Gastric juice electrolyte secretion in conscious dogs with gastric fistulae and its modification by FPL 52694, a mast cell stabilizing agent.

Studies have been made of the electrolyte output in the gastric juice of conscious dogs equipped with gastric fistulae during stimulation by intravenous infusion of either pentagastrin (2 micrograms kg-1 h-1), histamine (30 micrograms kg-1 h-1) or insulin (0.1 u kg-1 h-1). The mast cell stabilizing agent, FPL 52694 (4.35 mg ml-1) was instilled into the stomach for 30 min and caused a marked reduction of H+ output, H+ concentration and osmotic strength of the juice during stimulation with pentagastrin, histamine, or insulin. There was also a marked increase in the rate of Na+ output into the juice. When pentagastrin-stimulated acid secretion was inhibited by cimetidine (4 mumol kg-1 i.v.) acid output was reduced but there were no sustained changes in ion concentrations, osmolarity or Na+ output of the type seen following inhibition with FPL 52694. It is concluded that FPL 52694 may have a dual mode of action in this preparation; a direct reduction of the output of hydrochloric acid and a smaller effect to increase gastric NaHCO3 output leading to a post-secretory neutralization of the juice.

Inhibition of gastric acid secretion in the conscious dog by the mast-cell stabilizing agent, FPL 52694.

The effects of the mast-cell stabilizing agent, FPL 52694, on gastric acid secretion in conscious dogs with gastric fistulae have been studied. FPL 52694 (5 or 10 mg kg-1 h-1) given intravenously during a plateau response to pentagastrin stimulation (2 micrograms kg-1 h-1) caused a maximum inhibition of acid output of about 50% but had no significant effect on volume output so that the [H+] in the juice was markedly reduced. The ratio of mucosal blood flow/acid output (Ra) was increased in the presence of FPL 52694. There was no maintained reduction of [H+] when inhibition was due to cimetidine (4 mumol kg-1, i.v.). Instillation of FPL 52694 (4.35 mg ml-1) directly into the stomach via the fistula for 30 min also resulted in an inhibition of acid output and reduction of [H+] during both pentagastrin-(2 micrograms kg-1 h-1) and histamine-stimulated (30 micrograms kg-1 h-1) secretion. Inhibition of pentagastrin-stimulated acid output by intragastric administration of FPL 52694 was much greater than the maximum effect seen following intravenous infusion. The results are discussed in relation to the possible mode of action of FPL 52694. It is concluded that FPL 52694 is active orally and has a novel action on acid secretion which may include stimulation of gastric bicarbonate secretion.

Enhancement of pentagastrin-induced gastric acid secretion by clonidine in the conscious dog.

The effect of intravenous clonidine on pentagastrin-induced gastric acid secretion has been studied in conscious dogs with Heidenhain pouches. Dose-dependent enhancement of secretion was found in response to clonidine (5-20 mu/kg). Clonidine (20 mug/kg) increased the maximal secretory rate to pentagastrin to a value not significantly different from the maximal response to histamine.

Comparison of the agonist activity of impromidine (SK & F 92676) in anaesthetized rabbits and on the rabbit isolated fundic mucosa.

1 The actions of impromidine in vivo and in vitro have been compared on gastric acid secretion. In both preparations impromidine was more potent than histamine. 2 There were no statistically significant differences between the maximum responses to impromidine and histamine in vivo or in vitro although in vitro the maximum response to impromidine was only 67% of that to histamine. In vivo the maximum response to impromidine was significantly less than the maximum response to histamine plus mepyramine. 3 The results are discussed in the light of recent findings.

The effects of isoprenaline and noradrenaline on pentagastrin-stimulated gastric acid secretion and mucosal blood flow in the dog.

1. Isoprenaline (0.02 to 2.0 mug kg(-1) min(-1)) inhibited gastric secretion in response to pentagastrin in both conscious and anaesthetized dogs and in response to feeding in conscious dogs.2. The inhibition was unaffected during cardiac beta-adrenoceptor blockade by propranolol.3. The inhibition was not due to decreased mucosal blood flow.4. This effect of isoprenaline is different from its effect on histamine-induced gastric secretion.5. Noradrenaline (0.05-2.0 mug kg(-1) min(-1)) also decreased gastric secretion but it was less effective than isoprenaline.6. The mechanism of action of noradrenaline is probably a decrease in mucosal blood flow.

Effects of aspirin-like drugs on canine gastric mucosal blood flow and acid secretion.

