Effect of a histamine H2-receptor antagonist, famotidine, on gastric secretion in healthy subjects

The effects of 20 mg of famotidine or placebo on secretion of gastric juice and gastric acid were studied in ten healthy subjects in a randomized, crossover study. Gastric juice was aspirated and collected at hourly intervals for 24 hours after oral administration, and acid output was calculated based on gastric juice output and acid concentration. Secretion of gastric juice and acid output were lower after famotidine was administered than after placebo; over the 12-hour post-administration period, the hourly acid concentrations were significantly lower after famotidine than after placebo. During the 12 hours after famotidine or placebo, gastric juice output was 180.7 +/- 32.1 ml (mean +/- SE) in the placebo group and 64.7 +/- 9.1 ml in the famotidine group (P less than 0.01); acid concentrations were 49.3 +/- 3.8 mmol/L in the placebo group and 9.6 +/- 3.1 mmol/L in the famotidine group (P less than 0.01); acid output was 8.89 +/- 1.59 mmol in the placebo group and 0.55 +/- 0.17 mmol in the famotidine group (P less than 0.01). These results support the effectiveness of a 12 hour or possibly a 24-hour dosing interval for famotidine.     

Probing ligand-specific histamine H1- and H2-receptor conformations with NG-acylated Imidazolylpropylguanidines

Impromidine (IMP) and arpromidine (ARP)-derived guanidines are more potent and efficacious guinea pig (gp) histamine H(2)-receptor (gpH(2)R) than human (h) H(2)R agonists and histamine H(1)-receptor (H(1)R) antagonists with preference for hH(1)R relative to gpH(1)R. We examined N(G)-acylated imidazolylpropylguanidines (AIPGs), which are less basic than guanidines, at hH(2)R, gpH(2)R, rat H(2)R (rH(2)R), hH(1)R, and gpH(1)R expressed in Sf9 cells as probes for ligand-specific receptor conformations. AIPGs were similarly potent H(2)R agonists as the corresponding guanidines IMP and ARP, respectively. Exchange of pyridyl in ARP against phenyl increased AIPG potency 10-fold, yielding the most potent agonists at the hH(2)R-G(salpha) fusion protein and gpH(2)R-G(salpha) identified so far. Some AIPGs were similarly potent and efficacious at hH(2)R-G(salpha) and gpH(2)R-G(salpha). AIPGs stabilized the ternary complex in hH(2)R-G(salpha) and gpH(2)R-G(salpha) differently than the corresponding guanidines. Guanidines, AIPGs, and small H(2)R agonists exhibited distinct agonist properties at hH(2)R, gpH(2)R, and rH(2)R measuring adenylyl cyclase activity. In contrast to ARP and IMP, AIPGs were partial H(1)R agonists exhibiting higher efficacies at hH(1)R than at gpH(1)R. This is remarkable because, so far, all bulky H(1)R agonists exhibited higher efficacies at gpH(1)R than at hH(1)R. Collectively, our data suggest that AIPGs stabilize different active conformations in hH(2)R, gpH(2)R, and rH(2)R than guanidines and that, in contrast to guanidines, AIPGs are capable of stabilizing a partially active state of hH(1)R.     

Actions of nizatidine, a selective histamine H2-receptor antagonist, on gastric acid secretion in dogs, rats and frogs

Nizatidine (LY139037), a selective histamine H2-receptor antagonist, is a potent inhibitor of gastric acid secretion. It was 17.8 times as active as cimetidine on histamine (10(-5) M)-induced secretion from the isolated gastric mucosa of the bullfrog. Nizatidine was 8.9 times as active as cimetidine on basal acid secretion of the chronic gastric fistula rats after s.c. administration. Against acid secretion from the vagally innervated gastric fistula and Heidenhain pouch of dogs stimulated with submaximal doses of histamine, methacholine and gastrin, nizatidine was, respectively, 6.5, 5 and 4.7 times as active as cimetidine by i.v. administration. Nizatidine was very well absorbed from the gut and was 5 to 10 times as active as cimetidine on gastric acid secretion of dogs induced by submaximal and maximal doses of histamine when given p.o. Equal molar doses of nizatidine showed equal peak effects when given i.v., s.c. or i.m. Pharmacological data indicate that nizatidine is safe and effective as an agent for the control of excessive gastric acid secretion.     

