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.     

Pharmacological evaluation of cimetidine, a new histamine H2-receptor antagonist, in healthy man.

Cimetidine, a new H2-receptor antagonist, was safely administered to eighteen healthy man by the intravenous, intraduodenal or oral route. 2 When gastric secretion was maximally stimulated by either histamine or pentagastrin, the simultaneous administration of cimetidine produced marked inhibition of both acid and pepsin secretion. 3 Cimetidine was well absorbed by mouth and had a blood half-life of 2 hours. 4 Cimetidine was rapidly excreted via the kidneys and about 70% of the excreted material was unchanged drug. 5 Clinical evaluation of cimetidine in patients with peptic ulceration is recommended.     

Effects of ranitidine, a new histamine H2-receptor antagonist, on secretagogue-stimulated gastric secretion in Heidenhain pouch dogs (author's transl)

The effects of ranitidine on gastric secretion stimulated with gastric secretagogues were studied in 6 Heidenhain pouch dogs (both male beagle and mongrel). Cimetidine was used as a reference drug. Either histamine 2HCl (40 micrograms/kg), pentagastrin (2 micrograms/kg) or carbachol (2 micrograms/kg) was given intramuscularly, every 15 min for 120 min. Gastric juice was collected at each 15 min interval and analyzed for volume, acidity and pepsin activity. Either ranitidine (0.3, 1 or 10 mg/kg) or cimetidine (1 or 10 mg/kg), packed in a gelatin capsule, was given orally 60 min before the initial injection of each stimulant. Both ranitidine and cimetidine dose-dependently inhibited histamine- and pentagastrin-stimulated gastric secretion (volume, acid and pepsin output). These agents also inhibited the carbachol-stimulated secretion, but the antisecretory effects were weak as compared with their effects on histamine- and pentagastrin-stimulated secretions. The antisecretory effect of ranitidine on each stimulant is roughly 2 to 17 times more potent than cimetidine on the basis of ED50 (anti-secretory dose which inhibits gastric secretion by 50%). The antisecretory effect of ranitidine (10 mg/kg) on pentagastrin-stimulated secretion was observed even 10 hr after its oral administration.     

Gastroduodenal HCO3-secretion in anesthetized rats: effects of 16,16-dimethyl PGE2, topical acid and acetazolamide

Alkaline secretion was measured in the whole stomach and in the proximal duodenum (2 cm proximal to the outlet of the common bile duct) of anesthetized rats, under basal conditions and in response to topical acid and 16,16-dimethyl PGE2 (16-dmPGE2) given by various routes. Gastric alkaline secretion was unmasked by intraduodenal administration of omeprazole (30 mg/kg). Both the stomach and duodenum consistently secreted bicarbonate in amounts of 0.2-0.4 microEq/15 min and 1.5-2 microEq/15 min as a basal secretion, respectively. 16-dmPGE2, either given subcutaneously (1-30 micrograms/kg), intravenously (3 micrograms/kg/hr) or by topical application for 30 min (0.3-10 micrograms/ml), (concentration)-dependently increased HCO3- secretion in both tissues, but this effect disappeared quickly after sacrifice with KCI (i.v.). Stimulation of HCO3- secretion was also caused by topical acid to the stomach (100 mM HCI for 10 min) or to the duodenum (10 mM HCI for 10 min), but was completely blocked by pretreatment with indomethacin (5 mg/kg, s.c.). Acetazolamide, given subcutaneously at 100 mg/kg, which gives over 80% inhibition of carbonic anhydrase activity in the gastroduodenal mucosa, had no effect on either basal or stimulated HCO3- secretion caused by 16-dmPGE2 (10 micrograms/kg, s.c.). These results indicate that both endogenous and exogenous (16-dmPGE2) prostaglandins stimulate alkaline secretion in the gastroduodenal mucosa of rats, and this mechanism is independent from the carbonic anhydrase activity of the tissue.     

