Histamine H2 Blockers Research Articles

Brain mast cells act as an immune gate to the hypothalamic-pituitary-adrenal axis in dogs.

Mast cells perform a significant role in the host defense against parasitic and some bacterial infections. Here we show that in the dog, degranulation of brain mast cells evokes hypothalamic-pituitary-adrenal responses via histamine release. A large number of mast cells were found in a circumscribed ventral region of the hypothalamus, including the pars tuberalis and median eminence. When these intracranial mast cells were passively sensitized with immunoglobulin E via either the intracerebroventricular or intravenous route, there was a marked increase in the adrenal cortisol secretion elicited by a subsequent antigenic challenge (whether this was delivered via the central or peripheral route). Comp.48/80, a mast cell secretagogue, also increased cortisol secretion when administered intracerebroventricularly. Pretreatment (intracerebroventricularly) with anti-corticotropin--releasing factor antibodies or a histamine H(1) blocker, but not an H(2) blocker, attenuated the evoked increases in cortisol. These data show that in the dog, degranulation of brain mast cells evokes hypothalamic-pituitary-adrenal responses via centrally released histamine and corticotrophin-releasing factor. On the basis of these data, we suggest that intracranial mast cells may act as an allergen sensor, and that the activated adrenocortical response may represent a life-saving host defense reaction to a type I allergy.

Acute Effects of Substance P and Calcitonin Gene-Related Peptide in Human Skin – A Microdialysis Study

Upon activation nociceptors release neuropeptides in the skin provoking vasodilation and plasma protein extravasation in rodents, but only vasodilation in humans. Pivotal peptides in the induction of neurogenic inflammation comprise calcitonin gene-related peptide and substance P, the latter being suggested to act partly via degranulation of mast cells. In this study substance P and calcitonin gene-related peptide-induced vasodilation, protein extravasation, histamine release, and sensory effects were investigated simultaneously in human skin by dermal microdialysis. The vasodilatory prostaglandin E(2) and the mast cell activator codeine served as positive controls. Substance P and calcitonin gene-related peptide applied intradermally via large cut-off plasmapheresis capillaries induced dose-dependent local vasodilation, but only SP provoked protein extravasation in concentrations greater than 10(-9) M. Substance P-induced (10(-8)-10(-6) M) protein extravasation was not accompanied by histamine release and was unaffected by cetirizine (histamine H1 blocker, 200 microg per ml). Only the highest concentration of substance P (10(-5) M) induced significant histamine release. Neither neuropeptide caused any axon reflex erythema or any itch or pain sensation, whereas mast cell degranulation by codeine dose dependently provoked itch, flare, protein extravasation, and histamine release. In human skin calcitonin gene-related peptide and substance P induce vasodilation by a mechanism not involving histamine. No evidence for neuropeptide-induced activation of nociceptors was obtained. Our results suggest that endogenous calcitonin gene-related peptide and substance P have no acute sensory function in human skin. The lack of neurogenic protein extravasation in humans can most probably be attributed to low local concentrations of this neuropeptide still sufficient to exert trophic and immunomodulatory effects (10(-11) M), but too low to induce protein extravasation (10(-8) M) or even mast cell degranulation (10(-5) M). J Invest Dermatol 115:1015-1020 2000