1. The effects of aspirin, paracetamol and benorylate were studied on gastric mucosal blood flow (MBF) and acid secretion in canine denervated gastric pouches. 2. Aspirin 20 mM in the unstimulated pouch had no effect; pentagastrin-stimulated acid output, but not MBF, was reduced. Aspirin buffered to pH 6 was ineffective. 3. Aspirin 3-50 mg/kg reaching the pentagastrin-stimulated pouch through the blood, increased acid secretion and MBF, but the MBF:secretion ratio was variably affected. 4. Paracetamol (10 or 20 mg/kg i.v., or 20 mM in the pouch) or benorylate (280 mg/kg orally) mainly had little effect. 5. Circular muscle strips from dog arteries were contracted by prostaglandins E2, F1alpha or F2alpha, and often slightly by indomethacine, but prostaglandin E1 produced variable effects. 6. These results do not favour the view that aspirin causes gastric bleeding in dogs by breakdown of blood vessels due to ischaemia following mucosal vasoconstriction.

The effect of betahistine on gastric acid secretion and mucosal blood flow in conscious dogs.

In 3 conscious dogs, betahistine (2-(2'-methyl aminoethyl pyridine)) (80 or 160mug kg(-1) min(-1)) increased acid secretion from Heidenhain pouches to 8.8% and 17.6% respectively of the maximal response to histamine. Betahistine also increased mucosal blood flow (radioactive aniline clearance). The ratio of mucosal blood flow to secretion was greater for betahistine than for histamine but the difference between betahistine and histamine was significant in only one of the dogs.

A possible role for cyclic adenosine 3',5'-monophosphate in the regulation of acid secretion in the isolated stomach of guinea-pig.

1 The rate of acid secretion and mucosal cyclic adenosine 3',5'-monophosphate (cyclic AMP) content have been measured on the same guinea-pig isolated stomach preparation in response to histamine, theophylline and ICI 63197, a potent phosphodiesterase inhibitor. 2 Unstimulated control tissues had a spontaneous rate of acid secretion of 74.41 +/- 9.06 mumol H+/g wet wt. of mucosa per hour (s.e. mean, n = 20) and a cyclic AMP content of 0.517 +/- 0.058 mnol/g wet weight. 3 Each of the three drugs caused an increase in both the mucosal cyclic AMP content and the rate of acid secretion. These increases were inearly related to the logarithm of drug concentration for each drug. 4 There were no statistically significant differences between the three regression coefficients obtained for acid on drug and for cyclic AMP on drug. 5 There was a significant correlation between the rate of acid secretion and mucosal cyclic AMP content in stimulated preparations (P less than 0.001) and also in control preparations which received no drug (P less than 0.05). 6 These results are discussed in relation to the possible role of cyclic AMP in the mediation of acid secretory responses in the mammalian stomach.

Can the actions of adrenoceptor agonists and antagonists on pentagastrin-induced gastric secretion be due to their effects of histamine formation?

1 The effects of some adrenoceptor agonists and antagonists which have been reported to affect histamine formation in leucocytes (Assem & Feigenbaum, 1972) have been investigated on gastric secretion in conscious dogs with Heidenhain pouches.2 Submaximal secretion in response to pentagastrin was enhanced by propranolol (0.1-1.0 mg/kg i.v.) and phenylephrine (1.0 mug kg(-1) min(-1) i.v. for 20 min), which increase histamine formation, and was decreased by phentolamine (2 mg/kg i.v.) and isoprenaline (0.05-0.2 mug kg(-1) min(-1) i.v. for 30 min), which decrease histamine formation. Practolol (2 mg/kg i.v.), which has no effect on histamine formation, had no effect on secretion.3 Acid secretion in response to histamine was either unaffected or affected in the opposite direction by these drugs.4 The effects of the drugs on pentagastrin-induced secretion were not secondary to changes in mucosal blood flow (radioactive aniline clearance).5 The results are consistent with the hypothesis that acid secretion in response to pentagastrin involves the formation of endogenous histamine.

Histamine H1- and H2-receptors in the gastric vasculature of the rabbit.

The histamine receptors in the rabbit blood perfused gastric vasculature were analysed pharmacologically. Histamine elicited a monophasic increase in perfusion pressure which was antagonized by mepyramine and enhanced by metiamide. The maximum observed response was enhanced by metiamide to that produced by a specific H1-receptor agonist. It is concluded that the gastric vasculature responds to histamine with an H1-receptor mediated vasoconstriction and an H2-receptor mediated dilatation. In this preparation the H1-effect predominates in response to injection of histamine.

Inhibition of gastric acid secretion in conscious dog with fistula following intragastric administration of FPL 52694.

The effects of a mast cell stabilizing agent, FPL 52694, on gastric acid secretion have been investigated in conscious dogs with gastric fistulae. This drug, given by intragastric instillation, inhibited acid output in response to submaximal infusions of pentagastrin and of histamine. A prolonged and significant fall in the acid concentration of the gastric juice was also observed. In the same animals, secretory inhibition by cimetidine was not accompanied by a sustained fall in acid concentration. The inhibition of histamine-induced secretion makes it unlikely that these effects of FPL 52694 are due to prevention of endogenous histamine release.