Hepatic clearance and biliary secretory rate maximum of taurocholate in the recirculating and single pass isolated perfused rat liver. Effects of the cholestatic agent, estradiol-17 beta-(beta-D-glucuronide)

The ability of the cholestatic steroid glucuronide, estradiol-17 beta-(beta-D-glucuronide) (E(2)17G), to inhibit the hepatic clearance (ClH) and biliary secretory rate maximum (SRm) of taurocholate was investigated in the recirculating and single pass isolated perfused male rat liver. In the recirculating perfused liver, E(2)17G (0, 2, 4, or 6 mumol) was added as a bolus dose to the reservoir at zero time while taurocholate was infused into the portal vein in increasing amounts (15, 30, 45, or 60 mumol/mL; 1 mL/hr for 15 min each). E(2)17G (4 mumol) caused a significant (P less than 0.05) inhibition of bile flow and bile acid secretion at 10-15 min during infusion of 15 mumol/hr taurocholate but did not inhibit the SRm which occurred at 42 min, indicating that E(2)17G had not caused an irreversible inhibition of taurocholate transport. E(2)17G (6 mumol) caused a profound and irreversible inhibition of bile flow attributable to retention of E(2)17G in the liver. The noncholestatic estradiol-3-(beta-D-glucuronide) (E(2)3G; 6 mumol) had no significant effect on bile flow or the SRm. In the single pass perfused liver (10 mL/min flow rate), E(2)17G (0, 1, 2, 5, or 10 nmol/mL) or E(2)3G (2 nmol/mL) was added to the perfusate resulting in a stable infusion to the liver. [3H]Taurocholate was infused into the portal vein in increasing amounts to give inflow concentrations (Cin) of 25, 50, 75 or 100 nmol/mL. In the absence of E(2)17G, taurocholate ClH decreased from 0.92 to 0.70 mL/min/g liver with increasing taurocholate concentrations. Neither E(2)17G nor E(2)3G altered the ClH of 25 nmol/mL taurocholate. E(2)17G (10 nmol/mL) inhibited bile flow and bile acid secretion first at 20-25 min, followed by inhibition of ClH of 75 and 100 nmol/mL taurocholate (35-60 min). In contrast, E(2)3G stimulated bile acid secretion and increased the SRm by 80%. Thus, at doses that did not block its own elimination, E(2)17G did not cause an irreversible inhibition of taurocholate transport into bile. E(2)17G did not directly inhibit the uptake of taurocholate into the liver but first inhibited the biliary excretion of taurocholate, resulting in its intrahepatic accumulation and decreased clearance from the perfusate.     

Role of central prostaglandin E2 in the regulation of gastric acid secretion in the rat.

The central action of prostaglandin E2 (PGE2) on gastric acid secretion was investigated in rats by comparing the effects of intracisternal (i.ci.) and i.v. administration of PGE2 and the influence of i.ci. injection of indomethacin on acid secretion and PGE2 generation in the brain and stomach. I.ci. injections of PGE2 (1-10 micrograms) or the stable analog, 16,16-dimethyl PGE2, (0.01-0.1 micrograms) induced a dose dependent inhibition of baclofen-stimulated gastric acid secretion by 0-82% and by 7-87% respectively. I.v. infusion of PGE2 also induced a dose related inhibition of baclofen-stimulated acid secretion, but 10 fold higher doses were required. I.ci. or i.v. injection of indomethacin in doses ranging from 50 to 500 micrograms/rat, produced a similar dose dependent inhibition of the PGE2 generation in both the gastric mucosa and brain cortex measured 1 h post injection. I.ci. injection of indomethacin (500 micrograms) increased within 10 min acid secretion with a peak response at 20-30 min; 60-120 min post injection, when prostaglandin synthesis was inhibited by 90%, basal and baclofen-stimulated acid output were not altered. These results further establish that PGE2 acts in the brain to inhibit vagally stimulated gastric acid secretion in rats, and do not support a tonic inhibitory influence of endogenous brain PGE2 in the regulation of gastric acid secretion. In addition, these data showed that indomethacin injected i.ci. at 500 micrograms does not induce a selective inhibition of prostaglandin synthesis in the brain.     

