Cardiovascular effects of H2-receptor antagonists

The type II histamine receptor antagonists, cimetidine and ranitidine, widely used in treatment of peptic ulcer disease have been reported to cause bradycardia. To evaluate the cardiovascular effects of H2 antagonists nineteen healthy volunteers were entered into a double-blind crossover comparison of cimetidine 300 mg qid, ranitidine 150 mg bid, and placebo. Subjects ingested study medicine for 7 days prior to being tested by the Bruce Exercise Test. Heart rate, blood pressure, oxygen consumption, expiratory volume, and fractional expiration of CO2 and O2 were measured at rest, exercise and recovery. A plasma sample for determination of cimetidine and ranitidine levels were obtained prior to the exercise period. Multivariate analysis and paired t test revealed no significant differences for the cardiovascular or pulmonary variables. However, in 5 subjects, the heart rate at 25% maximum VO2 was depressed 8% (P less than or equal to 0.03). This effect in a small percentage of the population suggests that further studies are needed to determine if subpopulations are affected.     

Cardiac effects of the new H2-receptor antagonists

A series of new H2-receptor antagonists were tested for their effects on different isolated heart preparations. In the guinea-pig atria and papillary muscle the inhibitory effect on histamine H2-receptors was evaluated. In the perfused rabbit heart and in strips of human atria the effect of the H2-antagonists on the spontaneous or electrically-stimulated contractions was evaluated. In the first two preparations some main quantitative differences were pointed out, tiotidine and compound SKF 93479 being the most potent antagonists, cimetidine, metiamide and ranitidine the less effective. In the rabbit heart and in human atria results were quite different: cimetidine and ranitidine were virtually ineffective up to the maximum concentration tested (3 x 10(-3) M), oxmetidine and compound SKF 93479 had a negative inotropic and chronotropic effect starting from concentrations of 3 x 10(-6)-10(-5) M. On the basis of the behaviour of other compounds endowed with negative cardiac effects (propranolol, anaesthetic-like compounds, verapamil) and of that of compounds capable of counteracting the effect of oxmetidine (increased concentration of calcium ions and isoproterenol) it was hypothesized that oxmetidine may interfere in the transport of calcium ions. Our data emphasize the importance of the different structure of the H2-antagonists in determining non-specific effects absolutely independent of the primary action that is the H2-receptor blockade.     

Effect of some new histamine H2-receptor antagonists on the guinea-pig papillary muscle

Summary Several histamine H₂-receptor antagonists (cimetidine, ranitidine, oxmetidine and tiotidine) were tested for their activity on the papillary muscle of the guinea pig stimulated by histamine. All of the compounds exerted a competitive antagonism against histamine the order of potency being tiotidine > oxmetidine > ranitidine > cimetidine. Oxmetidine was the only drug which at high concentrations (10^–6 M) decreased the maximum response of histamine probably because of non specific effects of the molecule already described in the literature. As it was expected, the H₁-receptor antagonist, mepyramine, exerted a non-competitive antagonism.     

Inhibitory effects of H2-receptor antagonists on platelet function in vitro.

To evaluate in vitro inhibitory effects of four types of histamine H2-receptor antagonist (H2-receptor antagonists), famotidine, roxatidine, cimetidine and ranitidine, on platelet function, we examined aggregating potency and P-selectin levels with agonist-induced aggregation. Ranitidine and cimetidine inhibited, in concentration of 0.35 mM, the secondary aggregation induced by 5 microM adenosine diphosphate (ADP), the aggregation induced by 1 microg/mL collagen and 3 microM arachidonic acid. All of H2-receptor antagonists inhibited, in concentration of 1.4 mM, the aggregation induced by ADP, collagen and arachidonic acid. Ranitidine and cimetidine reduced markedly, in same concentration, P-selectin levels after induction of aggregation by 5 microm ADP, 1 microg/mL collagen and 3 microM arachidonic acid. When classified by the strength of inhibitory action, ranitidine and cimetidine were strong, followed by famotidine and roxatidine. It is considered that inhibitory effects of H2-receptor antagonists on platelet function are weaker than those of acetylsalicylic acid (ASA), since ASA inhibited platelet aggregation in concentration of 100 microM. No relationship was observed between inhibitory effects of H2-receptor antagonists on platelet aggregation induced by above agonists and the presence or absence of imidazole ring in the chemical structure.     

The effects of histamine H2-receptor antagonists on PHA induced lymphocyte proliferation

Histamine H2-receptor antagonists must be used with caution to define the pharmacology of histamine effects on lymphocyte mitogenesis induced by PHA, because they can enhance and/or suppress in their own right, because these effects are similar to those of histamine itself, because mitogenic doses of PHA can release significant amounts of histamine from supposedly pure mononuclear cell preparations.     

