H. J. Ruoff

Human gastric mucosal adenylate cyclase: activation by histamine-H2-receptor stimulation and inhibition by cimetidine in vitro and in peptic ulcer patients.

SummaryBiopsy specimens of human fundic mucosa from 96 subjects were assayed for adenylate cyclase activity to characterize specificity of the histamine receptor with selective agonists and antagonists in vitro, and to study the effect of cimetidine therapy. Histamine and the selective histamine H2-receptor agonist dimaprit were almost equally potent throughout the concentration-response curve (10−7–10−3 mol/l); maximal stimulation was obtained with concentrations of 10−4–10−3 mol/l, and half maximal stimulation with about 10−5 mol/l. The selective H1-receptor agonist PEA 10−5 and 10−3 mol/l failed to stimulate adenylate cyclase. Mepyramine 10−6 mol/l, a selective H1-receptor antagonist, and cimetidine 10−6 mol/l, a selective H2-receptor antagonist, did not affect basal adenylate cyclase activity. Histamine-stimulated adenylate cyclase was inhibited in a concentration dependent manner by cimetidine 10−7 and 10−5 mol/l, but not by the same concentrations of mepyramine. Almost identical basal adenylate cyclase activities of about 150 pmol cAMP/mg protein/20 min were found in gastric mucosal biopsies from controls and from peptic ulcer patients, whether or not treated with cimetidine. Histamine 10−5 mol/l doubled adenylate cyclase activity in the controls and the untreated ulcer group, but was completely ineffective in specimens from the cimetidine-treated peptic ulcer patients. The data underline the concept that the effects of histamine on acid secretion and on adenylate cyclase activity are linked together and that the therapeutic effect of cimetidine in ulcer treatment is related to histamine H2-receptor blockade followed by inhibition of adenylate cyclase.

Rat gastric mucosal cAMP and cGMP after adrenergic stimulation and blockade

The effect of adrenergic stimulation and blockade on the concentration of cAMP and cGMP was studied in the rat gastric mucosa. Adrenaline (0.5-2.0 mg/kg) elevated the gastric mucosal cAMP and cGMP levels up to 100% in a dose-dependent manner. Blockade of the beta-adrenoceptors with 4 mg/kg propranolol suppressed the adrenaline effect on the cAMP level and increased the effect on the cGMP concentration up to 500%. The opposite effect was found under alpha-adrenoceptor blockade. Phenoxybenzamine, 4 mg/kg, prevented the adrenaline effect on the cGMP level and increased the effect on the cAMP concentration up to 300%. Predominant stimulation of the beta-adrenoceptors by isoproterenol or of the alpha-adrenoceptors by phenylephrine caused smaller changes in the cyclic nucleotide concentration than did adrenaline. Their effect was more pronounced when the non-stimulated receptor was blocked. The data indicate that the rat gastric mucosa contains alpha- and beta-adrenoceptors. The effect of adrenaline on the gastric mucosal cAMP level is mediated by beta-adrenoceptors and that on the cGMP level by alpha-adrenoceptors.

Influence of atropine, metiamide and vagotomy on cAMP of resting and stimulated gastric mucosa

In normal rats the effect of atropine and metiamide was studied on cAMP levels of resting and histamine-, pentagastrin-, carbachol- and insulin-stimulated gastric mucosa. In vagotomized rats gastric mucosal cAMP levels were investigated under basal conditions and after insulin. Atropine and metiamide did not alter cAMP levels of resting gastric mucosa. Truncal vagotomy caused an increase in gastric mucosal cAMP, which was not affected by insulin. All gastric secretagogues caused a significant rise in gastric mucosal cAMP levels, which was not antagonized by atropine. Metiamide effectively blocked the rise in cAMP concentration after histamine and pentagastrin, but not that evoked by cholinergic stimulation. The results are consistent with the view that the in vivo rise of gastric mucosal cAMP after carbachol or insulin is not due to a direct cholinergic action. From the spectrum of inhibitory actions of metiamide it looks as if the increase in rat gastric mucosal cAMP concentration after histamine and pentagastrin administration is mediated by H2-receptor stimulation.