The effect of cimetidine on basal and stimulated pepsin secretion in the isolated whole stomach of the rat

1 The isolated stomach preparation of the immature rat has been used to study the stimulation and inhibition of pepsin secretion. 2 The isolated stomach secretes a basal level of pepsin. High concentrations (10(-3)M) of the H2-receptor antagonist, cimetidine, and the muscarinic receptor blocking drug, atropine, did not affect this secretion in a manner which was consistently of statistical significance. 3 Concentrations of histamine of 10(-5)M, 10(-4)M and 10(-3) M stimulated maximum levels of pepsin output of 126%, 155% and 299% respectively of control. There was no evidence that this secretion was secondary to the stimulation of acid secretion. 4 Cimetidine (10(-4)M and 10(-3)M) produced a dose-related inhibition of the pepsin output to 10(-3)M histamine, suggesting that histamine H2-receptors mediate this response. 5 Atropine (10(-3)M) had no effect on the pepsin response to 10(-3)M histamine, suggesting that muscarinic mechanisms play no part, even modulatory, in this secretion.     

Central neuropeptide Y and the sigma ligand, JO 1784, reverse corticotropin-releasing factor-induced inhibition of gastric acid secretion in rats.

1. The central interactions between the sigma ligand, JO 1784, [(+)-N-cyclopropylmethyl-N-methyl-1,4-diphenyl-1-ethylbut-3- en-1-ylamine hydrochloride], or neuropeptide Y (NPY) and corticotropin-releasing factor (CRF)-induced inhibition of gastric acid secretion were investigated in rats anaesthetized with urethane. Drugs were injected intracisternally (i.c.) or into specific hypothalamic nuclei. Gastric acid secretion was measured by the flushed technique under basal and pentagastrin (10 micrograms kg-1 h-1, i.v.) stimulated conditions. 2. Intracisternal injection of CRF (10 micrograms), bombesin (0.1 microgram) and human recombinant interleukin-1 beta (hIL-1 beta, 0.1 microgram) inhibited gastric acid response to pentagastrin by 72%, 56% and 62%, respectively. NPY (0.5 microgram) or JO 1784 (0.5 microgram) injected i.c. did not alter acid secretion but completely prevented the inhibitory effect of CRF. The antagonistic effect of NPY and JO 1784 against CRF was dose-related (0.01-0.5 microgram) and peptide-specific since NPY and JO 1784 did not alter the antisecretory action of bombesin or hIL-1 beta. 3. The putative sigma receptor antagonist, BMY 14802, (1 mg kg-1, s.c.) did not influence pentagastrin-stimulated acid secretion nor CRF-induced inhibition of gastric acid secretion; however, BMY 14802 administered s.c. 20 min before JO 1784 or NPY, abolished the antagonistic effect of both JO 1784 and NPY. 4. CRF (3 micrograms) microinjected into the hypothalamic paraventricular nucleus (PVN) and the lateral hypothalamus (LH) inhibited pentagastrin-stimulated gastric acid secretion by 61% and 51%; NPY (0.03 micrograms) or JO 1784 (0.03 micrograms) microinjected into the PVN had no effect by themselves but blocked CRF antisecretory action.(ABSTRACT TRUNCATED AT 250 WORDS)     

Enhancement of nasal absorption of insulin and calcitonin using polyacrylic acid gel

The effects of polyacrylic acid gel on the nasal absorption of insulin and [Asu1,7]-eel calcitonin were investigated in rats. The nasal administration of insulin (1 IU kg-1) in polyacrylic acid gel at 0.1 and 1% w/v showed maximum hypoglycaemic effects at 30 min and 1 h after administration, respectively. However, the nasal administration of insulin in carboxymethyl cellulose (1% w/v) solution had no hypoglycaemic effect at the same dose. When [Asu1,7]-eel calcitonin (10 U kg-1) was administered nasally in polyacrylic acid gel (0.1% w/v), a prominent hypocalcaemic effect was observed during the first 30 min. Nasal administration of [Asu1,7]-eel calcitonin in saline had no hypocalcaemic effect at the same dose. The results indicate that the polyacrylic acid gel base significantly enhanced the absorption of insulin and [Asu1,7]-eel calcitonin via the nasal cavity.     