Comparative effects of H2-receptor antagonists on drug interaction in rats

The most widely used H2-receptor antagonist, cimetidine, is known to interact with cytochrome P-450 drug-metabolizing enzymes and, therefore, interacts with other drugs which may be administered concurrently. In this study, effects of three H2-receptor antagonists, famotidine, ranitidine, and L-643,441, on drug interaction were studied using cimetidine as a positive control. Cimetidine and L-643,441, but not famotidine or ranitidine, prolonged antipyrine elimination and hexobarbital-induced sleeping time. The effect of cimetidine and famotidine on the anticoagulant effect on warfarin in rats was also investigated. Pretreatment of rats with cimetidine produced a significant depression of plasma prothrombin complex activity, whereas concomitant administration of famotidine did not alter the plasma prothrombin complex activity. Whereas cimetidine is known to impair the elimination of a number of drugs metabolized by microsomal mixed function oxidase enzyme systems, the results of the present study suggest that famotidine and ranitidine have little effect on these enzyme systems.     

Effects of histamine H1- and H2-receptor antagonists on cardiovascular function during systemic anaphylaxis in guinea pigs.

The heart is a target organ of anaphylaxis. In isolated perfused hearts, an anaphylactic reaction is characterized by arrhythmias, coronary constriction and severe impairment of ventricular contractile force. Various mediators such as PAF, thromboxane A2 and leukotrienes are responsible for anaphylactic coronary constriction and negative inotropic effects. The cardiac effects of anaphylactic histamine release are related to the stimulation of two antagonistic receptor types. Histamine induces atrioventricular conduction delay and constriction of the epicardial coronary vessels via H1-receptor stimulation. H2-receptors, however, mediate coronary vasodilation and an increase in heart rate and myocardial contractility. It may therefore be concluded that administration of histamine H2-receptor antagonists is disadvantageous. During anaphylactic states, the cardiodepressive effects of the other mediators of anaphylaxis are unmasked, resulting in a sustained coronary constriction and impairment of myocardial contractility. To verify this speculation, we investigated the effects of H1- and H2-receptor antagonists on cardiovascular function of guinea pigs during systemic anaphylaxis. In guinea pigs, sensitization was produced by subcutaneous application of ovalbumin. Fourteen days after sensitization, the effects of an intravenous infusion of ovalbumin were tested in the anesthetized artificially ventilated guinea pigs. The renewed administration of the antigen induced severe cardiac dysfunction. Within a few minutes, cardiac output markedly decreased and left ventricular end-diastolic pressure increased significantly, indicating left ventricular pump failure. In the same time range, ECG recordings uniformly showed signs of acute myocardial ischemia. In addition, arrhythmias occurred in terms of an atrioventricular block.(ABSTRACT TRUNCATED AT 400 WORDS)     

Antisecretory effects of two new histamine H2-receptor antagonists

N-(3-[3-(1-Piperidinylmethyl)phenoxy]propyl)acetoxyaceta mide hydrochloride (Hoe 760) and N-(3-[3-(1-piperidinylmethyl)phenoxy]propyl)glycolamine hydrochloride (Hoe 062) are highly specific H2-receptor antagonists. The compounds are equipotent after intragastrical or intravenous administration. The antagonists inhibited gastric acid secretion in the rat induced by all stimuli tested, carbachol, desglugastrin and histamine. In the Heidenhain pouch dog whose gastric acid secretion was stimulated by food or histamine the two receptor blockers proved to be 4-6 times more potent inhibitors than cimetidine.     

Potential histamine H2-receptor antagonists. 2. N-alpha-Guanylhistamine.

The agonist molecule, histamine, has been used as a starting point for the design of potential H2-receptor antagonists. Converting the side-chain amino group into a guanidine yielded the first histamine H2-receptor antagonist, Nalpha-guanylhistamine. Antagonism of H2 receptors was demonstrated by the inhibition of histamine-stimulated gastric acid secretion in the rat at high dose levels (approximate ID50 800 MUmol/kg, iv) and by the inhibition of histamine-stimulated tachycardia of guinea-pig right atrium (pA2 equals 3.9). Guanylhistamine behaves as a partial agonist at histamine H2 receptors.     

Biliary excretion of H2-receptor antagonists

Summary The biliary excretion of ranitidine and famotidine has been studied using percutaneous biliary drainage in patients with complete extrahepatic biliary obstruction due to pancreatic carcinoma. Following 50 mg ranitidine i. v. 0.7 to 2.6% of the dose was recovered in bile collected over 24 h. At steady state (300 mg ranitidine/d po) a similar amount (0.3 to 1.0% of daily dose) was excreted by this route (n = 3). Following single i.v. (20 mg) and oral (40 mg) doses of famotidine (n = 2), even lower percentages (0.1% and 0.4%, respectively) were recovered in the 24 h bile. This negligible biliary excretion cannot account for the so-called second peak phenomenon observed in some individuals following a single dose of an H2-receptor antagonist.     