Rapid symptom relief in rhinitis

In some patients, symptoms of allergic rhinitis can be severe and therefore rapid relief is required. There are many treatment options for allergic rhinitis but histamine H1 blockers and topical corticosteroids represent the first-line treatment. Although the latter drugs are usually very effective on nasal symptoms, their onset of action is around 24 h. Thus drugs that are more rapidly effective are of interest. Recently 400 French specialists (in Allergy, ENT and Pneumology) met together to define the criteria for selecting a drug for the treatment of rhinitis. Twelve criteria were proposed and rapid onset of action (less than 24 h) was among the foremost designated criteria. In the first trial, a comparison of mizolastine (10 mg once daily [od]) with cetirizine (10 mg od) and placebo was carried out in the management of seasonal allergic rhino-conjunctivitis (SAR) with special focus on onset of action. A total of 375 patients were included in this European multicentric, randomized, parallel group and placebo-controlled study. By comparison to placebo, both cetirizine and mizolastine reduced significantly nasal and ocular symptoms during the 28-day follow-up trial. The percentage of responders ranged from 40% in the placebo group to 55% in the mizolastine group and 53% in the cetirizine group. Both active drugs were effective from the first intake with a rapid onset within 2 h. However, mizolastine was more rapidly and more profoundly effective than cetirizine during the first 12 h. A second trial included 257 patients suffering from perennial allergic rhino-conjunctivitis (PAR) in a 4-week double-blind placebo-controlled multicentric study. During the study, patients recorded, using a diary card, ocular and nasal symptoms, including nasal blockage. The mean values of nasal score between day 1, 14 and 28 in the mizolastine group were statistically significantly lower than those in the placebo group. The mean values of ocular score showed a statistical difference in recordings between day 1 and day 14 in favour of the mizolastine group. Mizolastine was an effective drug both in SAR and PAR with a rapid onset of action. Mizolastine relieved symptoms more effectively than cetirizine (SAR) and placebo (SAR and PAR) at the beginning of treatment.

Histamine release and contrast media—induced renal vasoconstriction

The authors' purpose was to investigate the role of histamine release causing renal vasoconstriction induced by application of contrast media, an important element in contrast medium-induced nephrotoxicity. Isometric contractions in rabbit segmental renal arteries stimulated with KCl and increasing concentrations of the ionic contrast medium diatrizoate and the nonionic agents iomeprol and iodixanol were studied both with and without increasing concentrations of the histamine H1 and H2 blockers diphenhydramine and cimetidine. Histamine concentrations after contrast medium application were determined. Contrast-induced, dose-dependent, reversible renal artery contractions of 27%, 4.5%, and 5% of the control KCl contraction were found for diatrizoate, iodixanol, and iomeprol respectively. Those induced by the ionic contrast medium were statistically significantly higher (P < .01). Contractions were partially inhibited by diphenhydramine (49%) but not by cimetidine. Significant elevation of histamine concentrations (P < .05) was detected only after stimulation with diatrizoate but not with nonionic agents. Ionic contrast medium induces histamine release leading to renal vasoconstriction, which can be partly blocked by H1 blockers. Histamine has no effect on renal vasospasm induced by nonionic contrast media.

Lateral hypothalamic injection of GABA(A) antagonist induces gastric vagus-mediated hypocalcemia in the rat.

The involvement of lateral hypothalamic area (LHA) neurons in the regulation of blood calcium homeostasis was investigated in unanesthetized rats. The microinjection of the gamma-aminobutyric acid A receptor antagonist bicuculline methiodide (BM, 4-40 ng x 0.5 microl(-1) x 5 min(-1)) into the LHA decreased the blood concentration of ionized calcium. Total serum calcium also decreased after the BM injection. This hypocalcemic effect was eliminated by a bilateral vagotomy of the gastric branches. An intravenous injection of atropine methyl bromide (a muscarinic antagonist), nadolol (a beta-adrenergic blocker), or ranitidine (a histamine H2 blocker) suppressed the BM-induced hypocalcemia, whereas phenoxybenzamine (an alpha-adrenergic blocker) proved to be ineffective. Although the intra-LHA injection of BM increased the serum gastrin, which is known to have a hypocalcemic effect, neither secretin nor somatostatin (gastrin-release inhibitors) blocked the hypocalcemic response. These results suggest that the hypocalcemia observed after the excitation of LHA neurons was mediated by muscarinic, beta-adrenergic, and histamine H2 receptors through the gastric vagus.

Involvement of tachykinin receptors in oedema formation and plasma extravasation induced by substance P, neurokinin A, and neurokinin B in mouse ear.