Effect of histamine H2-receptor stimulation on postprandial pancreatic and gastric endocrine function in dogs

The effect of histamine H2-receptor stimulation via the infusion of impromidine was assessed with regard to postprandial plasma insulin, pancreatic polypeptide (PP), somatostatin, and gastrin levels. The effect of impromidine was assessed in the postprandial state during a liver extract/sucrose test meal which had a buffer capacity to maintain the intragastric pH at a constant level for the time impromidine was infused. Postprandial plasma insulin and gastrin levels were not changed by impromidine (10 micrograms/kg X h-1). Plasma somatostatin levels rose significantly, whereas the postprandial increase of plasma PP levels was attenuated. The effects on somatostatin and PP were antagonized by the infusion of cimetidine, a specific histamine H2-receptor blocker. In conclusion the present data demonstrate that in the postprandial state activation of H2-receptors stimulates somatostatin and inhibits PP release while insulin and gastrin release are not affected.     

Adenosine receptors on canine parietal cells modulate gastric acid secretion to histamine

Administration of theophylline has been shown to enhance gastric acid secretion in humans. Because theophylline has been reported to be a poor inhibitor of phosphodiesterase but a better adenosine receptor antagonist, we tested the hypothesis that there are inhibitory "R site" adenosine receptors on parietal cells. Utilizing isolated dispersed canine parietal cells, we measured acid secretion by the [14C]aminopyrine accumulation technique. We tested the effect of increasing concentrations of 2-chloroadenosine (10(-7), 10(-6), 10(-5) M) and L-N6-phenylisopropyl adenosine (L-PIA) (10(-7), 10(-6), and 10(-5) M), stable analogs of adenosine with specificity for the R sites, on aminopyrine uptake produced by submaximal stimulating concentrations of histamine (1 microM) plus isobutyl methylxanthine (3 microM) or carbachol (1 microM). Histamine-stimulated parietal cell aminopyrine uptake was 4.3- +/- 0.4-fold above basal; 2-chloroadenosine inhibited this response in a dose-dependent fashion with a 57 +/- 6% inhibition at 10(-5) M.L-PIA also inhibited histamine-stimulated aminopyrine uptake with a 67 +/- 11% inhibition at 10(-5) M. Carbachol-stimulated aminopyrine uptake was 5.8- +/- 1.6-fold above basal, but 2-chloroadenosine had no significant effect on this response. Theophylline, 300 microM, and 8-phenyltheophylline, 10 microM, reduced the inhibitory effect of 2-chloroadenosine. 8-Phenyltheophylline was inactive in inhibiting the parietal cell phosphodiesterase activity and the IC50 of theophylline for phosphodiesterase was 1 mM. Because prostaglandins inhibit parietal cell uptake of aminopyrine in a pattern similar to 2-chloroadenosine, we also tested the possibility that prostaglandins are involved in the 2-chloroadenosine response.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of the H2-receptor antagonists (burimamide and metiamide) on gastric secretion stimulated by histamine and its methyl derivatives.

This study was done to determine the comparative effectiveness of burimamide and metiamide as antagonists of gastric secretion stimulated by histamine and its methyl derivatives, Nalpha-methylhistamine, N-alpha,N-alpha-dimethylhistamine and 4-methylhistamine, in dogs with vagally denervated (Heidenhain pouches) and vagally innervated gastric mucosal septal pouches (Pavlov-type pouches). The secretagogues were always given by continuous i.v. infusion to produce steady states of secretory activity in the fasted conscious dogs; the antagonists were given by either rapid "bolus" i.v. injection or continuous i.v. infusion. With bolus injections, both antagonists promptly inhibited the secretion produced by histamine and its methyl derivatives. When control secretory rates were similar, 40 mumol of burimamide per kg and 4 mumol of metiamide per kg produced the same degree of inhibition. When the antagonists were also given by continuous i.v. infusion, the difference between them was greater, metiamide being 15 to 17 times more potent than burimamide. The effectiveness of the antagonists was not changed by vagal denervation. Symptoms of toxicity to burimamide developed at doses in excess of 30 mumol/kg/hr; none occurred with doses of metiamide ranging from 1.8 to 7.5 mumol/kg/hr.     

