Pharmacological control of the human gastric histamine H2 receptor by famotidine: comparison with H1, H2 and H3 receptor agonists and antagonists

Histamine 0.1 microM-0.1 mM increased adenylate cyclase activity five- to ten-fold in human fundic membranes, with a potency Ka = 3 microM. The histamine dose-response curve was mimicked by the H3 receptor agonist (R) alpha-MeHA, but at 100 times lower potency, Ka = 0.3 mM. Histamine-induced adenylate cyclase activation was abolished by H2, H1 and H3 receptor antagonists, according to the following order of potency IC50: famotidine (0.3 microM) greater than triprolidine (0.1 mM) thioperamide (2 mM), respectively. Famotidine has no action on membrane components activating the adenylate cyclase system, including the Gs subunit of the enzyme stimulated by forskolin and cell surface receptors sensitive to isoproterenol (beta 2-type), PGE2 and VIP. The Schild plot was linear for famotidine (P less than 0.01) with a regression coefficient r = 0.678. The slope of the regression line was 0.64 and differs from unity. Accordingly, famotidine showed a slow onset of inhibition and dissociation from the H2 receptor in human cancerous HGT-1 cells. The results demonstrate that famotidine is a potent and selective H2 receptor antagonist with uncompetitive actions in human gastric mucosa. Consequently, famotidine might be a suitable drug with long-lasting actions in the treatment of Zollinger-Ellison syndrome. The results also confirm and extend the previous observations that (R) alpha-MeHA and thioperamide are two selective ligands at histamine H3 receptor sites. In the human gastric mucosa, these drugs are respectively 330 and 6700 times less potent than histamine and famotidine on the adenylate cyclase system. The possible involvement of histamine H3 receptors in the regulation of gastric secretion is proposed.     

A comparison of some of the pharmacological properties of etintidine, a new histamine H2-receptor antagonist, with those of cimetidine, ranitidine and tiotidine

Etintidine is a competitive antagonist of histamine H2-receptors in the isolated spontaneously beating guinea-pig right atrium with a pA2 value of 6.6 relative to values of 6.2, 6.7 and 7.3 for cimetidine, ranitidine and tiotidine, respectively. Low affinities for histamine H1 (pA2 = 4.2), cholinergic (pA2 = 4.4) and beta adrenergic (pA2 = 3.8) receptors indicated that etintidine has a high degree of specificity for the H2-receptor. The other antagonists studied also exhibited low affinities for these receptors; however, relative to these compounds, etintidine demonstrated a somewhat greater affinity for cholinergic receptors. Etintidine also antagonized basal gastric acid secretion in the conscious gastric fistula rat and histamine, pentagastrin, carbachol, 2-deoxy-D-glucose and meal-stimulated gastric acid secretion in conscious gastric fistula and Heidenhain pouch dogs. After oral administration to conscious Heidenhain pouch dogs, ED50 values for the inhibition of near maximal gastric acid secretion stimulated by histamine were 7.1, 5.4, 0.74 and 0.69 mumol/kg for cimetidine, etintidine, ranitidine and tiotidine, respectively. Onset and duration of the gastric antisecretory activities of the four compounds were similar. The order of potency as histamine H2-receptor and gastric antisecretory antagonists was cimetidine less than etintidine less than ranitidine less than tiotidine. Based on the high degree of specificity for the H2-receptor and its potent gastric antisecretory activity, etintidine may prove to be a useful agent in the treatment of peptic ulcer disease.     

Prevention of aspirin-induced gastric mucosal injury by histamine H2 receptor antagonists: a crossover endoscopic and intragastric pH study in the dog

Histamine H2 receptor antagonists have been reported to protect the gastric mucosa of animals and humans against aspirin-induced damage. It is unclear, however, whether this protective effect can be observed at doses less than those needed to markedly inhibit gastric acid secretion. We have developed a single-dose endoscopic assay system of aspirin-induced gastric mucosal injury in normal conscious dogs. In this model, severe gastric mucosal injury and a decrease in the pH of the gastric luminal contents were consistently demonstrated 2 h after the oral administration of 100 mg/kg of aspirin. Pretreatment with three histamine H2 receptor antagonists (cimetidine, ranitidine, BMY-25271), prevented both of these effects in a dose-related manner. All three H2 receptor antagonists reduced gastric mucosal injury only at doses that were greater than those required to prevent the aspirin-induced decrease in gastric luminal pH or to inhibit histamine-stimulated gastric acid secretion in Heidenhain pouch dogs. Plasma levels of aspirin were not altered by histamine H2 receptor antagonism. These results indicate that acid inhibition is an important component of the mechanisms whereby histamine H2 receptor antagonists protect the gastric mucosa from aspirin-induced damage in the dog.     

