Histamine H2-receptor Blockers Research Articles

Alzheimer's disease and angiogenesis

Despite enormous investigative efforts, the pathological basis for Alzheimer's disease remains unclear. Suggested mechanisms for the disorder include cerebral hypoperfusion, inflammation, gene polymorphisms, and molecular lesions in the brain. In this Hypothesis, we argue that the vascular endothelial cell has a central role in the progressive destruction of cortical neurons in Alzheimer's disease. In Alzheimer's disease, the brain endothelium secretes the precursor substrate for the beta-amyloid plaque and a neurotoxic peptide that selectively kills cortical neurons. Large populations of endothelial cells are activated by angiogenesis due to brain hypoxia and inflammation. Results of epidemiological studies have shown that long-term use of non-steroidal anti-inflammatory drugs, statins, histamine H2-receptor blockers, or calcium-channel blockers seems to prevent Alzheimer's disease. We think this benefit is largely due to these drugs' ability to inhibit angiogenesis. If Alzheimer's disease is an angiogenesis-dependent disorder, then development of antiangiogenic drugs targeting the abnormal brain endothelial cell might be able to prevent and treat this disease. We suggest several laboratory and clinical approaches for testing our hypothesis.

Fentanyl-mediated reduction in the bispectral index and 95% spectral edge frequency is age-dependent

Fentanyl-mediated reduction in the bispectral index and 95% spectral edge frequency is age-dependent

Treatment of non-ulcer dyspepsia: a meta-analysis of placebo-controlled prospective studies.

Dyspeptic symptoms are commonly reported complaints in clinical practice and are mostly the result of functional disorders. Empirical treatment with histamine H2-receptor blockers or gastroprokinetics for 2-4 weeks has frequently been proposed as first line management of these patients. The clinical trials which support the use of these agents, show a high variation in clinical success rate and benefit of these treatments. The available clinical trials were evaluated, pooled where appropriate and subjected to a meta-analysis with the principal goal to provide valid treatment recommendations for patients with non-ulcer dyspepsia. In the present meta-analysis 19 studies on gastroprokinetics (cisapride, domperidone) and 10 studies on histamine H2-receptor antagonists (cimetidine, ranitidine) were included. Based on these studies, a total of 1540 patients were evaluated for histamine H2-receptor antagonists (verum n = 786, placebo n = 754) and 1235 patients for gastroprokinetics (verum n = 616, placebo n = 619). The probability for treatment success compared to placebo was 0.2026 (0.1261; 0.2791) for histamine H2-receptor antagonists and 0.4029 (0.3042; 0.5069) for gastroprokinetics. Based on these data both treatments are significantly more effective than placebo in the symptomatic treatment of non-ulcer dyspepsia, with gastroprokinetics (cisapride, domperidone) being more effective than histamine H2-receptor antagonists (cimetidine, ranitidine).

Gastric bleeding due to Dieulafoy's ulcer successfully treated with an esophageal variceal ligation (EVL) kit

Dieulafoy’s ulcer is a cause of life‐threatening upper gastrointestinal hemorrhage. With advanced endoscopic procedures, Dieulafoy’s ulcer is easily diagnosed and treated. However, a few patients still need surgery to stop bleeding or they will die of shock. Further improved procedures are therefore required to treat bleeding in Dieulafoy’s ulcer. A 77‐year‐old man was admitted to our hospital with hematemesis and general malaise. He had moderate anemia and azotemia but no past history of gastric ulcer. He was diagnosed with Dieulafoy’s ulcer endoscopically. Dieulafoy’s ulcer was ligated with an endoscopic variceal ligation kit without surgery. Although an ulcer was found at the ligation point after 1 week, the ulcer changed to the scar on administration of Histamine H2 receptor blockers. The patient has suffered no recurrent ulcer and no bleeding for 24 months. Endoscopic variceal ligation may be an alternative new method for hemostasis of Dieulafoy’s ulcer.

Clinical studies of enteritis caused by methicillin-resistant Staphylococcus aureus.