Pharmacokinetic, pharmacodynamic, and efficacy profiles of alogliptin, a novel inhibitor of dipeptidyl peptidase-4, in rats, dogs, and monkeys

The aim of the present research was to characterize the pharmacokinetic, pharmacodynamic, and efficacy profiles of alogliptin, a novel quinazolinone-based dipeptidyl peptidase-4 (DPP-4) inhibitor. Alogliptin potently inhibited human DPP-4 in vitro (mean IC(50), ~ 6.9 nM) and exhibited > 10,000-fold selectivity for DPP-4 over the closely related serine proteases DPP-2, DPP-8, DPP-9, fibroblast activation protein/seprase, prolyl endopeptidase, and tryptase (IC(50) > 100,000 nM). Absolute oral bioavailability of alogliptin in rats, dogs, and monkeys was 45%, 86%, and 72% to 88%, respectively. After a single oral dose of alogliptin, plasma DPP-4 inhibition was observed within 15 min and maximum inhibition was > 90% in rats, dogs, and monkeys; inhibition was sustained for 12 h in rats (43%) and dogs (65%) and 24 h in monkeys (> 80%). From E(max) modeling, 50% inhibition of DPP-4 activity was observed at a mean alogliptin plasma concentration (EC(50)) of 3.4 to 5.6 ng/ml (10.0 to 16.5 nM) in rats, dogs, and monkeys. In Zucker fa/fa rats, a single dose of alogliptin (0.3, 1, 3, and 10 mg/kg) inhibited plasma DPP-4 (91% to 100% at 2 h and 20% to 66% at 24 h), increased plasma GLP-1 (2- to 3-fold increase in AUC(0-20 min)) and increased early-phase insulin secretion (1.5- to 2.6-fold increase in AUC(0-20 min)) and reduced blood glucose excursion (31%-67% decrease in AUC(0-90 min)) after oral glucose challenge. Alogliptin (30 and 100 mg/kg) had no effect on fasting plasma glucose in normoglycemic rats. In summary, these data suggest that alogliptin is a potent and highly selective DPP-4 inhibitor with demonstrated efficacy in Zucker fa/fa rats and potential for once-daily dosing in humans.     

Effects of topical application of acidified omeprazole on acid secretion and transmucosal potential difference in anesthetized rat stomachs

Effects of topical application of omeprazole on transmucosal potential difference (PD), luminal pH and histamine-stimulated acid secretion were examined in anesthetized rat stomachs, and they were compared with those of systemic administration. Omeprazole was suspended in 1% CMC with NaHCO3 (pH 9.0) or dissolved in 0.1 N HCl (pH 1.0). Both omeprazole (30 mg/kg, pH 9.0) and cimetidine (100 mg/kg), given i.d., increased the pH and inhibited acid secretion induced by histamine (8 mg/kg/hr, i.v.), while basal gastric PD was markedly elevated only by the former. Similar responses in PD, pH and acid output were obtained dose-dependently after brief exposure of the stomach (10 min) to omeprazole (0.3-30 mg/kg), even in acidic conditions, but the effects of acidified omeprazole disappeared depending upon the latency period in 0.1 N HCl; there was no effect when applied at more than 30 min after dissolution. Of interest, subsequent exposure of the stomach to a mercaptane compound (cysteine, 100 mg/kg) for 30 min significantly reversed the antisecretory effect of omeprazole (both i.d. and i.g.) but not of cimetidine. These results suggest that omeprazole has a local antisecretory action even in acidic stomachs, probably through an inhibition of the H+/K+ATPase activity, and the increase of PD caused by omeprazole may be a characteristic phenomenon seen after the blockade of H+/K+ ATPase, but is not associated with acid inhibition itself.     

Modulation by fenoldopam (SKF 82526) and bromocriptine of the electrically evoked release of vasopressin from the rat neurohypophysis