The involvement of tachykinin receptors in skin inflammation induced by substance P (SP), neurokinin A (NKA), and neurokinin B (NKB) was investigated in mouse ears. Intradermal injection of tachykinins (0.1-100 pmol/site) into the ear skin produced oedema formation. RP 67580 (ED50: 0.34 mg/kg, i.v.) and SR 140333 (ED50: 0.19 mg/kg, i.v.), the non-peptide NK1 receptor antagonists, inhibited SP-induced oedema. SR 140333 was also effective in preventing NKA- and NKB-induced oedema. SR 48968 (1 mg/kg, i.v.), a non-peptide NK2 antagonist, induced a significant inhibition of NKA-induced oedema but had no effect on the response to SP and NKB. SR 142801 (3 mg/kg, i.v.), a non-peptide NK3 antagonist, prevented only NKB-induced oedema. In contrast, phosphoramidon (0.1 and 0.5 mg/kg, i.v.), an endopeptidase inhibitor, enhanced the oedema response to tachykinins. SR 140333, SR 48968, and SR 142801 blocked the enhancement by phosphoramidon of the response to SP, NKA, and NKB, respectively. Plasma extravasation in ear skin was induced by i.v. injection of tachykinins (0.7-17.6 nmol/kg). RP 67580 (ED50: 0.15 mg/kg, i.v. for SP) and SR 140333 (ED50: 14.3 micrograms/kg, i.v. for SP) inhibited tachykinin-induced plasma extravasation in ear skin. However, SR 48968 and SR 140281 had no effect on the vascular response to tachykinins. Chlorpheniramine (4 mg/kg, i.v.), a histamine H1 blocker, inhibited the response to local SP but not to i.v. SP. These results suggest that in addition to the NK1 receptors, functional NK2 and NK3 receptors may participate in the oedema response to local NKA and NKB in the ear skin. However, it appears that NK1 receptors on blood vessels are involved predominantly in plasma extravasation induced by i.v. tachykinins in the ear.

Safety of first trimester exposure to histamine H2 blockers. A prospective cohort study.

The objective of this study was to examine whether H2 blockers represent a major teratogenic risk. This prospective cohort study was done at the Motherisk Program, a Teratology Information Service, Toronto, Canada. The subjects included 178 women who contacted Motherisk about gestational H2-blocker use, and 178 controls matched for maternal age, smoking, and heavy alcohol consumption. The main outcome measures were primary--major malformations, and secondary--pregnancy outcome, method of delivery, gestational age, prematurity, birthweight, small for gestational age infants, neonatal health problems, and developmental milestones. No increase in major malformations was found following first trimester exposure to H2 blockers [2.1% vs 3.5% (controls), mean difference (95% CI) -1.4% (-5.2, +2.4)]. No other aspects of pregnancy outcome or neonatal health differed between groups. This study suggests that H2-blocker exposure during the first trimester does not represent a major teratogenic risk.

Role of Gastroesophageal Reflux Disease in Patients with Cervical Symptoms

Otolaryngologists commonly see patients with various nonspecific upper aerodigestive or "cervical" symptoms. The relationship between gastroesophageal reflux disease and these symptoms has been studied but remains unclear. We reviewed the records of 216 patients with various cervical symptoms. Each patient underwent a uniform investigation that included barium swallow, esophageal manometry, acid stimulation testing, and esophagoscopy with distal biopsy. Patients were treated with a combination of a histamine H2 blocker or omeprazole and a prokinetic agent. Follow-up was obtained in 194 patients. Overall, evidence of gastroesophageal reflux disease was detected in 73% of patients. Complete resolution or improvement of symptoms was seen in 84% of patients with treatment. We believe gastroesophageal reflux disease is an important factor in the cause of cervical problems.