Rat gastric mucosal cAMP following cholinergic and histamine stimulation

Abstract The gastric mucosal cAMP time course following i.p. injections of carbachol, insulin, 2-deoxy-D-glucose (2-DG) and histamine was investigated in rats. Cholinergic stimulation by either carbachol, insulin or 2-DG caused a double peak in rat gastric mucosal cAMP. A first peak was reached within 15 min, a second after 75 min post injection. The first cAMP rise preceded, the second outlasted, acid secretion of chronic fistula rats stimulated with insulin and 2-DG. After histamine cAMP was elevated within 15 min for about 30 min and then dropped to control values. The rise in gastric mucosal cAMP following cholinergic stimulation suggests: the first peak may be involved in initiating acid secretion, the second has to be related to other functions.

Adenylate cyclase in human gastric mucosa: its activation by histamine in morphologically different biopsy specimens.

ZusammenfassungIn morphologisch unterschiedlichen Biopsieproben aus der Fundus-, Antrum- und Duodenalschleimhaut von insgesamt 134 Personen wurde die basale und histaminstimulierte Adenylat-Cyclaseaktivität untersucht. Basale und stimulierte Adenylat-Cyclaseaktivität der Schleimhaut des oberen Gastrointestinaltrakts war log-normal verteilt. Nur die Adenylat-Cyclase der Fundusschleimhaut, nicht dagegen die der Antrum- und Duodenalschleimhaut war durch Histamin stimulierbar. In der Fundusschleimhaut betrug die basale Aktivität im Mittel 148, in Gegenwart von 10−5 mol/l Histamin 292 pmol cAMP/mg Protein/20 min. Die Stimulierbarkeit der Adenylat-Cyclase nahm in histologisch gesichert normaler Fundusschleimhaut mit dem Alter und im Biopsiematerial von Patienten mit histologisch diagnostizierter verschiedengradig chronischer Gastritis mit zunehmender Schleimhautatrophie ab. Die Stimulierbarkeit der Adenylat-Cyclase der Fundusschleimhaut durch Histamin war bei Patienten mit einem Magen- oder Duodenalulcus nicht signifikant von der des Normalkollektivs verschieden, obwohl in der Gruppe Duodenalulcus die höchsten Werte gefunden wurden. Demgegenüber war bei Patienten mit 2/3-Resektion nach Billroth I und II die Wirkung von Histamin auf die Enzymaktivität eindeutig vermindert. Da eine histamin-empfindliche Adenylat-Cyclase nur im sekretorischen Anteil des Magens nachweisbar ist und dieser Effekt einer morphologisch intakten Schleimhaut bedarf, lassen die hier vorliegenden Befunde darauf schließen, daß die Wirkungen von Histamin auf Adenylat-Cyclase und Säuresekretion zusammengehörige Vorgänge sind.SummaryIn morphologically different biopsy specimens from fundic, antral and duodenal mucosa of 134 persons, basal and histamine stimulated adenylate cyclase activity was studied: Basal and stimulated adenylate cyclase activities were log-normally distributed. Only in the fundic but not in the antral and duodenal mucosa adenylate cyclase was sensitive to histamine. The mean basal activity in the fundic gastric mucosa was 148, in response to 10−5 mol/l histamine 292 pmol cAMP/mg protein/20 min. In human fundic biopsy specimens histologically identified as normal gastric mucosa, the stimulatory effect of histamine on adenylate cyclase decreased with the individuals age. In bioptic material from patients suffering from histologically proven chronic gastritis the histamine effect decreased with the degree of atrophy. A similar loss of histamine sensitivity was found in gastric mucosal biopsies of antrectomized individuals operated at least 5 years before by the Billroth I or II method, whereas in the mucosa of patients with gastric or duodenal ulcer no loss occurred. In contrast, the most pronounced stimulatory action of histamine was found in this latter group. Since a histamine sensitive adenylate cyclase is localized only in the glandular area of the fundic mucosa and the histamine sensitivity depends on a morphological intact structure of the mucosa, it can be concluded, that the effects of histamine on adenylate cyclase and on hydrochloric acid secretion have to be considered as a mechanism linked together.