Single neurointermediate lobes were fixed by their stalks to a platinum wire electrode and incubated in Krebs-bicarbonate solution. Vasopressin release into the medium was determined by a radioimmunoassay. Vasopressin secretion was increased by electrical stimulation (15 Hz, 10 s trains with 10 s intervals for 10 min). Fenoldopam (SKF 82526) had a dual effect on vasopressin release, 30 nM decreasing (by 30%) and 3 microM increasing (by 32%) the evoked vasopressin secretion. The facilitatory effect of fenoldopam was antagonized in a concentration-dependent manner by flupenthixol but not by sulpiride. Sulpiride (1 microM) prevented the inhibitory effect of fenoldopam (30 microM). After pretreatment of the rats with the dopamine depleting agent, Ro4-1284 (2 mg/kg i.p. 1 h before the experiments), the evoked vasopressin release was decreased by 21% and the inhibitory effect of fenoldopam disappeared, but the facilitatory effect of fenoldopam was already seen at 30 nM. Similarly, bromocriptine (1-10 microM) decreased the evoked vasopressin release from untreated neurointermediate lobes by 30-40% but increased the vasopressin release by 30% after pretreatment with Ro4-1284. The present findings further support the concept that vasopressin from the neurohypophysis is modulated by dopaminergic mechanisms. Facilitatory effects are mediated via D 1 and inhibition via D 2 receptors. The presence of endogenous dopamine seems to be necessary for the inhibitory effects to occur.     

Declining catecholamine secretion in adrenal medulla on prolonged stimulation with acetylcholine

Perfused pig adrenal glands and cortex-free ox adrenal medullae were stimulated by continuous infusion of 10(-4) M acetylcholine (ACh). Secretion of adrenaline rose to a maximum in approximately 5 min but, after a further 15 min, declined to 36 +/- 19% (+/- S.D.) of maximum for pig (N = 5) and 27 +/- 10% of maximum for ox (N = 3), in spite of continued infusion of ACh. After 20 min, no further significant decline was detectable. Nevertheless, in ox medullae, oxygen consumption measured after stimulation showed no significant change relative to the pre-stimulation value, indicating that the decline in secretion did not arise from a failure of oxidative energy metabolism. In 4 pig adrenal glands subjected to a 1 hr infusion of ACh, adrenaline secreted in the last 20 min was only 52 +/- 10% of that secreted in the first 20 min but, after a 2 hr rest interval, recovered to 74 +/- 18% (P less than 0.05) in the first 20 min of a second 1 hr stimulation. In the same glands, no reproducible recovery was detectable for noradrenaline and, by the last 20 min of the second 1 hr stimulation, noradrenaline secretion had declined to 36 +/- 20% of the initial value, even though only 15% of the noradrenaline originally in the gland had been secreted. It is concluded that, while decline and recovery of adrenaline secretion may, in part, have arisen from desensitization and resensitization of the ACh receptor; the decline in noradrenaline secretion arose mainly from depletion of a readily secreted pool which was considerably smaller than the total in the gland.     

Endothelin-1 inhibits platelet aggregation in vivo: a study with 111indium-labelled platelets.

1. A non-invasive technique for the scintigraphic determination of 111indium-labelled platelet aggregation stimulated with submaximal doses of adenosine diphosphate (ADP, 56 micrograms kg-1 i.v.), collagen (100 micrograms kg-1 i.v.), platelet-activating factor (PAF, 0.1 microgram kg-1 i.v.) or thrombin (18 iu kg-1 i.v.) was used to investigate the platelet-inhibitory effects of endothelin 1 (ET-1) in anaesthetized rabbits in vivo. 2. ET-1 (1 nmol kg-1 i.v.) inhibited ADP-stimulated platelet aggregation in vivo; a maximum inhibition of 78% of the control value was reached at 3 min, with 45% inhibition at 15 min, and a return to control values at 30 min after injection of the peptide. 3. ET-1 (1 nmol kg-1 i.v.) inhibited in vivo platelet aggregation in response to collagen or PAF by 86% and 52%, respectively, but had no effect on thrombin-induced platelet aggregation. 4. Indomethacin (5 mg kg-1 i.v.) abolished the ET-1-induced inhibition of ADP-stimulated platelet aggregation and significantly potentiated and prolonged the pressor response brought about by ET-1. 5. In conclusion, the data demonstrate that ET-1 potently inhibits platelet aggregation in the anaesthetized rabbit in vivo by releasing a hypotensive and anti-aggregatory cyclo-oxygenase product, presumably prostacyclin, into the circulation.     

Anti-ulcer activity of SKP-450, a novel potassium channel activator, in rats.