Inhibition of gastric acid secretion in vivo and in vitro by a new calmodulin antagonist, CGS 9343B

The new calmodulin antagonist, CGS-9343B, was found to inhibit both histamine plus 3-isobutyl-1-methylxanthine and carbachol-induced [14C]aminopyrine accumulation in dispersed, fundic mucosal cells of rats. The IC50 value for CGS-9343B inhibition of histamine plus 3-isobutyl-1-methylxanthine-induced [14C]aminopyrine accumulation was 306 nM. The drug was more potent than the H2-histamine receptor antagonist, cimetidine (1128 nM), less potent than the nonspecific calmodulin antagonists, trifluoperazine and fenoctimine (IC50 = 40 and 224 nM, respectively), and equipotent with the H+, K+-adenosine triphosphatase inhibitor, omeprazole (365 nM). CGS-9343B showed an IC50 of 369 nM for carbachol-induced [14C]aminopyrine accumulation in dispersed mucosal cells. CGS-9343B must be added to cells before or simultaneously with acid secretagogues in order to be effective. The drug did not reverse previously stimulated secretion. Unlike trifluoperazine and fenoctimine, CGS-9343B had anticamodulin activity for inhibition of calmodulin-activated (Type I) phosphodiesterase in the same range of potency as observed for the inhibition of aminopyrine accumulation. In anesthetized rats and dogs the i.v. infusion of CGS-9343B did not block histamine plus pentagastrin-stimulated acid secretion. However, i.a. administration of CGS-9343B to anesthetized rats produced a significant inhibition of acid secretion. In vivo the order of potency was omeprazole greater than cimetidine much greater than CGS-9343B. These data provide evidence for involvement of calmodulin in the acid secretory process and suggest that the pursuit of selective calmodulin antagonists such as CGS-9343B may prove useful for understanding the regulation of the hydrogen ion secretory process.     

Isolated parietal cells: histamine response and pharmacology

Isolated, partially purified or enriched rat gastric mucosal parietal cells were shown to respond to histamine and other histaminic H2-receptor agonists as measured by an increased accumulation of [14C]aminopyrine. The response was temperature-dependent, related to parietal cell purity and inhibited selectively and reversibly by H2-receptor antagonists. H1-receptor antagonists noncompetitively inhibited histamine, carbamylcholine and dibutyryl cyclic AMP-stimulated aminopyrine accumulation. The affinity constants calculated for the H2-receptor agonists and antagonists were similar to those previously determined in the studies of activation and inhibition of adenylyl cyclase in enriched parietal cell preparations. The results strongly suggest that a correlation exists between the ability of histamine and its analogs to stimulate isolated rat parietal cell function and their ability to stimulate adenylyl cyclase activity. Potentiation of aminopyrine accumulation in the presence of histamine and carbamylcholine is due to specific receptor effects of each secretagogue.     

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)     

Histamine H2-receptor antagonists.

In summary, histamine initiates acid secretion by stimulating the H2 subtype histamine receptor on parietal cells. Cimetidine, rantidine, famotidine, and nizantidine are histamine H2-receptor antagonists that block this action of histamine, reducing gastric acid output and concentration under both basal and stimulated conditions. These agents are used for treatment and prevention of peptic and stress ulcers as well as for hypersecretory states. Because of their effectiveness and low incidence of side effects, H2-antagonists have largely replaced more traditional antiulcer regimens.     