Potential histamine H2-receptor antagonists. 4. Benzylhistamines

As part of our studies aimed at designing histamine H2-receptor antagonists, the effect on histaminergic activity of introducing benzyl substituents at various positions in the histamine molecule is described. New synthetic methods are reported for the novel 4-benzyl-, beta-benzyl- and 4,N tau-dibenylhistamines and the reported 2-benzylhistamine. The novel N tau-benzylhistamine was synthesized by the versatile route reported by us for the synthesis of N tau-methylhistamine. These benzylhistamines, together with the reported N alpha- and N pi-benzylhistamines, were tested for agonist and antagonist activity at both H1 and H2 receptors. The results obtained indicate that introduction of a benzyl group into the histamine molecule causes a marked reduction in H1- or H2-agonist activity, and none of the compounds showed consistent antagonist activity. Evidently, the sterically demanding benzyl substituent is not easily accommodated in the agonist binding mode and is unable to locate a lipophilic receptor region for potential hydrophobic binding.     

Central effects of histamine H2-receptor agonists and antagonists on nociception in the rat

The effects of intracerebroventricular injection of histamine H2-receptor agonists (4-methylhistamine, 4-MeH; dimaprit, DIM), H2-antagonists (cimetidine, CIM; ranitidine, RAN; famotidine, FAM) and of the DIM chemical analogue SK&F 91487 on hot-plate latency in rats were examined. Both DIM (0.4-0.8 mumol/rat) and 4-MeH (0.4-0.8 mumol/rat) significantly enhanced the pain threshold, whereas SF&F 91487 (0.8 mumol/rat) had no effect, indicating that DIM antinociception is specifically due to its activity on histamine (HA) receptors. The H2-antagonists CIM (0.8 mumol/rat) and RAN (0.6 mumol/rat) also enhanced the pain threshold, while FAM (0.03 mumol/rat) did not modify pain latency. When injected before 4-MeH, FAM reduced the antinociceptive effect of 4-MeH. These findings suggest that the antinociceptive activity of CIM and RAN is not related to specific blockade of H2-receptors and that the activation of HA-H2-receptors is inhibitory to nociception.     

The management of refractory gastric ulcer using H2-receptor antagonists.

BACKGROUND: There is little information on the natural history of refractory gastric ulcer, defined as non-healing on cimetidine > or = 1 g daily given for at least 3 months. SETTING: A district general hospital serving an industrial population. METHODS: Patients with refractory gastric ulcer had their treatment extended and/or the dose increased, and upon healing the majority were put on maintenance treatment with cimetidine 400 mg nightly or 1 g daily and their progress was followed. RESULTS: Of 536 patients with gastric ulcer, 74 (14%) were refractory. Fifty of the 74 (68%) refractory gastric ulcer patients were refractory on their very first course of cimetidine. They had no distinguishing demographic features. Healing occurred in 62 patients (84%) after a mean treatment period of 11.1 months; 28 patients required cimetidine > or = 2 g daily. Eleven of 23 (48%) patients relapsed on maintenance with cimetidine 400 mg compared with seven of 24 (29%) on 1 g daily. A total of 22 out of 62 (35%) relapsed; nine had a second refractory recurrence but none thereafter. Eleven patients were operated upon, seven for failed medical treatment. Only two patients eventually proved to have malignant disease. CONCLUSIONS: Refractory gastric ulcer is uncommon, transient and rarely malignant. Most patients can be satisfactorily managed medically.     

Role of H2-receptor antagonists in the treatment of duodenitis.

Non-erosive duodenitis is an ulcer-independent disorder, the pathogenesis of which is still unclear but apparently unrelated to gastric hyperacidity. However, antisecretory agents such as H2-blockers can be effective not only in relieving dyspeptic symptoms but also in promoting endoscopic healing or improvement. In this respect conflicting data are reported with cimetidine while promising, although preliminary, results were obtained with ranitidine and with nizatidine. Nizatidine seems especially effective when administered at a dose of 150 mg b.i.d., a regimen providing moderate, but continuous acid inhibition throughout a 24 hour period.     

The antianaphylactic action of histamine H2-receptor agonists in the guinea-pig isolated heart.