The anti-ulcer effects of SKP-450, a new potassium channel activator, were evaluated on basal and histamine-induced gastric acid secretion, and against experimentally-induced ulcers such as ethanol-induced and NaOH-induced gastric ulcers. In the pylorus-ligated rat, SKP-450 (0.1-0.5 mg kg(-1)) significantly decreased volume and concentration of gastric juice, and total acid output (ED(50): 0.12 mg kg(-1)). SKP-450 (0.3-3.0 mg kg(-1)) also inhibited histamine-induced gastric acid secretion, maximal effects being achieved at 1.0 mg kg(-1)(37.9% inhibition). In the 95% ethanol-treated rats, SKP-450 significantly reduced the mucosal lesions (46.9 and 31.4% inhibition at 0.1 and 0.2 mg kg(-1), respectively). A significant reduction in the ulcer index by SKP-450 was also observed in 0.3 n NaOH-treated rats (31.5 and 64.3% inhibition at 0.5 and 1.0 mg kg(-1), respectively). The effects of SKP-450 on histamine-induced acid secretion and on NaOH-induced ulcers were inhibited by glibenclamide (20 mg kg(-1), i.v.), a selective blocker of ATP-sensitive potassium channel. These results indicate that SKP-450 possesses anti-ulcer effects and its effects may be mediated by activation of ATP-sensitive potassium channels.     

Role of gastric acid and bile acids in the pathogenesis of compound 48/80-induced gastric lesions in rats

We studied the effects of various agents, which influence gastric acidity and bile acids, on compound 48/80 (48/80)-induced gastric lesions in rats. 48/80-Induced gastric lesions were produced by repeated intraperitoneal administration of 48/80 at 0.75 mg/kg once daily for 4 days. Test agents were given orally twice daily (30 min before and 9 hr after 48/80 administration) for 4 days. AI(OH)3 and sucralfate at 2000 mg/kg/day, a weak antacid dose, significantly inhibited (about 50-60%) the development of 48/80-induced lesions. Propantheline at 60 mg/kg/day and omeprazole at 60 or 200 mg/kg/day, which reduced gastric secretion for more than 12 hr, also significantly inhibited (about 30-40%) these lesions. Cimetidine at 200 mg/kg/day, which reduced gastric secretion for only 5 hr, had little effect on the lesion formation. Cholestyramine, which is a potent bile acids binding agent, had no effect on 48/80-induced lesions in doses of 600 or 2000 mg/kg/day. These results suggest that gastric acid, but not bile acids, is partly involved in the pathogenesis of 48/80-induced gastric lesions.     

Gastric acid inhibitory profile of saviprazole (HOE 731) compared to omeprazole.

Saviprazole (HOE 731), a substituted thienoimidazole, caused a dose-dependent inhibition of gastric acid secretion in dogs and rats with ID50 values which were not significantly different from that of omeprazole indicating that both compounds are equally effective. The duration of action in dogs lasted for more than 24 h and was dependent on the state of stimulation. Measurement of serum concentrations of 1 mg/kg saviprazole after intravenous or intraduodenal administration revealed a bioavailability of about 60% in dogs. The elimination half-life was about 30 min following both routes of administration. In rats basal acid secretion was inhibited by saviprazole. In addition stimulation of acid secretion by histamine, desglugastrin, carbachol and isobutylmethylxanthine-forskolin was equally inhibited. This was in agreement with the known mechanism of action, inhibition of the gastric proton pump which is the last step of acid secretion within the parietal cell. Surprisingly, at high dose levels, saviprazole differed from omeprazole. After saviprazole, 1 mg/kg i.v. to dogs, acid output dropped to zero but recovered within 30 min to a level of 90%, whereas omeprazole depressed acid output completely over the whole observation period (4.5 h). Similar results were obtained in pylorus-ligated rats.     