Histamine H1 and H2 effects on gastric acid and pepsin, heart rate and blood pressure in humans

Gastric acid and pepsin secretion, heart rate and blood pressure were studied simultaneously during an infusion of histamine in eight patients with peptic ulcer or esophagitis. We found that histamine equally stimulated both acid and pepsin via H2 receptors. No evidence for any gastric H1 effect was found. Heart rate was increased modestly (12 beats/min) and this effect was reversed by diphenhydramine, an H1 antagonist, which did not by itself or in combination with the H2 antagonist cimetidine modify the hypotensive effect of histamine. The histamine effects in humans contrasts with those in the conscious dog where histamine inhibits pepsin secretion and strongly stimulates heart rate. The results emphasize major species and organ differences in both gastric and cardiac histamine effects.     

Effects of H2-receptor antagonists upon physiological acid secretory states in animals

The results reported in this paper indicate that representative H2-receptor antagonists are capable of maximally inhibiting gastric acid secretion in animals under the two general circumstances in which it occurs physiologically. Interdigestive or basal secretion was examined in chronic gastric fistula rats and food-stimulated secretion in vagally innervated, lesser curvature pouch dogs. The H2 antagonists studied and omeprazole, an inhibitor of the proton pump H+, K+-adenosine triphosphatase, also decreased pepsin secretion in rats, although not to the same maximal degree as acid secretion. Gastric emptying was increased by each H2 antagonist but only at high acid inhibitory doses. Omeprazole, in contrast, did not alter gastric emptying at a similar antisecretory dosage level. In dogs, a representative H2-receptor antagonist markedly inhibited food-stimulated acid secretion. These data suggest that the predominant effect of omeprazole and H2-receptor antagonists upon gastric function is to inhibit acid secretion and that H2-receptor antagonists may be capable of maximally inhibiting endogenous acid secretion in humans, as does omeprazole, if given under proper conditions.     

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.     

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.     

Inhibition of acid secretion in guinea pigs by tricyclic antidepressants: comparison with ranitidine and omeprazole

The antisecretory properties of imipramine on gastric secretion in guinea pig in comparison with other antisecretory agents was determined. In awake guinea pigs s.c. infusion of histamine (30 micrograms/kg/hr) increased acid and fluid secretion by 3- to 4-fold. When acid output peaked, a bolus administration of the tricyclic anti-depressant imipramine inhibited acid and fluid secretion. Imipramine and other agents, such as ranitidine and omeprazole, inhibited gastric secretion in a dose-dependent fashion. The most potent was the H2-antagonist ranitidine (IC50, 0.2-0.3 mumol/kg), followed by the gastric H-K-adenosine triphosphatase inhibitor, omeprazole (IC50, 0.5-0.6 mumol/kg). Imipramine (IC50 1-2 mumol/kg) was the least potent of the inhibitors. Both ranitidine and omeprazole could abolish acid secretion, but maximal inhibition with imipramine was 60% of initial. Promethazine (25 mumol/kg), an H1 antagonist, and atropine (12 mumol/kg), a muscarinic antagonist, inhibited gastric secretion by 40 to 50%. Imipramine and atropine also inhibited basal acid secretion. In dispersed gastric cells comparison between imipramine and omeprazole showed that imipramine was about 5-fold more potent than omeprazole in blocking histamine or dibutyryl cyclic AMP stimulation of aminopyrine accumulation. Imipramine probably acts as a protonophore by increasing the rate of proton-gradient dissipation rather than by interfering with the hydrogen-pump system because, in gastric membranes, imipramine was 20-fold less potent than omeprazole in inhibiting the gastric H-K-adenosine triphosphatase activity. These results suggest that imipramine administered s.c. in guinea pigs is a potent antisecretory drug. Its action may be due to a combination of anticholinergic and antihistamine H2 activities.     