To study the clinical features of methicillin-resistant Staphylococcus aureus (MRSA) enteritis in our surgical ward. Retrospective study. Teaching hospital, Japan. 16 men and 1 woman who developed MRSA enteritis from January 1995 to October 1999. Causes and treatments. The underlying diseases were as follows: gastric cancer (n = 13), colorectal cancer (n = 2), recurrent cancer (n = 1) and bowel obstruction following gastrectomy (n = 1). 16 patients were operated on. Two cases were treated with histamine H2 receptor blockers. The mean age of patients was 65 years (range 50-80). In 13 cases MRSA enteritis developed within 6 days of operation. 10 strains of MRSA were isolated from stools, 8 from gastric juice, and 3 from intra-abdominal exudate. 10 patients were treated with vancomycin given through a nasogastric tube and 2 through a nasogastric tube and by drip intravenous infusion. 15 patients survived and 2 died. Patients who are given broad-spectrum antibiotics and whose gastric secretion is reduced are at high risk of MRSA enteritis. In the surgical ward, early diagnosis, treatment, and isolation are essential for patients with MRSA enteritis.

Drug-induced angioedema without urticaria.

Angioedema without urticaria is a clinical syndrome characterised by self-limiting local swellings involving the deeper cutaneous and mucosa tissue layers. Most occurrences of angioedema respond to treatment with a histamine H1 receptor blocker (antihistamine) because they are an allergic or parallergic reaction. A small number of cases do not respond to antihistamine treatment. Such cases tend to occur in patients with deficiency or dysfunction of the inhibitor of the first component of the complement (C1-INH), but more rarely can occur in patients with other conditions and as an adverse drug reaction. Angioedema is well documented in patients taking ACE inhibitors. Considering that 35 to 40 million patients are treated worldwide with ACE inhibitors, this drug class could account for several hundred deaths per year from laryngeal oedema. ACE inhibitors certainly do not mediate angioedema through an allergic or idiosyncratic reaction. For this reason the relationship with this drug is often missed and consequently quite underestimated. Rare instances of angioedema have also been reported with angiotensin II receptor antagonists. This adverse effect seems to occur less frequently with angiotensin II receptor antagonists than with ACE inhibitors. However, we do not know whether this adverse effect has the same mechanism with the 2 classes of medications. Some cases of severe angioedema have been recently reported after treatment with fibrinolytic agents. Scattered reports suggest the possibility of angioedema associated with the use of estrogens, antihypertensive drugs other than ACE inhibitors, and psychotropic drugs. Angioedema can also occur with nonsteroidal anti-inflammatory drugs. Prevention of angioedema relies first on the patient history. Estrogen and ACE inhibitors should be avoided in a patient with congenital or acquired C1-INH deficiency. In the case of ACE inhibitors, the appearance of angioedema following long term treatment does not lessen the probability that such an agent could be the cause. The most important action to take in a patient with suspected drug-induced angioedema is to discontinue the pharmacological agent. Epinephrine (adrenaline), diphenydramine and intravenous methylprednisolone have been proposed for the medical management of airway obstruction, but so far no controlled studies have demonstrated their efficacy. If the acute airway obstruction leads to life-threatening respiratory compromise an emergency cricothyroidotomy must be performed.

Treatment of Non-Ulcer Dyspepsia: a Meta-Analysis of Placebo-Controlled Prospective Studies

Background: Dyspeptic symptoms are commonly reported complaints in clinical practice and are mostly the result of functional disorders. Empirical treatment with histamine H2-receptor blockers or gastroprokinetics for 2-4 weeks has frequently been proposed as first line management of these patients. The clinical trials which support the use of these agents, show a high variation in clinical success rate and benefit of these treatments. Methods: The available clinical trials were evaluated, pooled where appropriate and subjected to a meta-analysis with the principal goal to provide valid treatment recommendations for patients with non-ulcer dyspepsia. In the present meta-analysis 19 studies on gastroprokinetics (cisapride, domperidone) and 10 studies on histamine H2-receptor antagonists (cimetidine, ranitidine) were included. Results: Based on these studies, a total of 1540 patients were evaluated for histamine H2-receptor antagonists (verum n = 786, placebo n = 754) and 1235 patients for gastroprokinetics (verum n = 616, placebo n = 619). The probability for treatment success compared to placebo was 0.2026 (0.1261; 0.2791) for histamine H2-receptor antagonists and 0.4029 (0.3042; 0.5069) for gastroprokinetics. Conclusions: Based on these data both treatments are significantly more effective than placebo in the symptomatic treatment of non-ulcer dyspepsia, with gastroprokinetics (cisapride, domperidone) being more effective than histamine H2-receptor antagonists (cimetidine, ranitidine).

