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.

The inhibitory effects of 5-hydroxytryptamine on gastric acid secretion by the rat isolated stomach.

1 The effect of 5-hydroxytryptamine (5-HT) on acid secretion by a rat isolated stomach preparation has been studied. 2 5-HT at 10(-5)M in the serosal bathing fluid produced significant inhibition of the acid secretory responses to histamine, pentagastrin and isoprenaline but was without effect on basal secretion or that due to bethanechol, dibutryl cyclic adenosine 3',5'-monophosphate (db cyclic AMP) or phosphodiesterase inhibition with ICI63197. Increasing the concentration of 5-HT to 5 x 10(-5) M did not change this pattern of response whilst 5-HT at 10(-6) M did not cause consistent inhibition. 3 The inhibitory action of 5-HT could be prevented by the antagonist methysergide (2.5 x 10(-5) M). This concentration of methysergide alone did not affect responses to secretagogues or basal acid output. 4 Neither propranolol (2.5 x 10(-5) M) nor tetrodotoxin (10(-6) M) antagonized the inhibitory action of 5-HT. 5 Both indomethacin (2.8 x 10(-5) M) and ibuprofen (2.4 x 10(-4) M) antagonized the action of 5-HT. Indomethacin alone had no effect upon secretagogue responses. 6 5-HT at 10(-5) M had no inhibitory action when applied to the mucosal side of the preparation. 7 The results indicate that 5-HT can act directly on the stomach of the rat to produce inhibition of acid output. This inhibition is selective and may involve the products of cyclo-oxygenase activity.

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.

The action of morphine and naloxone on acid secretion by the rat isolated stomach.

The action of morphine and naloxone on acid secretion by the rat isolated stomach has been studied. Morphine (10(-7) to 10(-4) M) had no effect upon spontaneous acid secretion. Morphine (10(-6) M) did not modify the acid output in response to sub-maximal stimulation by pentagastrin, histamine, bethanechol or isoprenaline. Naloxone (10(-6) M) was without effect on the response to pentagastrin or histamine. Our results suggest that opiate receptors do not modify acid secretion in this preparation.

Inhibition of acid secretion in the rat isolated stomach preparation by 5-hydroxytryptamine.

The effect of 5 hydroxytryptamine (5-HT) on gastric acid secretion by the rat isolated stomach has been studied. 5-HT (10 microM) significantly inhibited secretory responses to pentagastrin, histamine and isoprenaline but not those due to bethanechol, dibutyryl cyclic AMP or a phosphodiesterase inhibitor. The response was antagonized by methysergide (25 microM), indomethacin (28 microM) and ibuprofen (240 microM) but not by TTX (1 microM). It is concluded that 5-HT can exert a direct, inhibitory effect on acid secretion by the rat stomach and that this may involve the products of cyclo-oxygenase activity.

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.

The mechanical properties and heat production of chicken latissimus dorsi muscles during tetanic contractions.

1. A study has been made of the mechanical properties and heat production of chicken anterior (ALD) and posterior (PLD) latissimus dorsi muscles during contractions at 20 degrees C.2. There is a difference between these two muscles in the time course of the isometric response. The PLD reaches maximum tetanic tension 10 times faster and relaxes 8 times faster than ALD. The ratio of heat rate to isometric tension (heat rate/tension x length) for PLD is 7-8 times larger than for ALD.3. ALD maintains substantial isometric tension for more than 2 min of stimulation. In PLD tetanic tension begins to fall after only 1 sec.4. The ALD muscle does not show the ;activation' heat seen at the start of contraction with frog and toad muscle but this may be present in PLD.5. There is a range of stimulation frequencies for both muscles over which the fused tetanic tension increases with stimulation frequency.6. The tension-length curve of ALD has a pronounced plateau and is broader than that of PLD.7. The normalized force-velocity relations for the two muscles are similar and may be fitted by Hill's equation with a value of a/P(0) = 0.15-0.16. The maximum velocity of unloaded shortening of PLD is 4-5 times that of ALD.8. Preliminary experiments indicate that the resting heat rate of both muscles is 4 times greater than that of frog muscle at the same temperature. The recovery heat rate of ALD is similar to that of frog.

A comparison of the effects of sympathomimetic agents on gastric acid secretion by the rat stomach in vivo and in vitro.

1. The action of isoprenaline on gastric acid secretion in rats with Heidenhain pouches has been compared with its action in a rat isolated stomach preparation. 2. Isoprenaline (40 micrograms kg-1 h-1) inhibited the acid secretion in response to pentagastrin (20 micrograms kg-1 h-1) in conscious rate with Heidenhain pouches. 3. This inhibition could be abolished by propranolol (2 mg kg-1) and butoxamine (8 mg kg-1) and partially reversed by practolol (8 mg kg-1). 4. Propranolol (2 mg kg-1) significantly increased the response to pentagastrin (20 micrograms kt-1 h-1) but butoxamine and practolol (both at 8 mg kg-1) and the inactive isomer (+)-propranolol (2 mg kg-1) were without any effect on the pentagastrin response in the rats with pouches. 5. In the rat isolated stomach preparation isoprenaline stimulated acid secretion over the range 10(-7) M-10(-3) M whereas phenylephrine and methoxamine were without effect. 6. Propranolol (2 X 10(-5) M) inhibited this stimulatory effect of isoprenaline in vitro but (+)-propranolol (2 X 10(-5) M), practolol and butoxamine (both at 10(-4) M) had no effect on the response. 7. Propranolol (2 X 10(-5) M) did not have any effect on the response of the isolated stomach to pentagastrin (5 X 10(-7) M) or bethanechol (1.7 X 10(-5) M). 8. Phenylephrine (2 X 10(-5) M) did not affect the in vitro responses to pentagastrin (2.17 X 10(-7) M), bethanechol (1.7 X 10(-5) M) or histamine (5.4 X 10(-5) M). 9. It is concluded that isoprenaline has a direct stimulatory effect and an indirect inhibitory effect on gastric acid secretion in the rat. Both effects involve stimulation of beta-adrenoceptors. The relative predominance of one or other of these two opposing effects may help to explain the contradictory results in the literature regarding the actions of beta-adrenoceptor agonists on gastric acid secretion.

