Electrical field stimulation of isolated guinea pig lung parenchyma strips: a method to study peripheral bronchi and peripheral blood vessels.

The reaction of isolated guinea pig lung parenchyma strips to electrical field stimulation (EFS) has been characterized in vitro. Lung parenchyma strips reacted to EFS with a frequency-dependent initial twitch followed by a long-lasting contraction. The initial fast contraction was abolished by tetrodotoxin, whereas the tonic contraction was not influenced by this substance. The initial twitch was reduced but not abolished by atropine as well as by phentolamine. It was concluded that the reaction of guinea pig lung parenchyma strips to EFS consists of a cholinergic and an adrenergic component representing probably the responses of small bronchi and small blood vessels, respectively. The nature of the nonadrenergic-noncholinergic component of the initial twitch as well as of the nature of the nonneural tonic contraction are still unclear.

Influence of capsaicin on the reagibility of the isolated guinea pig trachea.

Capsaicin induced a concentration dependent contraction of isolated guinea pig tracheal spirals but did not reduce the tone of submaximally precontracted preparations neither per se nor after pretreatment with a tachykinin antagonist. The contractile reactions to capsaicin did not differ significantly between tracheal preparations obtained from sensitized and nonsensitized animals. A single application of capsaicin (10(-5) M for 15 min) induced a strong contraction of the preparations followed by complete tachyphylaxis to further applications of capsaicin. Such pretreatment with capsaicin did not influence the reagibility of isolated guinea pig tracheas to acetylcholine added exogenously but reduced the allergic contractions of preparations obtained from actively sensitized animals significantly. It is suggested that neuropeptides (e.g. substance P) might be involved in the allergic bronchoconstriction in vitro.

Effects of ketotifen and clenbuterol on beta-adrenergic receptor functions of lymphocytes and on plasma TXB-2 levels of asthmatic patients.

Clinical observations indicate that beta-adrenergic drugs may increase bronchial reactivity in asthmatics. To find out possible reasons for this phenomenon the beta-adrenergic receptor function of isolated lymphocytes of asthmatic patients treated with clenbuterol alone or with ketotifen and clenbuterol together were studied. The cAMP levels of lymphocytes stimulated by different doses of isoproterenol were measured by radioimmunoassay and have been compared in the groups of healthies, and asthmatic patients after 3-months running of clenbuterol (Spiropent, Sandoz), as well as in the same asthmatics after one-week running of parallel administration of ketotifen and clenbuterol. There was no difference between the beta-adrenergic receptor function in asthmatic patients treated with clenbuterol alone vs. untreated healthies. Applying ketotifen and clenbuterol together the beta-adrenergic receptor function increased compared to the values obtained after application of clenbuterol alone (intraindividual-control) as well as vs. the group of healthies (control). Data presented support the view that therapeutic doses of selective beta 2-agonists do not lead to damage of the beta-adrenoceptor function. The improvement of receptor function after parallel administration of clenbuterol and ketotifen may be a consequence of the participation of ketotifen in the control of beta-adrenergic receptor system. Thus it seems unlikely that down-regulation of beta-adrenergic receptors is responsible for the beta-agonist induced bronchial hyperreactivity. That's why TXB-2 levels in the plasma of the same asthmatic patients and healthy volunteers were determined by RIA.(ABSTRACT TRUNCATED AT 250 WORDS)

A one-year double-blind clinical study of the efficacy and tolerability of picumast dihydrochloride versus ketotifen in patients with bronchial asthma.

The efficacy and tolerability of picumast dihydrochloride (3,4-dimethyl-7-[4-(4-chlorobenzyl)piperazine-1-yl]propoxycoumarin dihydrochloride) (2 mg twice daily orally) in comparison with ketotifen (1 mg twice daily orally) was investigated in 400 patients with bronchial asthma (picumast dihydrochloride n = 202, ketotifen n = 198) in a double-blind, controlled, parallel group study. Assessment of therapeutic and preventative efficacy was by means of symptom scores, quantitative measurements (accumulatory threshold dose) of the bronchial hyperreactivity by means of inhalatory acetylcholine provocation, measurements of peak expiratory flow, vital capacity (VC) and 1-s capacity (FEV1) as well as global assessment of efficacy by the doctor and patient. Tolerability was assessed by recording side effects and global assessment of tolerance on a rank scale at the end of the treatment as well as by means of clinico-chemical parameters. Picumast dihydrochloride and to a lesser extent ketotifen both led to a clinically relevant and statistically significant increase in the inhalatory provocation dose (PD50) for acetylcholine. There was a moderate improvement in the symptom scores and a rise in peak flow values in both treatment groups. The mean total score of asthmatic symptoms of both drugs showed a clear but quantitatively low improvement after 12 months' treatment. The differences in efficacy between picumast dihydrochloride and ketotifen were not statistically significant. During the course of the study, adverse reactions were recorded on 117 occasions (picumast dihydrochloride n = 41, ketotifen n = 76).(ABSTRACT TRUNCATED AT 250 WORDS)

[The role of substance P in regulating bronchomotor tone and the pathogenesis of bronchial hyperreactivity]. / Rolle von Substanz P in der Regulation der Bronchomotorik und der Pathogenese der bronchialen Hyperreagibilität.