Effects of ranitidine, a new histamine H2-receptor antagonist, on secretagogue-stimulated gastric secretion in rats: comparison with cimetidine (author's transl)

Antisecretory effects of ranitidine on secretagogue-stimulated gastric secretion in acute fistula rats were studied. Histamine 2HCl (8 mg/kg/hr), pentagastrin (125 micrograms/kg/hr) or carbachol (128 micrograms/kg/hr) was continuously given i.v. by an infusion pump, through the tail vein to acute fistula rats. Gastric secretion was collected hourly for 5 hr and analyzed for its components. Cimetidine was used as a reference drug. Both drugs were given i.v. by a bolus injection in the tail vein 30 min after the injection of each stimulant. Both ranitidine (1 and 10 mg/kg) and cimetidine (10 and 60 mg/kg) significantly (P less than 0.05) inhibited the histamine-stimulated gastric secretion (volume, acid and pepsin output) for 1 to 4 hr. Both ranitidine (10 mg/kg) and cimetidine (60 mg/kg) significantly (P less than 0.05) inhibited the pentagastrin-stimulated gastric secretion for 2 to 3 hr. both ranitidine (10 mg/kg) and cimetidine (10 and 60 mg/kg) markedly inhibited the gastric acid secretion in response to carbachol. However, cimetidine (10 or 60 mg/kg) significantly (P less than 0.05) stimulated the volume and pepsin output by carbachol. We conclude that ranitidine is about 6 times more potent than cimetidine for histamine- or pentagastrin-stimulated gastric secretion and almost equal to cimetidine for carbachol-stimulated gastric acid output in rats.     

Cimetidine decreases aspirin-induced gastric mucosal damage in humans

Aspirin induces gastric mucosal damage in animals and humans. The purpose of this study was to examine whether cimetidine protects the human gastric mucosa from acute aspirin-induced damage. Eight healthy subjects were studied on 4 separate days. Cimetidine, 400 mg, or placebo was given orally 1 hour before initial endoscopy. The stomach was isolated and atropine given to suppress basal acid secretion. Each study consisted of four 15 min periods during which an acidic test solution was instilled into the stomach. During the second period only, either aspirin (1300 mg, 36 mmol) or control for aspirin (36 mmol HCl) was added to the test solution. Ion fluxes and gastric mucosal potential difference were measured, and endoscopy performed following each test. After placebo, aspirin significantly altered hydrogen ion flux and potential difference versus basal and control. Cimetidine decreased the damaging effect of aspirin. Endoscopic scores increased after aspirin plus placebo, whereas they remained unchanged after aspirin plus cimetidine. Therefore, cimetidine decreased aspirin-induced gastric mucosal damage in humans. As gastric acidity was identical during all studies, the effect of cimetidine was independent of gastric acid secretion.     

Cisapride inhibits meal-stimulated gastric acid secretion and post-prandial gastric acidity in subjects with gastro-oesophageal reflux disease

BACKGROUND AND AIMS: KCNQ1 potassium channels in human gastric parietal cells are thought to be involved in gastric acid secretion. As cisapride can inhibit similar channels in other tissues and is an effective treatment for nocturnal heartburn, we examined the effects of cisapride on gastric and oesophageal acidity, gastric emptying and heartburn severity in subjects with gastro-oesophageal reflux disease. METHODS: Subjects (n = 11) had suffered from heartburn four times or more per week for at least 6 months. Gastric pH and oesophageal pH were measured before, during and after a standard meal ingested over 15 min. Each subject received placebo or 10 mg cisapride orally, 30 min before the beginning of the meal. Meal-stimulated gastric acid secretion was calculated from the amount of HCl required to titrate the homogenized standard meal to pH 2 in vitro and the time required for the pH of the ingested meal to decrease to pH 2 in vivo. Heartburn severity was assessed at 15-min intervals beginning at the end of the meal. Gastric emptying of solids was measured using a [(13)C]-octanoic acid breath test. RESULTS: Cisapride significantly decreased meal-stimulated gastric acid secretion by 20%, decreased integrated gastric and oesophageal acidity by 50-60% and transiently increased the expiration of (13)CO(2). Cisapride did not significantly alter heartburn severity. CONCLUSIONS: The cisapride-induced decreases in meal-stimulated gastric acid secretion, gastric acidity and oesophageal acidity in subjects with gastro-oesophageal reflux disease can account for its beneficial clinical effects. These results also raise the possibility that gastric KCNQ1 potassium channels are important in meal-stimulated gastric acid secretion and possibly in the pathophysiology of gastro-oesophageal reflux disease.