Histamine H4 receptor mediates chemotaxis and calcium mobilization of mast cells

The diverse physiological functions of histamine are mediated through distinct histamine receptors. Mast cells are major producers of histamine, yet effects of histamine on mast cells are currently unclear. The present study shows that histamine induces chemotaxis of mouse mast cells, without affecting mast cell degranulation. Mast cell chemotaxis toward histamine could be blocked by the dual H3/H4 receptor antagonist thioperamide, but not by H1 or H2 receptor antagonists. This chemotactic response is mediated by the H4 receptor, because chemotaxis toward histamine was absent in mast cells derived from H4 receptor-deficient mice but was detected in H3 receptor-deficient mast cells. In addition, Northern blot analysis showed the expression of H4 but not H3 receptors on mast cells. Activation of H4 receptors by histamine resulted in calcium mobilization from intracellular calcium stores. Both G alpha i/o proteins and phospholipase C (PLC) are involved in histamine-induced calcium mobilization and chemotaxis in mast cells, because these responses were completely inhibited by pertussis toxin and PLC inhibitor 1-[6-[[17 beta-3-methoxyestra-1,3,5 (10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione (U73122). In summary, histamine was shown to mediate signaling and chemotaxis of mast cells via the H4 receptor. This mechanism might be responsible for mast cell accumulation in allergic tissues.     

Effects of four H2 histamine antagonists on bethanechol-stimulated acid and pepsin secretion in the dog

In five gastric fistula dogs, each of four H2-receptor antagonists was given (at doses roughly equal to the dose inhibiting histamine stimulation at 50%) as background infusion to graded doses of i.v. bethanechol. We measured acid and pepsin secretion and gastrin release. All four compounds noncompetitively inhibited acid secretion, reducing maximum acid outputs by 50 to 70%. Two compounds, tiotidine and cimetidine, shifted the bethanechol dose-response for pepsin secretion about 30% to the right at midpoint without reducing maximum output significantly, whereas the other two, ranitidine and metiamide, did not alter the dose-response. Dose-dependent gastrin release was unaffected by cimetidine, an imidazole compound, and augmented by tiotidine and ranitidine, the two nonimidazole compounds. Actions on pepsin and gastrin are thus not related to H2-receptor effects. The uniform effect of the four antagonists on acid secretion indicates an essential interaction between cholinergic and histamine effects on the parietal cell, although we could not distinguish between prereceptor, receptor and postreceptor sites for such interaction.     

Activity of selective dopamine DA1 and DA2 agonists and antagonists on experimental gastric lesions and gastric acid secretion

Selective dopamine (DA) DA1 and DA2 receptor agonists and antagonists were examined for their effects on cold-stress gastric lesions, 100% ethanol gastric lesions and basal gastric acid secretion. The selective DA1 agonist SKF 38393 [R-(+)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol.HCl] attenuated cold-stress and ethanol lesions and blocked basal acid output. The protective effects of SKF 38393 were reversed by the cyclooxygenase inhibitors indomethacin, sodium meclofenamate, by the peripherally selective DA receptor antagonist domperidone and by the tissue sulfhydryl blocker, N-ethylmaleimide. The DA1 antagonist, SCH 23390, worsened lesion formation and augmented gastric acid secretion. N-0437 [S-(-)-2-N-propyl-N-2-thienylethylamino)-5-hydroxytetralin], a DA2 agonist, was less potent than SKF 38393 at reducing experimental gastric lesion formation, but slightly more potent at attenuating gastric secretion. The DA2 antagonist, eticlopride, was inactive in all models. Based upon these in vivo data, we suggest that: 1) the gut DA receptor may be of the DA1 subtype and 2) that activation of gut DA1 receptors produces gastroprotection by several mechanisms, at least one of which is by reducing gastric acid output.     

Omeprazole: a new approach to gastric acid suppression

Omeprazole, one of a new group of antisecretory drugs, is a substituted benzimidazole that does not exhibit the anticholinergic or histamine H2 antagonistic properties of drugs such as cimetidine. This agent suppresses gastric acid secretion by inhibiting the proton pump mechanism, thereby blocking the final step of acid secretion. Omeprazole is significantly more effective than the histamine H2 receptor antagonists in eliminating acid secretion; thus, it may be beneficial in patients who are resistant to these agents. Omeprazole is indicated for severe erosive esophagitis, gastroesophageal reflux disease that does not respond to H2 receptor antagonists, and hypersecretory diseases such as Zollinger-Ellison syndrome and systemic mastocytosis. Because of the theoretic risk of carcinogenesis, short-term therapy is recommended, although long-term therapy is required for hypersecretory diseases.     

Interaction of prostaglandins and histamine with enzymes of cyclic AMP metabolism from guinea pig gastric mucosa.