Indomethacin inhibition of ossification induced by direct current stimulation

In this study, we sought to clarify the mechanism of ossification induced by direct current stimulation by analyzing changes in local blood flow and vascular permeability and by examining the involvement of chemical mediators. Changes in blood flow were studied with laser Doppler flowmetry, and vascular permeability was determined by microquantification. To examine the involvement of chemical mediators, we determined the effect on vascular permeability of histamine H1 and H2-receptor blockers and indomethacin. In addition, direct current stimulation was performed during administration of indomethacin to determine whether indomethacin inhibits electrically induced callus formation. Local blood flow remained unchanged in the control group and in the group receiving 5 microA of stimulation, but it increased in the groups receiving 10 and 50 microA. Vascular permeability increased in the 5 and 10 microA stimulation groups. This increase was not suppressed by histamine-receptor blockers, but it was suppressed by indomethacin. Two weeks of electrical stimulation without concomitant indomethacin treatment resulted in active callus formation around the needle electrode and in the vicinity of the endosteum; however, direct current stimulation during administration of indomethacin inhibited callus formation. The results suggest that these changes serve as microenvironmental factors that play an important role in the promotion of ossification and that a prostaglandin-mediated mechanism is involved in the promotion of ossification by direct current stimulation.

Positive inotropic activity of the novel histamine H2-receptor agonist, amthamine, on the human heart in vitro

1.1. We tested the novel thiazole derivative, amthamine, for its ability to stimulate histamine H2-receptors in the human myocardium.2.2. Experiments were carried out on isolated, electrically-driven pectinate muscle segments, excised from atrial appendages of patients undergoing corrective heart surgery.3.3. Amthamine (0.3–100μM) induced a positive inotropic activity, resembling histamine in terms of potency and efficacy. In comparison, impromidine was 10–30 times more active than histamine and amthamine, but its maximum effect was significantly lower, while dimaprit was as effective as histamine, but 10 times less potent.4.4. The selective histamine H2-blocker, famotidine antagonized in a competitive fashion the amthamine-induced positive inotropic effect. pA2 value of famotidine against amthamine (7.21 ± 0.45) was close to that measured against histamine (6.88 ± 0.31) in the same conditions.5.5. The effect of amthamine was not modified by β-adrenoceptor blockade, excluding direct or indirect sympathomimetic activities of the compound.6.6. These data provide evidence that amthamine is a selective and full acting histamine H2-receptor agonist in the human heart in vitro.

Antiulcer drugs and gastric prostaglandin E2: an in vitro study.

Prostaglandin (PG) has been reported to be an important protective and acid-suppressive factor in the gastric mucosa. Although the mechanisms of some antiulcer drugs are attributed to their stimulatory effects on endogenous prostaglandins, an understanding of these actions has not been established. In the present study we investigated the effects of antiulcer drugs on PGE2 using cultured gastric mucosal cells. Rabbit gastric mucosal cells were cultured after isolation with collagenase and ethylenediaminetetraacetic acid. PGE2 was measured by enzyme-linked immunoassay. Histamine H2-blockers (cimetidine, ranitidine, famotidine), omeprazole, and sucralfate did not modulate the media content of PGE2, whereas sofalcone dose- and time-dependently increased it. Sofalcone-induced increase of PGE2 was dose-dependently prevented by indomethacin. Sofalcone did not affect intracellular Ca2+ as assessed by the calcium-sensitive probe indo-1. Deprivation of Ca2+ in the media did not modulate the action of sofalcone. Sofalcone significantly suppressed 15-OH-PG dehydrogenase. These results suggest that among the various antiulcer drugs only sofalcone increases PGE2, which may be a factor in its therapeutic effect against peptic ulcer diseases.

Some decision in the development of cimetidine

AbstractThe histamine H2 blocker, cimetidine (TagametTM), was one of the first drugs discovered bya mechanism‐based approach under the direction of Sir James black at Smith, Kline &amp; french in the United Kingdom. Cimetidine also holds the distinction of being the first drug ever to achieve more than $1 billion a year in sales. In this case study, the crucial scientific milestones in the discovery and development of cimetidine are recounted from the perspective of the Director of Research and placed within the context of the organizational dynamics ongong in the mid‐1960s as Smith, Kline &amp; french sought to retain its independence as a pharmaceutical company. The impact of the tremendous success of cimetidine as an anti‐ulcer medication on the SK&amp;F organization and the issue of managing success within a multinational drug research are presented to provide younger scientists with a feel for the tactical issues involved and the outcomes. © 1993 wiley‐Liss, Inc.