Substance P (SP) is localized in sensory nerves of the respiratory tract in close connection to the effector cells of inflammatory and allergic bronchial diseases. SP is proposed to play an important role in the pathogenesis of bronchial asthma because of its ability to induce bronchoconstriction, vasodilatation and an edema of the mucous membrane and to enhance the secretion of tracheobronchial glands. Furthermore inflammatory and immune cells are influenced by SP. SP seems to have a complex action in the regulation of the bronchial tonus. Especially differences in the action of partial sequences of the peptide may be important in the pathogenesis of asthma.

[The effect of climatic and meteorologic factors on bronchial hyperreactivity and the course of bronchial asthma diseases and their potential significance in asthma prevention: hypotheses, methodologic approaches and initial results]. / Der Einfluss klimatischer und meteorologischer Faktoren auf die bronchiale Hyperreaktivität und den Verlauf von Asthma-bronchiale-Erkrankungen und ihre potentielle Bedeutung in der Asthmaprophylaxe: Hypothesen, methodische Ansätze und erste Erkenntnisse.

Bronchial hyperresponsiveness (BHR) as the main condition for the development of asthma may be modulated either by intrinsic or by extrinsic stimuli as well as by climatic and meteorologic factors. Proinflammatory mediators in combination with alterations of airway mucosa induce or amplify BHR. Upper airway viral infections, exposure to allergens in atopic subjects, chronic hyperplastic changes of the upper airways, airway irritants and analgesics are supposed to be the most likely asthma triggers in predisposed children and adults. There is the suggestion that BHR can be improved not only by treatment with steroidal and nonsteroidal antiinflammatory drugs but also by maritime climatotherapy. The latter could be the result not only of the reduction of inhalative irritants, e.g. of allergen concentration, but also by the involvement or more complex mechanisms. Possible theoretic approaches and hypotheses regarding the mode of action of maritime climatic cures are discussed. First preliminary results obtained in a mediterranean region have demonstrated a negative impact of metereologic events like passages of cold weather fronts or increase of wind velocity on the course of asthma disease. An improvement of BHR assessed by histamine challenge test has been observed at the end of climatotherapy in the Baltic sea area. Prospective studies about asthma prevention in subjects at risk with BHR and atopy that have been starting should contribute to the evaluation of the therapeutic effects and the prognostic importance of maritime climatotherapy for getting exact scientific indications for climatotherapy in patients with bronchial asthma.

[Bronchial hyperreactivity: pathomechanisms, diagnosis and perspectives of therapy]. / Bronchiale Hyperreaktivität: Pathomechanismen, Diagnostik und Perspektiven der Therapie.

Bronchial asthma is a problem with increasing importance for health care. Bronchial hyperreactivity can be considered as the precondition of the development of bronchial asthma. The biological and pathophysiological activities of the phospholipid mediators discovered during the last years induced considerable progress in the research of pathogenesis in bronchial asthma. Thus, a central role of leucotrienes, HPETE and PAF in regulation of bronchomotoric actions is suggested. From recent epidemiologic and clinical research certain risk factors of manifestation of bronchial asthma can be derived. At present, theoretical, completely new therapeutical concepts are directed on inhibition of synthesis or receptor antagonism in different levels of the phospholipid metabolism.

[Drug-induced bronchial asthma]. / Medikamenteninduziertes Asthma bronchiale.

In any case of acute bronchoconstriction the possibility of an adverse reaction to a drug should be considered. In many of such side reactions no allergic mechanism can be detected. Therefore, they are included into the category of pseudoallergic reactions (PAR). The clinically most important form of drug-induced bronchial asthma, analgesics asthma, belongs to this PAR group. A further risk for asthmatics are intravenous applications of contrast-media for roentgenography which in about 15% induce a severe, sometimes life-threatening pseudo-allergic adverse reaction. In asthmatics, the application of any beta-receptor blocking agents and also the use of parasympathicotonic eye drops for treatment of glaucoma are contraindicated. Paradoxical bronchial constriction following application of antiasthmatics are preponderantly caused by locally irritative actions, less frequently by genuine allergic phenomena or additive intolerance. The most reliable prophylaxis against drug-induced bronchial asthma consists in strong avoidance of all derivatives possibly capable to trigger any intolerance. A respective warning should entered into the emergency passport.