Inhibition of canine gastric acid secretion by an H-1 receptor antagonist to histamine.

Histamine H-2 receptors are thought to mediate gastric acid secretory responses, whereas H-1 receptors supposedly regulate mucosal vascular responses to histamine. In an in vivo chambered canine stomach flap preparation, the H-1 receptor antagonist, tripelennamine, injected intraarterially (22.1 mumol/kg) into the stomach flap reduced histamine-stimulated (1.25 micron/kg/min intravenously) acid secretion by approximately two thirds with a secondary reduction in gastric mucosal blood flow. This antisecretory action does not appear to be due to nonspecific mucosal damage. The H-2 receptor antagonist, metiamide, injected intraarterially (2.5 mumol/kg) also inhibited gastric acid secretion by about two thirds as did intravenously injected metiamide (4.5 mumol/kg), whereas intravenously administered tripelennamine (40.8 mumol/kg) was ineffective as an acid secretory inhibitor. Intraarterial tripelennamine reduced the secretory actions of the H-2 agonist, 4-methylhistamine (2.2 micron/kg/min intravenously), while intravenous metiamide depressed the gastric mucosal dilator responses to the H-1 agonist, 2-methylhistamine (5 micron/kg/min intravenously). Both histamine-receptor antagonists also reversed the systemic circulatory depressor effects of histamine and its analogs. These results suggest the need for reevaluation of inferences based upon the assumed specificity of H-2 and H-1 agonists and antagonists.     

Endogenous adenosine modulates gastric acid secretion to histamine in canine parietal cells

We have recently demonstrated the presence of A1 adenosine receptors on canine parietal cells which are involved in the inhibition of histamine-stimulated acid secretion. In order to demonstrate the importance of endogenously generated adenosine on acid secretion we examined the effect of compounds that either increase or decrease the availability of adenosine to the A1 receptor on histamine-stimulated parietal cell aminopyrine (AP) accumulation. Inclusion of 10 microM 8-phenyltheophylline, an adenosine receptor antagonist, with the cells resulted in a 35 +/- 12% and 31 +/- 9% increase in parietal cell AP accumulation at histamine concentrations of 1 microM and 10 microM, respectively. The effect of 8-phenyltheophylline was specific to histamine in that it did not affect carbachol-stimulated AP accumulation or dibutyryl cyclic AMP-stimulated AP accumulation. Inclusion of 1 microM dipyridamole, an inhibitor of adenosine transport, resulted in a 34 +/- 6% and 31 +/- 5% decrease in parietal cell AP accumulation at histamine concentrations of 1 microM and 10 microM, respectively. Again the effect of dipyridamole was specific to histamine in that it did not affect either carbachol- or dibutyryl cyclic AMP-stimulated AP accumulation. The addition of adenosine deaminase, 500 mU/ml, resulted in an enhanced histamine-stimulated AP accumulation at all the histamine concentrations. The effect was specific to histamine because the enzyme had no effect on either carbachol- or dibutyryl cyclic AMP-stimulated AP uptake. Our present data suggest that endogenous adenosine generated by the gastric cells can interact with parietal cell adenosine receptors to modulate acid secretion to histamine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of H2-receptor blockade on gastric mucus composition. A comparative study with ranitidine and famotidine

The effects on gastric mucus by two different H2-receptor antagonists, famotidine and ranitidine, have been investigated in 20 patients with duodenal ulcer. Before and after 4 weeks' treatment with either drug the quality of mucus secretion was assessed by means of a 'mucoprotective index'. A significant (P less than 0.01) decrease in the values of this index was observed in famotidine-treated subjects, whereas no changes were detected in those given ranitidine. The findings of this study with famotidine are in keeping with the results previously reported with cimetidine using the same method. It is suggested that blockade of gastric H2-receptors alters the composition of gastric mucus in man. This effect is not shared by ranitidine.     