Effect of neonatal capsaicin treatment on neurogenic pulmonary edema from fluid-percussion brain injury in the adult rat

The frequent occurrence of acute death from pulmonary failure in experimental head injury studies on Sprague-Dawley rats prompted an investigation into the manner in which acute neurogenic pulmonary edema develops in these animals as a result of an applied fluid pressure pulse to the cerebral hemispheres. Studies were performed in adult animals using histamine H1 and H2 blocking agents, or in adult animals treated as neonates with capsaicin to destroy unmyelinated C-fibers. Recordings were made of either the pulmonary arterial or the right ventricular pressure, and the left atrial and femoral arterial pressures before, during, and after injury to provide a record of the hemodynamic response throughout the development of neurogenic pulmonary edema. Head injury triggered the almost immediate development of pressure transients with and without neurogenic pulmonary edema. All rats, regardless of treatment, reacted with nearly identical systemic arterial pressure responses; however, the pulmonary responses followed a time course that was independent of systemic arterial pressure changes. Acute neurogenic pulmonary edema was always associated with a substantial increase in pulmonary arterial and left atrial pressures; conversely, pressure increases of similar magnitude were not always associated with edema. Histamine H1 and H2 blockers significantly reduced the pulmonary pressure surges only in rats free of neurogenic pulmonary edema. All capsaicin-treated rats showed suppressed pulmonary pressure responses, normal lung water content, elevated lung surface tension, and significantly reduced levels of immunoreactive substance P in the spinal cord and vagus nerve. While the pressures cannot clarify how edema influences the observed hemodynamics, they do not support the view that edema is the direct consequence of pulmonary hypertension. It is proposed that neurogenic pulmonary edema is a functional disturbance provoked by adverse stimuli from outside the lungs and that in the rat the primary afferent fiber is essential to the production of this entity.

P-49 - Effects of TRM-115, a novel histamine H2-blocker, on gastric mucus in rats.

P-49 - Effects of TRM-115, a novel histamine H2-blocker, on gastric mucus in rats.

P-50 - Effects of TRM-115, a novel histamine H2-blocker, on gastric acid secretion and acute gastric lesions.

P-50 - Effects of TRM-115, a novel histamine H2-blocker, on gastric acid secretion and acute gastric lesions.

P-320 - Effects of IGN-2098 (IGN), a novel histamine H2-blocker, on gastric acid secretion and gastric and duodenal lesions in rats

P-320 - Effects of IGN-2098 (IGN), a novel histamine H2-blocker, on gastric acid secretion and gastric and duodenal lesions in rats

Reversing Effect of Anti-Asthmatic Drugs on Bronchoconstriction Induced by Antigen Challenge and Histamine in Anesthetized Guinea Pigs.

We performed an in vivo evaluation of bronchodilation using a model of antigen-induced bronchoconstriction in anesthetized guinea pigs pretreated with indomethacin, pyrilamine and propranolol, and the results were compared with those for the histamine-induced response. Test drugs were administered intravenously when the antigen or histamine response reached its peak. Leukotriene (LT) D4 antagonists, FPL55712 and LY171883, gradually reduced the antigen-induced response, whereas the lipoxygenase inhibitor phenidone had no such effect. The bronchodilator theophylline rapidly reduced the antigen-induced response, and the adenylate cyclase activator forskolin had a similar effect. The following drugs also had no effect: nifedipine (calcium-channel antagonist), cromakalim (potassium-channel opener), amlexanox and disodium cromoglycate: DSCG (anti-allergic drugs), OKY-046 (thromboxane A2 synthetase inhibitor), and dapsone (anti-inflammatory drug). Theophylline, the beta-adrenoceptor agonist salbutamol and the histamine H1-blocker pyrilamine had only a small reversing effect on histamine-induced bronchoconstriction. These results suggest that antigen-, but not histamine-, induced bronchoconstriction in anesthetized guinea pigs is a useful in vivo model for evaluating the bronchodilating effect of anti-asthmatic drugs.

