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 (3×10^?3 M), oxmetidine and compound SKF 93479 had a negative inotropic and chronotropic effect starting from concentrations of 3×10^?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.     

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

1. because they can enhance and/or suppress in their own right,
2. because these effects are similar to those of histamine itself
3. because mitogenic doses of PHA can release significant amounts of histamine from supposedly pure mononuclear cell preparations.

     

Endocrine effects of the H2-receptor antagonists cimetidine and ranitidine

This paper reviews investigations on the endocrine effects of two H2-receptor antagonists, cimetidine and ranitidine. Cimetidine has hyperprolactinaemic properties and interferes with the peripheral activity of the sexual hormone (DHT) and probably with the pituitary LH secretion. A possible effect on TSH and thyroid hormone secretion or peripheral metabolism is suggested. Ranitidine seems to have no central or peripheral effects (after both acute and chronic administration) on sexual hormones. High doses (300 mg i.v. bolus) of the drug induce a significant increase in prolactin basal levels, whereas no effects follow oral administration. The effects on PRL are sex-related and less marked than those obtained with cimetidine. The chronic administration of this drug does not affect basal or TRH-stimulated PRL levels. No effects were apparent on TSH serum levels after either oral or i.v. acute administration, whereas lower basal and TRH-stimulated T4 values were registered after chronic treatment. On the basis of these results, a possible interference of ranitidine on iodothyronine metabolism can be suggested.     

Histamine receptors on guinea-pig alveolar macrophages: Chemical specificity and the effects of H1- and H2-receptor agonists and antagonists

Various guinea-pig leucocytes were tested for their capacity to bind histamine coupled as a rabbit serum albumin conjugate (H-RSA) to formalised ox red cells. The percentage of rosette-forming target cells was directly related to the concentration of erythrocyte-bound H-RSA. Under optimal experimental conditions the numbers of rosettes varied from 60 to 81% for alveolar macrophages, 14 to 73% for peritoneal macrophages, 14 to 30% for blood monocytes, 27 to 48% for lymph node cells, 7 to 24% for blood lymphocytes and 0 to 29% for peritoneal and blood neutrophils. Virtually no histamine rosettes were formed with eosinophils or basophils.

Free histamine partially inhibited rosette formation by alveolar macrophages in a dose-dependent fashion from 10⁻³ to 10⁻⁵ mol/l, and complete inhibition was achieved by the H-RSA conjugate. In contrast, amines closely related to histamine such as L-histidine and the major histamine catabolites, imidazoleacetic acid, 1,4-methylhistamine, l-methyl-4-imidazoleacetic acid and N-acetylhistamine, had no inhibitory effect.

The histamine H1–receptor antagonists, mepyramine and chlorpheniramine, and the H1-receptor agonist, 2– (2–aminoethyl) thiazole, all inhibited rosette formation by alveolar macrophages in a dose-dependent fashion. However, the H2-receptor antagonists, burimamide and metiamide, and the H2-receptor agonists, Dimaprit and 4–methyl–histamine, were inactive.

These experiments suggest that (1) compared to other leucocytes, histamine receptors are particularly well expressed on the alveolar macrophage, (2) these receptors have a high degree of specificity for histamine in that other amines, closely related chemically, did not inhibit rosette formation, and (3) the binding of histamine to the alveolar macrophage membrane is H1- and not H2- receptor dependent.

     

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, mediatecoronary 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. After 4 min, blood pressure rapidly declined. All animals died within 12 min. Pretreatment with the selective H₁-receptor antagonist astemizol (5 mg/kg i.v.) delayed the onset of myocardial ischemia, arrhythmias and cardiac pump failure. After 10 min, however, left ventricular contractility and blood pressure steadily declined, leading to severe hypotension within 30 min. In the case of a pretreatment with astemizol (5 mg/kg i.v.) and the H₂-receptor antagonist famotidine (10 mg/kg i.v.), no relevant changes of cardiovascular function were seen compared to pretreatment with astemizol alone. It is therefore concluded that endogenous histamine, via H₁-receptor stimulation plays an important part during the early phase of systemic anaphylaxis, whereas mediators other than histamine are involved at a later stage of the process. Furthermore, H₂-receptor-mediated effects are of minor importance in cardiovascular manifestation of anaphylaxis. Pretreatment with H₂-receptor antagonists has no detrimental effects on cardiovascular function during anaphylactic reactions in guinea pigs underin vivo conditions.Supported by grant Fe250/1-1 from the Deutsche Forschungsgemeinschaft (DFG).     