Influence of bilateral subnodular vagotomy and section of retrotracheal plexus on allergic bronchial constriction in guinea pigs.

A bilateral subnodular vagotomy and a tracheal dissection with immediate readaptation (n = 18) or one of both (n = 8) was performed on ovalbumin sensitized guinea pigs. Control animals got a shame operation (n = 13). About one week later the animals were narcotized by ethylurethane 1.3 g per kg b.w. intraperitoneally and received a tracheotomy with insertion of a tracheal cannula and an additional insertion of a flexible catheter into the right jugular vein. Then the animals were artificially ventilated in a tank respirator by rhythmical exposure to a negative chest wall pressure, the ventilator settings were f = 20 per min, I: E = 1: 1, and rectangular pressure = -2 kPa. Breathing parameters were measured pneumotachographically. Flow, tidal volume, ECG and ventilation pressure were recorded with a 12-channel UV-light recorder. After the recording of initial parameters an intratracheal bolus-instillation of 0.5 mg/kg b.w. ovalbumin was given and 5 min later, a second ovalbumin bolus i.v. of 1 mg/kg b.w. Mean minimal tidal volumes reached after i.t. OA-provocation were: 17.6 +/- 19 in controls, 39.7 +/- 30 after vagotomy and tracheotomy, 40.5 +/- 20 after vagotomy alone, and 27.6 +/- 18 after tracheotomy alone. We found a significant inhibition of allergic bronchial constriction by bilateral vagotomy. The dissection of the retrotracheal plexus by tracheotomy was without significant effect on the allergic response. The investigation could demonstrate the significance of vagotomy on asthmatic reactions.(ABSTRACT TRUNCATED AT 250 WORDS)

[Possible significance of the lipoxygenase pathway of arachidonic acid metabolism for the pathogenesis of constrictive reactions of lung blood vessels]. / Mögliche Bedeutung des Lipoxygenaseweges des Arachidonsäuremetabolismus für die Pathogenese konstriktorischer Reaktionen an Lungengefässen.

Recent studies suggest a key role of lipoxygenase (LOX) pathway of arachidonic acid (AA) metabolism in the regulation of pulmonary artery tone. We investigated the influence of specific inhibition of leucotriene biosynthesis on constrictory reactions of isolated rabbit pulmonary arteries in the organ bath. The substance FLM 5,011 selectively inhibiting the LOX pathway leads at a bath concentration of 5 X 10(-5) M to an inhibition in the order of 75% of AA- and phospholipase (PLP) A2-induced contraction (cumulative measurement, 37 degrees C, pH 7.4, isotonic contraction). The inhibitory effect on calciumionophore A 53,712-induced contraction was only 31.4%. We compared these findings with actions of nordihydroguiaretic acid and PAMBA. Our findings suggest that in rabbit lung arteries receptors for AA-products must exist and that the activation of AA depends on calcium. The present investigations underline the relevance of LOX products to genesis of pulmonary hypertension in man.

[Bronchial hyperreactivity: state and perspective of drug intervention]. / Bronchiale Hyperreaktivität: Stand und Perspektiven einer medikamentösen Intervention.

A decreased threshold of bronchial contractility under the influence of nonspecific and specific factors (bronchial hyperreactivity--BHR) is a disposing factor and precondition to the development of asthmatic disease. Probably the disturbance of the barrier function of the bronchial epithelium plays a central role in bronchial hyperreactivity. The release of phospholipid mediators from membrane phospholipids might be decisive for the establishment of bronchial hyperreactivity. This is documented, before all, by the decreasing effect of glucocorticosteroids upon the hyperreactivity since their pharmacologic efficacy is realized in first line by an inhibition of the release of arachidonic acid. We are arguing that an endogenously not compensated basical release of arachidonic acid and platelet activating factor is causally related to bronchial hyperreactivity. Prevention of asthma as well as therapy must aim at systematic reduction of bronchial hyperreactivity. Beside glucocorticosteroids and other inhibitors of phospholipase could prospectively be of therapeutic interest inhibitors of synthesis or antagonists of 5-lipoxygenase, of platelet activating factor, of leukotrienes or thromboxanes. There exist theoretical bases for practical measures of directed prevention of asthma in persons at risk. Their efficiency still awaits scientific evaluation.