Anti-ulcer compound from Voacanga africana with possible histamine H2 receptor blocking activity

Voacanga africana is used in Cameroonian ethnomedicine for the treatment of peptic ulcers. We have tested the cytoprotective, anti-secretory and ulcer healing actions of an alkaloid (TN) obtained from the fruit extract. Oral administration of TN (50-100 mg/kg) dose-dependently prevented ulcer formation by HCl/ethanol (36-75%), absolute ethanol (43-75%), HCl-ethanol/indomethacin (58-84%), Pylorus ligation (31-100%), cold restraint stress (68-100%) and histamine (49-100%). The inhibitory effect at 50 and 100 mg/kg against HCl/ethanol was not suppressed by pre-treatment with indomethacin (20 mg/kg, i.p.). TN reduced Shay-ligated gastric acid secretion from 77 mEq/l in the controls to 46 and 25 mEq/l for the 50 and 100 mg/kg doses. Augmented histamine-induced gastric acid secretion was reduced from 84 mEq/l in the controls to 45 and 21 mEq/l for the two doses of TN, with total inhibition of gastric and duodenal ulcers by the 50 mg/kg dose. Healing rate of chronic acetic acid-induced ulcers was 62 and 83%, respectively, for the dose of 50 and 100 mg/kg of TN compared with the controls. TN has gastric anti-secretory effects similar to histamine receptor blockers. Its cytoprotective and ulcer healing properties are related to its ability to strengthen gastric mucosal defenses through enhanced gastric mucus production.

Acute effects of bradykinin on cerebral microvascular permeability in the anaesthetized rat.

1. The permeability response to acutely applied bradykinin and [des-Arg9]-bradykinin on single cerebral venular capillaries has been investigated using the low molecular mass fluorescent dyes Lucifer Yellow and Sulforhodamine B with the single vessel occlusion technique. 2. When bradykinin was applied repeatedly for up to 2 h, the permeability increase was small and reversible for concentrations that ranged from 5 nM to 50 microM. 3. The logEC50 of the permeability response to bradykinin was -5.3 +/- 0.15 (logM; mean +/- s.e.m.). This was reduced to -6.37 +/- 0.24 with the angiotensin-converting enzyme inhibitor captopril, to -6.33 +/- 0.19 with the neutral endopeptidase inhibitor phosphoramidon and to -7.3 +/- 0.20 with captopril and phosphoramidon combined. 4. The permeability response to bradykinin was blocked by the bradykinin B2 receptor antagonist HOE 140, by inhibition of the Ca2+-independent phospholipase A2, by the scavenging of free radicals, or by inhibition of both cyclo-oxygenase and lipoxygenase in combination. Block of Ca2+ entry channels with SKF 96365 had no effect on the response. 5. Application of [des-Arg9]-bradykinin also increased permeability over the concentration range 5 nM to 50 microM, with a logEC50 of -5.6 +/- 0. 37. This response was not affected by free radical scavenging, but was completely blocked by the histamine H2 receptor blocker cimetidine. 6. These results imply that the acute permeability response to bradykinin is mediated via the release of arachidonic acid, which is acted on by cyclo-oxygenase and lipoxygenase resulting in the formation of free radicals, and that the response to [des-Arg9]-bradykinin is mediated via histamine.

Drugs That Induce Delirium

Drug-induced delirium is often seen in clinical practice. Most knowledge about delirium-inducing drugs comes from reports on side effects, and few systematic studies have been done in the field. Delirium is strongly associated with anticholinergic activity; drugs of different classes, including tricyclic antidepressants and traditional high-dose neuroleptics, constitute a high-risk group. A large number of drugs, including benzodiazepines, sedatives, dopamine-activating drugs, antiepileptics, histamine H2 receptor blockers, digitalis and analgesics, are less frequently associated with delirious reactions and constitute a medium-high-risk group. Some of these drugs do not have anticholinergic effects but in vitro have shown to bind to muscarine receptors. The risk of inducing delirium in frail elderly and demented persons clearly suggests that drugs which might induced delirium should be avoided.

Diagnosis and Management of Acute Pancreatitis

Acute pancreatitis usually occurs as a result of alcohol abuse or bile duct obstruction. A careful review of the patient's history and appropriate laboratory studies can help the physician identify the etiology of the condition and guide management. Serum amylase and lipase levels are still used to confirm the diagnosis of acute pancreatitis. Although not routinely available, the serum trypsin level is the most accurate laboratory indicator for pancreatitis. Ultrasonography, computed tomography and endoscopic retrograde cholangiopancreatography are additional modalities that can help the family physician choose the best treatment approach. Prompt identification of patients who need intensive care referral or subspecialty consultation is crucial. The APACHE II and the multiple organ system failure scales provide prognostic information at the time of admission and may be repeated daily to monitor disease progression. Therapies such as nasogastric suctioning, anticholinergics and histamine H2-receptor blockers have not been shown to decrease symptoms or hospital stays in patients with acute pancreatitis. Systemic antibiotics have been found to improve outcome in patients with severe disease. With supportive care, most patients have a good clinical outcome.