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 mol/rat) and 4-MeH (0.4–0.8 mol/rat) significantly enhanced the pain threshold, whereas SF&F 91487 (0.8 mol/rat) had no effect, indicating that DIM antinociception is specifically due to its activity on histamine (HA) receptors. The H₂-antagonists CIM (0.8 mol/rat) and RAN (0.6 mol/rat) also enhanced the pain threshold, while FAM (0.03 mol/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 preferential localization of H2-receptor antagonists in the parietal cell

Conclusion The parietal cell labelling may well be related to the inhibition of acid secretion mediated by the H₂-receptor antagonists, and could indicate a site of action.     

Gastric emptying in non-responders to H2-receptor antagonists

Summary H₂-receptor antagonists are known to fail to increase the intragastric pH in some patients (so-called non-responders), and we have recently found a higher frequency of non-responders among cirrhotics. Since intragastric pH is also affected by gastric emptying, in the present study we determined the gastric emptying of 300 ml orange juice labelled with [^99mTc]-Solco Nanocoll using a gamma camera. Measurements were made over a period of 60 min in cirrhotic patients and controls without liver disease who either responded to 300 mg ranitidine or showed no response. The mean (±SD) liquid half-emptying time (T_1/2) was 26.3±17.5 min (range, 9–75 min) in responders (n=10), 20.9±8.6 min (range, 7–34 min) in non-responders (n=10), 19.4±19.2 min (range, 7–75 min) in cirrhotics (n=11), and 27±4.6 min (range, 17–33 min) in controls (n=9). In 19 of the 20 subjects gastric emptying was normal (T _1/2, <40 min). Since gastric emptying was not delayed in any of the non-responders, it would appear very unlikely that gastric motility plays a major role in the non-response to H₂-receptor antagonists.Abbreviations MBq mega-Becquerel - SD standard deviation - Tc technetium - T_1/2 Half-emptying time     

Prevention of acid aspiration by H2-receptor antagonists

Summary Cimetidine, a histamine H₂-receptor-antagonist, was administered either as a single 400 mg dose perorally 10–12 h before operation, or in a 400 mg dose perorally 10–12 h before operation plus 200 mg intravenously 1–2 h before operation, in 63 patients awaiting general elective surgery. Distribution of patients showed a significantly greater number of patients with a pH >2.5 in cimetidine groups, as compared to controls only, if the whole time of anaesthesia is taken into consideration. Between the two cimetidine regimens there was no statistically significant difference. These findings suggest that cimetidine is not necessary as a routine pre-operative medication in general elective surgery.     

Histamine release with intravenous narcotics: Protective effects of H1 and H2-receptor antagonists

Summary High dose narcotic anesthesia with fentanyl or morphine is not associated with significant direct myocardial depression. Morphine is reported to produce arteriolar dilatation and a decrease in SVR (probably due to histamine release) while fentanyl is not. Studies were undertaken to determine if morphine or fentanyl caused histamine release; if such a release correlated with hemodynamic changes, and if H₁ and H₂ antagonists could provide protection. In a randomized double blind study of 40 patients in 4 groups, patients who received morphine (1 mg/kg) demonstrated significant increases in plasma histamine (880±163 to 7,437±2,684 pg/ml–p<0.01) accompanied by an increase in CI (2.4±0.2 to 3.0±0.2 l/min/m²–p<0.01) and decreases in (88±4 to 61±4 torr–p<0.01) and SVR (15.5±1 to 9.0±1 torr-l-min^–1 p<0.01). The prior administration of H₁ (dyphenhydramine 1 mg/kg) and H₂ (cimetidine 4 mg/kg) antagonists provided significant protection (SVR 17.4±1 to 14.6±1 torr-l-min^–1–p<0.05) although histamine increased comparably (1,059±22 to 7,653±4,242 pg/ml–p<0.05). In a separate study, seven patients receiving fentanyl 50 µg/kg showed no histamine changes (935±51 to 685±51 pg/ml) and no significant hemodynamic response. Eight patients receiving morphine 1 mg/kg again showed significant increases in plasma histamine (880±163 to 7,480±2,230 pg/ml–p<0.05) which collelated with the decrease in SVR (r=0.81). These data demonstrate that morphine releases histamine in amounts which correlate with the hemodynamic changes seen. Prior administration of H₁ and H₂ histamine antagonists provide significant protection — more so than either alone. Fentanyl produced no histamine release which may account for much of the cardiovascular stability reported with this drug.     

Effect of some new H2-receptor antagonists on gastrointestinal motility

Inflammation Research - Some new histamine H2-receptor antagonists were tested for their effects on gastrointestinal motility. Ranitidine was found to possess definite stimulatory effects which...     