Pharmacological study of basal acid secretion by the rat isolated fundus preparation.

The rat isolated stomach preparation secretes acid in the absence of exogenous stimulants. This basal secretion of acid was unaffected by high concentration of antagonists to stimulated secretion in this preparation and by TTX. Basal secretion was inhibited by omeprazole (10(-7)-10(-5) M), KSCN (10(-4)-10(-2) M) and to a lesser extent by somatostatin (10(-6)-10(-5) M) but not by verapamil (3 X 10(-4) M), nifedipine (3 X 10(-4) M) and trifluoperazine (10(-3) M). Two long-acting H2-antagonists, oxmetidine and SKF 93479 (10(-5)-10(-4) M) inhibited basal secretion by a mechanism not involving an action at H2-receptors. It is concluded that basal secretion in this in vitro preparation is independent of the endogenous release of known stimulants of acid secretion and activity of the intrinsic nervous system.

Acid secretion and mucosal cyclic nucleotide content of the guinea pig isolated stomach during bethanechol stimulation.

Acid secretion and mucosal cyclic AMP and cyclic GMP content of guinea pig isolated stomach preparations were measured at various times after stimulation with bethanechol (1.7 X 10(-5) M). Significant increases in acid secretion were observed without changes in cyclic nucleotides. Pre-incubation of the tissues with theophylline (10(-3) M) increased acid secretion and nucleotide content. An additional increase in acid secretion was then obtained with bethanechol in these tissues but without further change in nucleotides. Carbachol (30 micrograms/kg) administered by interperitoneal injection to conscious guinea pigs also failed to change gastric mucosal cyclic nucleotides when the animals were sacrificed 15 min later. These results are discussed in relation to the mechanisms of cholinergic stimulation of gastric acid secretion.

Acid secretion and cyclic nucleotide content of the guinea pig isolated stomach in the presence of the ionophore A23187.

The involvement of calcium ions in stimulus-secretion coupling in the gastric mucosa is uncertain. Acid secretion and mucosal cyclic nucleotide content of an isolated stomach preparation from the guinea-pig have been measured in the presence of the ionophore A2318 (Lilly) over the concentration range 10(-6) M both in the presence and absence of a phosphodiesterase inhibitor (ICI 631978 1 X 10(-4) M). The rate of acid secretion and cyclic nucleotide content were increased by ICI 63197 as expected but were unaltered by the ionophore. These results suggest that a change in intracellular calcium ion concentration does not alter acid secretion in this preparation.

Rat gastric secretion "in vitro": interaction between histamine and various antisecretagogues acting by different mechanisms.

The interaction between histamine and various antisecretagogues acting by different mechanisms has been investigated in the isolated fundus from the rat stomach. Histamine evoked a concentration-dependent stimulatory effect which was competitively antagonized by the H2-receptor antagonist, ranitidine and non competitively by the H+/K+-ATPase inhibitor, omeprazole. The histamine induced secretion was highly resistant to the action of the calcium entry blocker verapamil, somatostatin and KSCN, but some inhibition was obtained with the calmodulin antagonist, trifluoperazine. Removal of calcium ions from the bathing media (both mucosal and serosal) greatly enhanced histamine-induced gastric secretion. The results suggest that the relationship between receptor stimulation and the intracellular events leading to acid secretion is far from being elucidated.

The action of beta-adrenoceptor agonists on acid secretion by the rat isolated stomach.

1. The action of beta-adrenoceptor agonists on acid secretion by an immature rat isolated stomach preparation has been studied. 2. Isoprenaline, salbutamol, salmefamol, adrenaline and noradrenaline all stimulated acid output over a concentration range of 2 X 10(-7) M--10(-5) M. 3. These responses were antagonized by propranolol (2 X 10(-5) M), pindolol and timolol (10(-6) M). 4. The antagonism of isoprenaline and salmefamol by propranolol was consistent with competitive inhibition. 5. Selective beta-adrenoceptor antagonists (practolol, atenolol, butoxamine and ICI 118 551) caused significant inhibition of noradrenaline-stimulated secretion but not of that due to the other agonists. 6. An adult rat isolated mucosa preparation responded to adrenaline in a similar manner to the immature stomach preparation. 7. Acid secretion stimulated by beta-adrenoceptor agonists was not antagonized by atropine (10(-5) M), metiamide (10(-4) M) or prostaglandin E2 (10(-5) M). The concentrations of these three antagonists caused marked inhibition of the responses to submaximal concentrations of bethanechol, histamine and pentagastrin respectively. 8. The results are discussed in relation to the possible mechanisms of action of beta-adrenoceptor stimulation of acid secretion: it is concluded that the response is probably mediated by beta-receptors on the parietal cell.