Effect of histamine H2-receptor antagonists on vitamin B12 absorption.

OBJECTIVE: To discuss the potential of histamine H2-receptor antagonists (H2RAs) to cause malabsorption of vitamin B12 (cyanocobalamin). DATA SOURCES: Pertinent literature was identified via a MEDLINE search. Journals and references cited in published articles also were used as data sources. STUDY SELECTION: Studies evaluating the effect of H2RAs on vitamin B12 absorption were reviewed. DATA SYNTHESIS: H2RAs decrease acid secretion by the gastric parietal cells. Gastric acid and pepsin produced by these cells are required for the cleavage of vitamin B12 from dietary sources. Intrinsic factor (IF), also produced by gastric parietal cells, is required for vitamin B12 absorption from the gastrointestinal tract. Although H2RAs have not conclusively been shown to decrease IF secretion, studies have demonstrated a significant reduction in food-bound vitamin B12 absorption secondary to decreased acid secretion in patients taking these drugs. CONCLUSIONS: H2RAs have the potential to cause vitamin B12 deficiency. This may be important in patients with inadequate stores of vitamin B12 (e.g., poor diet), particularly those receiving H2RA therapy continuously for more than two years. Healthcare providers should be aware of this potential adverse effect.     

Inhibition of sympathetic nervous system by histamine:studies with H1- and H2-receptor antagonists.

A study was designed to investigate the effect of histamine on sympathetic transmission to the myocardium in pentobarbital-anesthetized dogs. Intravenous infusion of histamine (1.0 and 2.0 microgram/kg/min) produced dose-related decreases in blood pressure and caused significant impairment of cardioacceleration observed during stimulation of the right postganglionic cardiac sympathetic nerve fibers. Positive chronotropic effects of intravenously administered norepinephrine as well as tyramine were not altered during histamine infusion. Blockade of neuronal reuptake with desipramine did not modify the inhibitory action of histamine on sympathetic nerve function. Prior administration of mepyramine (pyrilamine), a histamine type H1-receptor antagonist caused partial attenuation of the depressor action of histamine, but did not prevent histamine-induced inhibition of neurogenic function. Further treatment with metiamide, a histamine type H2-receptor antagonist caused nearly complete attenuation of the depressor response to histamine and also significantly antagonized the inhibitory action of histamine on sympathetic transmission to the myocardium. It is concluded that while the depressor action of histamine is due to the activation of both H1- as well as H2-receptors, histamine causes impairment of sympathetic nerve function to the myocardium by acting on H2-receptors which may be located on sympathetic nerve terminals.     

The new histamine H2-receptor antagonist ranitidine

The antisecretory effects of a new histamine H2-receptor antagonist, ranitidine hydrochloride, have been investigated on basal and pentagastrin-stimulated acid secretion in healthy volunteers 5 and 10 h after oral administration of 150 mg. In addition, the 24-h intragastric pH-profiles have been measured in patients undergoing parenteral nutrition after three doses of 150 mg ranitidine per day. A 40% inhibition of basal acid output has been noted even 10 h after drug intake. The intragastric pH-values were raised above 5 for at least 24 h. The new H2-antagonist ranitidine has been proven to be a potent and long-acting antisecretory compound.     