Enhancement of the antimalarial effect of chloroquine by chloropheniramine in vivo.

The efficacy of chloroquine and chloroquine plus chloropheniramine, a histamine H1 receptor blocker which reverses chloroquine insensitivity in Plasmodium falciparum in vitro, was studied in 96 children with acute symptomatic uncomplicated falciparum malaria. The chloroquine/chloropheniramine combination produced a significantly higher cure rate than chloroquine alone and cured 77% of children with chloroquine treatment failures. Children with chloroquine treatment failure had mean plasma chloroquine concentrations above the minimum therapeutic concentration for the area. Chloroquine concentrations in plasma and red blood cells and ratio of red cell to plasma chloroquine concentrations on days 3 and 7 after initiation of therapy were not significantly different in the two groups. Chloroquine/chloropheniramine produces a higher cure rate than chloroquine alone and reverses chloroquine insensitivity in Plasmodium falciparum in vivo. It may be a useful way of optimising the antimalarial effect of chloroquine.

Omeprazole, other antiulcer drugs and newly diagnosed gout.

Case-reports describing patients who developed a first episode of acute gout while being treated with the proton pump inhibitor omeprazole led us to compare incidence rates of newly diagnosed gout cases among omeprazole, ranitidine and cimetidine users. We conducted a cohort study with a nested case-control analysis using the UK-based General Practitioner Research Database (GPRD). The study encompassed a cohort of more than 53,000 subjects who received some 185,000 prescriptions for the three study drugs. Neither current omeprazole vs recent use (age- and sex-adjusted relative risk 1.1, 95% CI 0.5-2.1), nor current omeprazole use in comparison with current use of the two histamine H2-receptor blockers was associated with an increased risk of developing newly diagnosed gout. Higher age (RR 2.4, 95% CI 1.5-3.9), male gender (RR 5.4, 95% CI 2.8-10.3), high body mass index (OR 3.3, 95% CI 1.0-10.9) and hypertension (OR 4.5, 95% CI 1.6-12.9) were all important risk factors for gout. While other known risk factors were significantly associated with gout, current omeprazole use was not materially associated with an increased gout incidence.

High-dose pancreatic-enzyme supplements and fibrosing colonopathy in children with cystic fibrosis.

Fibrosing colonopathy has been reported in young children with cystic fibrosis, the majority of whom take high-strength pancreatic-enzyme supplements to control intestinal malabsorption. We conducted a case-control study in the United States to investigate the relation between dose and type of pancreatic-enzyme supplement and fibrosing colonopathy. Children with histopathologically confirmed cases of fibrosing colonopathy who required colectomy for colonic strictures from January 1, 1990, through December 31, 1994, were identified. Each of these patients was matched according to age at the time of surgery and medical center with up to four controls with cystic fibrosis who did not have fibrosing colonopathy. We studied 29 patients (mean age, 5.0 years) with fibrosing colonopathy (case patients) and 105 controls (mean age, 5.2 years). The mean dose of pancreatic-enzyme supplement was 50,046 units of lipase per kilogram of body weight per day for the case patients and 18,985 units per kilogram per day for the controls. A history of gastrointestinal complications attributed to cystic fibrosis and the use of histamine H2-receptor blockers, corticosteroids, or recombinant human DNase (dornase alfa) were associated with a higher incidence of fibrosing colonopathy. After adjustment for a history of such complications and the use of these medicines, the relative risk of fibrosing colonopathy that was associated with a dose of 24,001 to 50,000 units of lipase per kilogram per day, as compared with a dose of 0 to 24,000 units per kilogram per day, was 10.9 (95 percent confidence interval, 1.6 to 71.8), and that associated with a dose of more than 50,000 units per kilogram per day was 199.5 (95 percent confidence interval, 9.9 to 4026.0). The strength, coating, and manufacturer of the products used were not associated with the risk of fibrosing colonopathy. In young children with cystic fibrosis, we found a strong relation between high daily doses of pancreatic-enzyme supplements and the development of fibrosing colonopathy. Our findings support recommendations that the daily dose of pancreatic enzymes for most patients should remain below 10,000 units of lipase per kilogram.