Prostaglandins (PGE1, PGE2, PGA1) and histamine have opposing effects on gastric HCl secretion, but we found that both stimulate adenylate cyclase activity in cell-free membrane preparations of guinea pig gastric fundic mucosa. The stimulatory effect of prostaglandins was found in this study to be specific and dose-dependent over a concentration range from 10(-7) to 10(-4) M. In similar preparations from antral regions of guinea pig gastric mucosa, the adenylate cyclase was stimulated only by PGE1, PGE2, and PGA1 and not by histamine. Maximum stimulating doses of PGE1, PGE2, or PGA1, and of histamine had an additive effect on the adenylate cyclase activity from fundic gastric mucosa. Metiamide, a histamine H2-receptor antagonist, inhibited the stimulation of fundic mucosa adenylate cyclase by histamine but did not interfere with the stimulation by prostaglandins. Cyclic AMP phosphodiesterase activity of guinea pig gastric mucosa was unaffected by PGE1 and PGE2 or by histamine, and was slightly depressed by PGA1. These results indicate that histamine and prostaglandins stimulate two different adenylate cyclase systems both present in guinea pig gastric mucosa tissue. Therefore, the known inhibitory effect of prostaglandins on gastric acid secretion is not related to the interference with the stimulation of the histamine H2-receptor-sensitive adenylate cyclase complex by histamine nor do prostaglandins accelerate cyclic AMP breakdown by cyclic AMP phosphodiesterase to reduce cyclic AMP levels.     

Characterization of the H2 receptor antagonist and gastric acid antisecretory properties of Wy-45,727

Wy-45,727, structurally similar to ranitidine, was characterized in various models to define its gastric acid antisecretory potency and mechanism of action. In vitro it antagonized the histamine-induced 1) positive chronotropism in isolated guinea pig right atria (pA2 = 8.23, Schild coefficient +/- S.E.M. = 1.09 +/- 0.01), and 2) [14C]aminopyrine uptake in rat isolated gastric mucosal cells. It inhibited acid secretion in dogs (p.o.) prepared with innervated gastric pouches (ED50 = 0.2 mg/kg) and in the pylorus-ligated rat (ED50 = 0.43 mg/kg). ED50 values for ranitidine were 0.9 mg/kg (dog) and 9.97 mg/kg (rat). After an 18-hr pretreatment period with doses up to 300 mg/kg p.o., inhibition of acid secretion in the rat barely exceeded 50%, indicating that the duration of action of Wy-45,727 was not excessive. Wy-45,727 appears to be a selective histamine H2 receptor antagonist.     

Adrenergic beta receptors mediating submandibular salivary gland hypertrophy in the rat

Multiple injections of dobutamine, a selective adrenergic beta-1 receptor agonist, or isoproterenol, a nonselective beta receptor agonist, produced significant dose-dependent enlargement of the submandibular glands of male rats. The glandular enlargement induced by dobutamine or isoproterenol was characterized by significant increases in glandular protein and nucleic acid content and a marked increase in the RNA/DNA ratio. Metoprolol, a selective beta-1 receptor antagonist, significantly inhibited the glandular enlargement induced by dobutamine or isoproterenol and produced a parallel shift in the isoproterenol dose-response curve. Metoprolol also inhibited the increased protein and nucleic acid content induced by dobutamine or isoproterenol. Multiple injections of selective adrenergic beta-2 receptor agonists, terbutaline, fenoterol or salmefamole, failed to produce submandibular gland enlargement. These results indicate that adrenergic beta-1 receptors mediate submandibular gland hypertrophy in the rat.     

Histaminergic H1 and H2 receptors do not mediate cortisol release in response to naloxone in normal men

In order to evaluate the role of histamine as a possible mediator of the ACTH-cortisol response to naloxone, a specific opioid receptor antagonist, 12 normal men were treated with naloxone before and after the administration of dexchlorpheniramine and cimetidine, respectively H1 and H2 histamine receptor antagonists. Cortisol levels in the plasma were measured before and after drug injections. Naloxone significantly stimulated the secretion of cortisol in all subjects; the administration of dexclorpheniramine or cimetidine failed to modify this response. These data confirm the stimulatory effect of naloxone on cortisol secretion, but do not support the hypothesis that a histaminergic pathway mediates this response.