Central nervous system effects of H1-receptor antagonists in the elderly.

BACKGROUND: The potential adverse central nervous system effects of H1-receptor antagonists have not been optimally studied in the elderly. OBJECTIVE: We hypothesized that newer H1-receptor antagonists such as cetirizine and loratadine would cause less central nervous system dysfunction than the older H1-receptor antagonists diphenhydramine and chlorpheniramine in this population, as they do in younger subjects. METHODS: We performed a randomized, double-blind, single-dose, placebo-controlled, 5-way crossover study in 15 healthy elderly subjects (mean age 71 +/- SD 5 years). On study days at least 1 week apart, they received cetirizine 10 mg, loratadine 10 mg, diphenhydramine 50 mg, chlorpheniramine 8 mg, or placebo. Outcome measures, recorded before and 2 to 2.5 hours after dosing were latency of the P300 event-related potential in which increased latency reflects a decreased rate of cognitive processing, visual analogue scale for subjective somnolence, and histamine skin tests for measurement of peripheral H1-blockade. RESULTS: The changes in P300 following each treatment yielded variances that were not equal (P > .05), precluding usual statistical analysis of the means. These variances were ranked: chlorpheniramine > diphenhydramine > loratadine > placebo > cetirizine. The rank of mean differences in the visual analogue scale increase from pre-dose baseline was: diphenhydramine > chlorpheniramine > cetirizine > loratadine > placebo. All H1-receptor antagonists suppressed the histamine-induced wheal and flare significantly compared to baseline. CONCLUSION: In the elderly, the new H1-receptor antagonists cetirizine and loratadine are less likely to cause adverse central nervous system effects than the old H1-antagonists chlorpheniramine or diphenhydramine, but this requires confirmation using additional objective tests of central nervous system function.     

Direct effects of second-generation H1-receptor antagonists on the activation of human basophils

The present study was performed to investigate the putative suppressive effects of H₁-receptor antagonists (HRA) of the second generation (astemizole (AS), cetirizine (CT), loratadine (LO), oxatomide (OX) and terfenadine (TF)) on the mediator release from human basophils activated by two classical stimuli. Anti-IgE-mediated histamine release was inhibited in a dose-dependent fashion by TF (maximum inhibitory value: 33.8±7.6%, 100 μM,n=7), whereas the other HRA exhibited weaker activity. The anti-IgE-induced LTC₄ production was strongly suppressed by TF, LO and OX (92.4±6.3%, 90.8±6.0% and 88.5±5.6%, 100 μM,n=4−5), while As was less active (56.4±4.1%, 100 μM,n=5). Histamine release induced by incubation with grass pollen antigen (0.01%) was inhibited by TF (40.7±4.1%, 50 μM,n=4), but the other HRA showed only low activity. The present findings suggest that some HRA might exhibit direct inhibitory effects on activation of IgE-receptor bearing cells.

     

H2-receptor antagonists protect against aspirin-induced gastric lesions in the rat

Gastric mucosal lesions were produced in rats by dosing orally with aspirin, 300 mg/kg. Predosing orally with either ranitidine or cimetidine inhibited this lesion formation; the respective ED₅₀ values were 0.8 and 3.9 mg/kg p.o. Oral ranitidine also inhibited lesion formation in the presence of exogenous 160 mM HCl, with an ED₅₀ value of 23.2 mg/kg p.o. Subcutaneous injection of ranitidine inhibited the formation of aspirin-induced lesions both in the presence and in the absence of excess HCl. The ED₅₀ values were respectively 3.4 and 0.9 mg/kg s.c. Mepyramine maleate (5 mg/kg p.o.) alone had no effect on gastric lesion formation, and did not influence the level of inhibition produced by ranitidine either in the absence or presence of exogenous acid.     

Second-generation H1-receptor antagonists.

The second-generation H1-receptor antagonists do not penetrate into the central nervous system as readily as the first-generation H1-receptor antagonists do. They bind preferentially to peripheral rather than central H1-receptors. They cause no more sedation than placebo does. These medications differ considerably from one another in some aspects of basic pharmacology and in pharmacokinetics and pharmacodynamics. An understanding of these differences will facilitate their optimal clinical usage. The second-generation H1-receptor antagonists are replacing the first generation H1-receptor antagonists in the symptomatic treatment of allergic rhinoconjunctivitis, and in relieving pruritus in patients with urticaria. They have a mild beneficial effect in patients with chronic asthma. They have not supplanted the first generation H1-receptor antagonists in atopic dermatitis treatment or as adjunctive treatment of pruritus and other symptoms in patients with anaphylaxis.