ROBISON, AND R. B. ADKINS. Cyclic AMP in the regulation of gastric secretion in dogs and humans. Am. J. Physiol. 224(l) : 158-164. 1973.-Gastric juice of dogs and humans was examined for cyclic AMP by the protein-binding method of A. G. Gilman (A protein binding assay for adenosine 3’) 5’-cyclic monophosphate. Proc. Natl. Acad. Sci., U.S. 67 : 3053 12, 1970). The amounts secreted were compared to the values of hydrochloric acid secretion. The basal output of cyclic AMP in Heidenhain pouch dogs (3.1 =t 0.5 pmoles/min or 5.2 X 10m8 M) can be increased in a dose-dependent manner by infusions of histamine and pentagastrin. After both stimulators the peak cyclic AMP secretion preceded that in HCl secretion. In the innervated gastric fistula dog, the cyclic AMP content of the mucosa reached maximal levels before the HCl secretion reached its highest secretion rate. Theophylline not only potentiates the effect of histamine and food on gastric acid secretion, but also the output of cyclic AMP. Insulin and PGE2 both decreased cyclic AMP and HCl secretion into the gastric juice. In normal volunteers betazole(1 mg/kg SC) stimulated gastric secretion is also associated with an enhanced cyclic AMP secretion. Our data together with those of others obtained on cellular cyclic AMP in vitro support the secondmessenger concept for cyclic AMP in mammalian gastric secretion.

Cyclic AMP in the regulation of gastric secretion in dogs and humans.

Previous studies had shown that caffeine when given alone does not stimulate gastric acid secretion in the dog but does in the cat and man. The present study shows that theophylline given alone does not stimulate gastric secretion in the dog. It is demonstrated, however, that caffeine, theophylline, theobromine and xanthine increase or potentiate the effect of histamine on gastric secretion in dogs with pouches of the entire stomach. Caffeine also potentiates the gastric secretory stimulation produced by Urecholine (a parasympathomimetic drug) in dogs with pouches of the entire stomach and greatly increases the secretory response to a meal of horse meat in Heidenhain pouch dogs. The possible mechanisms of these effects are discussed.

D. Blickenstaff

Papers

The potentiating action of certain xanthine derivatives on gastric acid secretory responses in the dog

The effect of tetraethylammonium chloride on gastric secretion in the dog