Interaction of antihistaminics with muscarinic receptor (III)

The muscarinic antagonist 1-[benzilic 4,4′-3H]quinuclidinyl benzilate ([3H] QNB) bound to a single class of muscarinic receptors with high affinity in rabbit ileal membranes. The K D and B max values for [3H]QNB calculated from analysis of saturation isotherms were 52.5 pM and 154 fmol/mg, respectively. Chlorpheniramine (CHP), histamine H1 blocker, increased K D value for [3H]QNB without affecting the binding site concentrations and Hill coefficient. The K i value of CHP for inhibition of [3H]QNB binding in ileal membranes was 1.44μM and the pseudo-Hill coefficient for CHP was close to unit. In the functional assay carbachol, muscarinic agonist, increased the contractile force of ileum with ED50 value of 0.11μM. CHP caused the rightward shift of the dose-response curve to carbachol. The pA2 value of CHP determined from Schild analysis of carbachol-induced contraction was 5.77 and the slope was unity indicating competitive antagonism with carbachol. The dissociation constant (K i ) of CHP obtained in competitive experiments with [3H]QNB was similar to the K A value (1.69μM) of CHP as inhibitor of carbachol-induced contraction in rabbit ileum. This result suggests that the binding of H1 blocker, CHP, vs [3H]QNB to muscarinic receptors in ileal membranes represents an interaction with a receptor of physiological relevance.

Role of capsaicin-sensitive nerves in airway hyperresponsiveness induced by platelet activating factor in the rabbit

A new hypothesis for the pathophysiological mechanism underlying the development of oedema after a thermal injury has been tested in an experimental burn model. Support was given to the suggestion that oxygen-derived free radicals produced by invading leucocytes which upon activation release the superoxide radical (O2−), may be partly responsible for the increase in microvascular permeability seen after thermal injury. By removal of oxygen-derived free radicals with radical scavengers (superoxide dismutase and catalases) it was possible to reduce significantly the post-burn oedema formation. For comparison, one series of rats was pretreated with hydrocortisone and another with the histamine H2-blocker cimetidine. Hydrocortisone reduced the very early post-burn oedema formation which might partly be due to its membrane-stabilizing influence and partly to a direct effect on the microvasculature, causing a reduction of the vasodilatation observed post-burn. The inhibition of post-burn oedema formation by cimetidine, earlier demonstrated in animal burn models, was confirmed in the present study. The mean arterial blood pressure (MAP) in the cimetidine-treated rats decreased, however, after treatment. It is therefore difficult to determine to what extent the concentration of oedema is attributable to histamine H2-receptor blockade and to what extent to the reduced blood pressure. The influence of MAP on post-burn oedema formation was further illustrated in two series of rats anaesthetized with Inactin and Hypnorm/Valium respectively. The results underline the importance of using the same anaesthetic throughout the experimental series.

Pharmacological characterization of mare uterus motility with special reference to calcium antagonists and beta-2-adrenergic stimulants

1. 1. Uterine motility was studied in vitro in the myometrial tissue obtained from pregnant and non-pregnant mares. 2. 2. The spontaneous contractions of the preparations were not modified by tetrodotoxin, by anticholinergics, antiadrenergics, histamine H1 and H2 blockers, antiserotoninergic and opioid antagonists; but disappeared in Ca 2+ and Na + free medium. 3. 3. β 2-adrenergic stimulants like salbutamol and hexoprenaline and the calcium channel blockers nifedipine and verapamil were effective inhibitors of the amplitude of phasic contractions (ID 50s for salbutamol and nifedipine were 7.7 nM and 14.6 nM, respectively in oestrus preparations). 4. 4. The above data indicated that the mare myometrium contractility in vitro is very sensitive to the action of β 2 mimetic compounds and calcium antagonists; nifedipine, in particular, seems to be a very promising alternative to β 2 stimulants in the tocolytic therapy.