Inhibition of Antigen‐Induced Muscle Contractions by‐Inhibitors of Thromboxane Pathway in Rat Small Intestine

Rats were sensitized against egg albumin and the response of the longitudinal muscle from the proximal small intestine to the antigen was tested. Egg albumin (1-100 micrograms/ml) concentration-dependently induced a contraction of the longitudinal muscle in tissues from sensitized animals but not from nonsensitized animals. The response to the antigen was resistant to neuronal blockers like tetrodotoxin, atropine and hexamethonium. Inhibitors of thromboxane synthesis such as the cyclooxygenase inhibitor, indomethacin, the thromboxane synthase blocker, 1-benzylimidazole, or the combined cyclooxygenase/lipoxygenase/thromboxane synthase inhibitor, sulfasalazine, inhibited the contraction evoked by egg albumin. A similar concentration-dependent inhibition of the antigen response was observed with two thromboxane A2 receptor blockers, SK&F 88046 and KW-3635. None of these blockers affected the response to the muscarinic agonist, carbachol, excluding unspecific effects of the drugs on smooth muscle contractility. The effect of antigen was reduced by the mast cell stabilizing agent, quercetin, and by the histamine H1 receptor blocker, mepyramin. These drugs, however, also inhibited the response to carbachol. When contractions were stimulated directly by the stable thromboxane derivative, carbocyclic thromboxane A2, the smooth muscle proved to be more than three orders of magnitude more sensitive to this agonist of the thromboxane pathway compared to histamine. Consequently, thromboxane A2 seems to be one of the main mediators of anaphylactically induced longitudinal muscle contractions in the rat small intestine.

The surgery of complicated gastro-oesophageal reflux.

A properly performed anti-reflux operation is the most effective and durable method of control l ing gastrooesophageal reflux and its complications but is only required in a minority of affected patients TM. Because of recent advances in the medical management of reflux disease, maintenance medical therapy is a legitimate alternative to surgery and the frequency of anti-reflux operations has been reduced. In consequence, only those patients with the most severe form of disease or complex symptomatology are referred for surgical correction. Thus the surgical challenge is now greater and the avoidance of failure requires strict selection of the right patient with the right disease (reflux) for the right operation. Upper gastro-intestinal contrast studies, endoscopy, oesophageal manometry and 24 hour oesophageal pH monitoring are mandatory preoperative base-line investigations. Prior to selecting patients for surgery, the following cri teria should be satisfied: (a) pathological gastrooesophageal reflux should he demonstrated to he the cause of the symptoms. (b) complications of reflux should be sought these include oesophagitis, stricture, Barrett 's oesophagus, motor dysfunction, pulmonary aspiratio n and failure to thrive in children. (c) an oesophageal motility disorder such as achalasia, diffuse spasm or scleroderma should be excluded. (d) co-existing diseases with similar or overlapping symptoms such as angina pectoris, peptic ulceration and gallstones should be excluded. (e) the patient should have had an adequate trial of modern medical therapy. This should include a programme of weight reduction, withdrawal of alcohol or nicotine, and drug therapy with optimal doses of either an Histamine H2 receptor blocker or proton pump inhibitoi" together with antacids and/or prokinetic agent. Modern drugs are safe in the long term and economic reasons are a weak and rare justification for surgery. (f) The patient should be evaluated for a contraindicat ion to surgery such as intercurrent cardiac or pulmonary disease or a general medical problem. Patients undergoing definitive surgery for gastrooesophageal reflux fall into two general categories, the complex and the straight-forward case. The presence of an oesophageal stricture, oesophageal foreshortening, deep ulceration, irreducibility of an associated hiatal hernia, suspected carcinoma, scleroderma and previous surgery define the complex case and should b e approached

Effects of trepelennamine on brain monoamine turnover in morphine dependent and abstinent mice.