Adenylate cyclase of the dog gastric mucosa: Stimulation by histamine and inhibition by metiamide

SummaryThe activity of the non-stimulated, basal adenylate cyclase of the dog gastric mucosa is reduced by the histamine H2-receptor antagonist metiamide but not by the histamine H1-receptor antagonist mepyramine. Histamine activates the adenylate cyclase only slightly. In the presence of 10−5 M metiamide a concentration-dependent stimulation of the enzyme by histamine was found. These data indicate that endogenous histamine in dog gastric mucosal homogenate is contributing at least in part to what is measured as “basal” adenylate cyclase activity. This effect is mediated by H2-receptor excitation and in earlier studies has prevented the demonstration of a stimulatory effect of exogenous histamine on this enzyme.

Histamin, Histidindecarboxylase und Gastrin im oberen Verdauungstrakt des Huhns

Summary1.The histamine, histidine decarboxylase and gastrin content of the oesophagus, crop, glandular stomach, gizzard and duodenum was determined in chickens.2.Only minute amounts of histamine were found in the oesophagus (0.8 μg/g) and crop (0.5 μg/g). In the glandular stomach (7.7 μg/g), however, the gizzard (4.8 μg/g) and the duodenum (12.9 μg/g) the histamine content was considerably higher.3.Measurable amounts of the specific histidine decarboxylase activity were found only in the glandular stomach (25.3 nMole newly formed histamine/g · hr−1).4.In none of the organs investigated, could any gastrin activity be definitely detected.5.From the experiments it was concluded that gastric acid secretion in chickens may be controlled by systems other than gastrin. The role of histamine in this process is uncertain.

Die Wirkung von Histamin, Carbachol, Pentagastrin und Hühnergastrinextrakten auf die Magensekretion von nicht narkotisierten Hühnern mit einer Magenfistel

Summary1.The effect of histamine, carbachol, pentagastrin and gastrin extracts of different organs (glandular stomach, gizzard, duodenum) on gastric acid secretion was investigated in unanaesthetized chickens with a gastric fistula.2.On a molar basis, pentagastrin was three times as potent as carbachol and 12 times as potent as histamine. The dose of pentagastrin required for stimulation of gastric secretion in chickens was very much higher than in mammals.3.Extracts from the glandular stomach, the gizzard and the duodenum were free from acid secretion stimulating activity.4.It was concluded that gastric acid secretion in chickens is controlled by a mechanism other than gastrin.

Die Rolle des Kropfs bei der Steuerung der Magensaftsekretion von Hühnern

Summary1.The contribution of the crop to gastric acid secretion was investigated in unanaesthetized chickens with a gastric fistula.2.Basal secretion was enhanced by removal or distension of the crop and reduced by irrigating the crop with food suspension, acetylcholine, glycine or propyl alcohol as compared with phosphate buffer.3.It was concluded that the crop is able to release stimulating and inhibiting impulses towards the glandular stomach. The stimulating impulses were elicited by mechanical, the inhibiting ones by chemical excitation.

[Inhibition of gastric acid secretion in chickens by atropine, insulin and 2-deoxy-D-glucose].

Summary1.In unanaesthetized gastric fistula chickens the effect on gastric acid secretion was studied of atropine, insulin and 2-deoxy-D-glucose (2-DG).2.The basal secretion of H+ was diminished by insulin and 2-DG. The concentration of H+ was reduced by insulin, but not by 2-DG suggesting a less stronger effect of 2-DG on volume than on H+ secretion.3.The histamine stimulated secretion was inhibited competitively by atropine and noncompetitively by insulin and 2-DG. The inhibiting action of atropine on pentagastrin stimulated secretion was also of a competitive type; whether or not insulin and 2-DG inhibited pentagastrin noncompetitively could not be clearly decided.4.The inhibiting actions are discussed in the light of mechanism concerning the glucose metabolism in mammals. It is concluded that in chickens the control of gastric secretion differs considerably from that of mamals.