Effects of ORF 17583, other histamine H2-receptor antagonists and omeprazole on gastric acid secretory states in rats and dogs

ORF 17583, a histamine H2-receptor antagonist, inhibited gastric acid secretion in pylorus-ligated rats (ED50 = 4.9 mg/kg intraduodenal; 3.4 mg/kg p.o.; and 0.21 mg/kg i.p.) and in total gastric fistula or Heidenhain pouch dogs stimulated by betazole (ED50 = 0.12 mg/kg p.o. and 0.08 mg/kg i.v.), histamine, tetragastrin, bethanechol, 2-deoxy-D-glucose or a meal (ED50 values ranged from 0.11-0.26 mg/kg p.o.). The nonspecific inhibition of gastric acid by ORF 17583 supports the existence of interdependence between histamine and the gastrin and cholinergic receptors on the parietal cell surface. Antisecretory potency of ORF 17583 after intraduodenal administration in pylorus-ligated rats was 6.4 times greater than cimetidine, 1.8 times greater than ranitidine, equal to that of omeprazole and 8 times less than that of famotidine. Oral antisecretory potency of ORF 17583 in gastric fistula dogs was 31 times greater than cimetidine, 3.7 times greater than ranitidine and equal to that of omeprazole and famotidine. Studies using equieffective antisecretory doses of ORF 17583 and ranitidine in dogs suggested that ORF 17583 has a short duration of antisecretory activity similar to that of ranitidine.     

Movement of gastric acid secretion and influence of proton pump inhibitors on histamine H2 receptor antagonist resistant ulcer]

Treatment of peptic ulcers has become easier with the advent of H2 blockers. However, H2 resistant ulcer still remain. These cases were screened by 24 hr-intragastric pH monitoring, which well reflects the status of gastric acid secretion. On the one hand, there were cases in which no nocturnal elevation in gastric pH was seen even after administration of H2 blocker (H2 blocker resistant ulcer). On the other hand, there were cases which were resistant to treatment with H2 blocker, although the gastric pH elevated. It is considered that omeprazole is effective for the former cases.     

Effects of histamine, H1- and H2-receptor antagonists on the activity of serotonergic neurons in the dorsal raphe nucleus

We investigated the effects of histamine applied by microiontophoresis onto serotonin-containing (serotonergic) cells recorded extracellularly in the dorsal raphe nucleus of the rat. Application of histamine at low iontophoretic currents (1-5 nA) produced a rapid depression of the firing of all serotonergic neurons tested. The H1-receptor antagonists mepyramine and diphenhydramine were unable to attenuate the histamine-induced response. Antagonism of the effect of histamine by the iontophoretic application of the H2-receptor antagonists cimetidine and metiamide was not possible to evaluate since both were found to exert potent inhibitory effects by themselves. In contrast, the nonimidazole-derived H2-receptor antagonist ranitidine, which had no effect by itself, selectively antagonized the histamine-induced depression of neuronal activity. Histidine, 3-methylhistamine and a variety of histamine agonists selective for H1- or H2-receptors were unable to mimic the effect of histamine in dorsal raphe. Histamine's effects may, in part, be mediated at a gamma-aminobutyric acid receptor complex as the gamma-aminobutyric acid antagonists bicuculline and picrotoxin rapidly and reversibly antagonized both the histamine- and the cimetidine-induced depression of serotonin cell firing; the glycine antagonist strychnine selectively blocked the inhibitory effect of glycine without altering the histamine-induced response. These data show an inhibitory effect of histamine on serotonin-containing neurons in the dorsal raphe; this effect may be partially mediated at a subtype of H2-receptor. These data further indicate that the inhibitory effects of histamine and cimetidine observed in the dorsal raphe nucleus may result, in part, from an action directly or indirectly at a gamma-aminobutyric acid receptor complex.     

The effect of ranitidine hydrochloride, a new histamine H2-receptor antagonist, on intrinsic factor secretion

The effect on intrinsic factor (IF) secretion of eight weeks' continuous treatment with a clinically relevant oral dose of ranitidine hydrochloride, a new histamine H2-receptor antagonist, has been studied in 11 patients with duodenal ulcer. There was no significant difference between the mean IF output during treatment of after drug withdrawal as compared with the control value, despite highly significant (p less than 0.001) reduction in acid output during treatment. In the short term this potent drug is unlikely to cause pernicious anemia from interference with IF secretion, although further study is necessary to exclude this possibility after long-term use.