Previous studies have reported that the histamine H1 receptor blocker tripelennamine potentiates morphine withdrawal. In this paper, the in vivo effects produced by tripelennamine on the turnover of serotonin (5-HT), dopamine (DA) and noradrenaline (NA) in the whole brain, excluding the cerebellum, were studied in control, morphine-dependent (by SC implantation of a 75 mg morphine pellet) and morphine-dependent male CD1 mice just before naloxone-precipitated withdrawal. Tripelennamine (1-10 mg/kg) was administered SC 45 min. before the animals were killed. Serotonin, 5-hydroxyindole-3-acetic acid (5-HIAA), dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and noradrenaline were measured by high performance liquid chromatography coupled with electrochemical detection (HPLC-ECD) and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) was measured by HPLC coupled with fluorimetric detection. Ratios 5-HIAA/ 5-HT, DOPAC + HVA/DA and MHPG/NA were taken as an index of serotonin, dopamine and noradrenaline turnovers, respectively. Tripelennamine (1 and 10 mg/kg) significantly reduced serotonin turnover in control and morphine-dependent mice, and potentiated the serotonin turnover reduction when it was administered 30 min before naloxone injection. The dopamine turnover was diminished by tripelennamine (1 and 10 mg/kg) in the morphine-dependent group. Tripelennamine (10 mg/kg) reduced noradrenaline turnover during abstinence. These results suggest that the potentiation of opiate abstinence by tripelennamine could be related to its antiserotonergic profile.

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.

The role of the mast cell in acute inflammatory responses of copper-deficient rats.

Macromolecular leakage associated with mast cell degranulation was studied in the cremaster muscle microcirculation of copper-deficient rats. Male Sprague-Dawley rats were fed a purified diet either adequate for copper (6 micrograms copper/gram diet) or deficient (no added copper) 4 weeks prior to experimentation. The rats were anesthetized and the cremasters (with nerve and blood supply intact) were spread in a tissue bath filled with Kreb's solution. In vivo television microscopy was used to observe the microcirculation. Intravascular fluorescein isothiocyanate conjugated to bovine serum albumin was injected and interstitial fluorescent emission intensity was used as an index of macromolecular leakage. Topical administration of the mast cell degranulator compound 48/80 (1.0 and 10.0 micrograms/ml) induced a significantly greater macromolecular leakage in the copper-deficient animals. The compound 48/80 leakage was blocked in both groups of rats by pretreatment with diphenhydramine which is a histamine H1 receptor blocker. Topical administration of the inflammatory mediators histamine, serotonin, and bradykinin all induced macromolecular leakage which was not significantly different between groups. These results suggest that copper deficiency increases macromolecular leakage associated with mast cell degranulation by a primary effect on the mast cell rather than on the endothelium.

Involvement of apamin-sensitive K+ channels in antigen-induced spasm of guinea-pig isolated trachea.

1. In order to examine whether K+ channels play a role in antigen-induced airway responses, the effect of K+ channel blockers on antigen-induced airway smooth muscle contraction and mediator release was examined in vitro in guinea-pigs actively sensitized with ovalbumin (OA). 2. Tracheal strips from sensitized animals were suspended in organ baths under a resting tension of 1 g and isometric tension was continuously measured. Cumulative concentration-response curves to OA (0.1-1000 ng ml-1) or histamine (10 nM-1 mM) were obtained in the presence and absence of K+ channel blockers. 3. OA (10, 100 or 1000 ng ml-1) was incubated with minced lung tissues from the same animals for 15 min in the presence and absence of K+ channel blockers, and released histamine and leukotriene C4 (LTC4) in the incubating medium were measured. 4. Apamin, a small conductance Ca(2+)-activated K+ channel (PK,Ca) blocker, (0.1, 0.3 and 1 microM) significantly inhibited OA-induced smooth muscle contraction, while charybdotoxin (ChTX, 10 nM), an intermediate and large conductance PK,Ca blocker, and iberiotoxin (IbTX, 3 nM), a large conductance PK,Ca blocker, were without effect. Apamin (0.3 microM) had no effect on exogenously administered histamine-induced airway smooth muscle contraction, suggesting that the inhibition of OA-induced contraction by apamin did not occur at the smooth muscle level. 5. The inhibition of OA-induced contraction by apamin (0.3 microM) was not significantly affected by pretreatment with a leukotriene antagonist, ONO-1078 (10 microM), but was abolished by pretreatment with a histamine H1-receptor blocker, pyrilamine (1 microM). 6. Apamin by itself (up to 0.1 MicroM) had no effect on spontaneous histamine release from minced lung tissues. Histamine release induced by low and intermediate concentrations of OA (10 and 100 ng ml-1)was significantly suppressed by apamin pretreatment (P<0.05 and P<0.001), whereas LTC4 release was not affected. ChTX (0.1 MicroM) and IbTX (10 nM) had no significant effect on either spontaneous or OA (100 ng ml-1)-induced histamine release.7. These results suggest that apamin partially but substantially inhibits antigen-induced smooth muscle contraction, presumably by inhibiting antigen-induced histamine release from airway mast cells through small conductance PKca closure.