The effects of histamine and of H1- and H2-receptor agonists on the response to specific antigen were studied in isolated hearts taken from actively sensitized guinea-pigs. Histamine and H2-receptor agonists (dimaprit, impromidine) dose-dependently decrease the positive chronotropic and inotropic effects, and the severity of arrhythmias evoked by the challenge of sensitized hearts with specific antigen. Nordimaprit and the selective H1-receptor agonist 2-pyridyl-ethyl-amine (2-PEA) did not modify the patterns of cardiac anaphylaxis. The positive inotropic and chronotropic responses of the isolated heart to exogenous histamine appear to be partly reduced in the presence of dimaprit. The H2-receptor agonists decrease the amount of histamine released during cardiac anaphylaxis which is increased by cimetidine, while nordimaprit and PEA were ineffective, indicating an inhibitory function afforded by H2-receptors in cardiac anaphylaxis.     

Potential histamine H2-receptor antagonists. 3. Methylhistamines.

Syntheses are described for all the mono- and some di- and trimethylhistamines. New methods are given for the known Npi, Ntau-, Nalpha-, 2-, and 4-methylhistamines and for the novel compounds, beta-methyl-, 4,Nalpha-dimethyl-, and 4,Nalpha,Nalpha-trimethylhistamines. Agonist activities are reported for stimulation of histamine H1 (guinea-pig ileum) and H2 (rat gastric acid secretion) receptors. H2-Receptor agonist activities indicate that a methyl group is more readily accommodated at the 4 and Nalpha positions than elsewhere in the histamine molecule and that receptor binding is substantially retained with a methyl substituent in these positions. Thus, for the design of potential antagonists, two sites are identified as being worthwhile exploring for the introduction of lipophilic substituents.     

Inhibitory histamine H2-receptor in the guinea-pig urinary bladder

The histamine H2-receptor in the guinea-pig urinary bladder was characterized by determining the effects of histamine and impromidine on contractions induced by electrical transmural stimulation (ETS). The contractile responses to ETS (0.5 ms, 15 V, for 15 s) at frequencies of 1 to 30 Hz were abolished by treatment with tetrodotoxin, and were partly inhibited by scopolamine, indicating that the ETS-induced contraction has scopolamine-sensitive and -resistant components. Histamine and impromidine inhibited the scopolamine-resistant contraction induced by ETS but not the ETS-induced scopolamine-sensitive contraction and nicotine- and acetylcholine (ACh)-induced contractions. The inhibitory effects of histamine and impromidine were antagonized by cimetidine, but not by diphenhydramine and mepyramine. Thus, the inhibitory effect of histamine may be mediated through H2-receptors. As impromidine did not affect the tetrodotoxin-sensitive and Ca2+-dependent ETS-evoked release of ACh and noradrenaline (NA) from the isolated urinary bladder preloaded with [3H]choline and [3H]NA, respectively, the H2-receptor may not be involved in the cholinergic and adrenergic mechanisms. These results indicate that histamine H2-receptors are present in the guinea-pig urinary bladder. The H2-receptor located on non-cholinergic excitatory neurons may be involved in the inhibitory action produced by histamine.     

The effect of allosteric antagonists in modulating muscarinic M2-receptor function in guinea-pig isolated trachea.

1. We have assessed the influence of a range of synthetic cationic polypeptides with putative inhibitory actions at prejunctional muscarinic M2-receptors on electrical field stimulation-induced contraction of guinea-pig isolated tracheal preparations. Electrical field stimulation of epithelium-denuded guinea-pig trachea resulted in frequency-dependent contractile responses. As expected, tracheal smooth muscle sensitivity to electrical field stimulation was increased in tissues pretreated with the muscarinic M2-receptor antagonist, gallamine. In contrast, gallamine did not significantly alter the contractile potency to acetylcholine. 2. Unlike gallamine, the synthetic cationic polypeptides, poly-L-arginine, poly-L-lysine, poly-D-lysine, the cationic dye ruthenium red and the anionic polysaccharide, heparin, failed to increase significantly tracheal smooth muscle sensitivity to electrical field stimulation. 3. Poly-L-arginine, ruthenium red and heparin had no effect on the contractile response to exogenously applied methacholine. 4. These data are consistent with the concept that in guinea-pig tracheal smooth muscle, gallamine is an allosteric antagonist of guinea-pig tracheal muscarinic M2-receptors, whereas the various cationic polypeptides and the polyanion, heparin, are not.     

Effects of H2-receptor antagonists on ethanol metabolism in Japanese volunteers.

The effects of H2-receptor antagonists (cimetidine, ranitidine, and famotidine) on ethanol metabolism were investigated. Neither in aldehyde dehydrogenase (ALDH)-1 deficient subjects nor in those with normal ALDH-1, did the three H2-receptor antagonists and placebo differ in their effects on the pharmacokinetic parameters of ethanol (i.e. peak time (tmax), metabolic rate (k0), peak serum concentration (Cmax), volume of distribution (V) and area under the concentration-time curve (AUC). The AUC of acetaldehyde was slightly but significantly (P less than 0.05) larger only after treatment with cimetidine. Cmax and tmax of acetaldehyde were unchanged.