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Biomedical subjects

C G Persson

Publications and source records attributed to C G Persson.

At least 163 records · Page 9Linked to original sources
PubMed1986

Role of plasma exudation in asthmatic airways.

In normal airway defence and especially in asthma, mediators released from inflammatory cells will directly affect the walls of the abundant airway microvessels, making them much more permeable to macromolecules. Through large gaps between actively separated (contracted?) endothelial cells of venules of the tracheobronchial circulation, there is a bulk flow of proteinaceous plasma. The plasma exudate is distributed in the airway wall and it readily passes across an inflamed mucosa into the airway lumen. Plasma in the airway wall causes oedema, which may result in hyperresponsiveness and epithelial shedding. In the lumen its effects are formation of mucus plugs and inhibition of mucociliary transport, and its potent mediators such as the protein products of the kinin, complement, and clotting systems are released. Thus plasma exudation may operate in several aspects of asthmatic diathesis. By positive feedback mechanisms and recruitment and conditioning of inflammatory cells plasma exudate may amplify the inflammatory process.

Asthma↗
PubMed1986

Relaxant effects of xanthines, a beta 2-receptor agonist and Ca2+ antagonists in guinea-pig tracheal preparations contracted by potassium or carbachol.

Potassium (124 mM K+ Krebs) produced a biphasic contractile response in the guinea-pig isolated trachea. An initial phasic contraction was followed by a larger and sustained contraction. Repeated potassium-induced contractions in spontaneously contracted guinea-pig tracheas were not reproducible. However, reproducible K+ responses were obtained in the presence of indomethacin (10(-6) M) that almost abolished the spontaneous tone. This suggested that endogenous cyclooxygenase products were variably released by K+ and interfered with its contractile effects. Both phases of K+-induced contractions were inhibited in Ca2+-free/EGTA Krebs. In contrast, about 80% of the contractile response to carbachol persisted in this medium. Tracheas contracted by potassium (indomethacin present) were completely relaxed by theophylline and enprofylline but only partly relaxed by terbutaline. All bronchodilators completely relaxed carbachol-contracted preparations. Each bronchodilator was 2-3 times less potent to relax K+- than carbachol-induced contractions. In sharp contrast, two Ca2+ antagonists, verapamil and nimodipine, preferentially relaxed K+-induced contractions. The results obtained with Ca2+ antagonists, which are poorly effective in asthma, compared to the established antiasthma drugs, xanthines and beta 2-receptor agonists, may indicate that depolarization-induced mechanisms contribute little to bronchoconstriction in asthma.

Animals↗
PubMed1986

Effects of enprofylline and theophylline may show the role of adenosine.

It is well established that at low and clinically relevant concentrations theophylline (and caffeine) exerts antagonism at cell surface receptor sites for adenosine. However, it is not known which actions of theophylline are due to adenosine antagonism, because theophylline apparently activates other cellular mechanisms at the same low concentrations. Investigations into the actions of xanthines and their structure activity relationships have identified xanthine compounds like enprofylline (3-propylxanthine) that only has some actions in common with theophylline and that has a negligible ability to antagonize adenosine. Enprofylline is a more potent smooth muscle relaxant and antiasthmatic drug than theophylline but does not produce, e.g., theophylline-like diuretic effects, CNS-stimulant behavioural effects (restlessness - seizures), gastric secretory effects and release of free fatty acids. It is proposed that pharmacodynamic dissimilarities between enprofylline and theophylline may indicate physiological roles of adenosine.

Adenosine↗
PubMed1986

Overview of effects of theophylline.

Ever since xanthines were introduced into asthma therapy, more than 125 years ago, their therapeutic effectiveness has been explained as being due to extrapulmonary rather than, or in addition to, pulmonary drug actions. This article emphasizes that theophylline may have several potentially important effects in the lung. Theophylline relaxes the smooth muscle of large and small airways in humans and animals. Its relaxant effect is relatively independent of the type of mediator that constricts the airway. This suggests that functional antagonism, rather than specific pharmacologic mediator antagonism (e.g., adenosine antagonism), explains its bronchodilator effect. The consistent relaxant property of such xanthines as theophylline distinguishes these compounds from many other classes of established and experimental bronchodilator agents. Furthermore, many anti-inflammatory effects have been noted, suggesting that xanthines might be considered as prophylactic agents. Theophylline may not only attenuate the activity of stationary and blood-borne pulmonary inflammatory cells; it may also exert an anti-inflammatory action by directly affecting targets such as the epithelial lining (increasing the mucociliary transport rate) and the microvasculature (possibly reducing plasma exudation). The experimental anti-inflammatory pharmacology of theophylline is compatible with the observation that theophylline inhibits late pulmonary reactions in patients with atopic asthma and in sensitized animals challenged with allergen. The mechanism(s) of action behind the pulmonary actions of theophylline has not been assessed (neither phosphodiesterase inhibition nor adenosine antagonism may be involved). Central nervous system, gastroesophageal, renal, and metabolic actions of theophylline are briefly reviewed. Headache, nausea, and the relaxation of the lower esophageal sphincter can perhaps be classified as nonexcitatory and inhibitory effects in which the mechanism(s) of action is unknown.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Agonists↗
PubMed1986

Development of safer xanthine drugs for treatment of obstructive airways disease.

Antiasthma drug development, for the most part, seems based on three classes of therapeutic agents. Many new sympathomimetic and corticosteroid drugs with increased specificity for the lung have been introduced. The third class of drugs, the xanthines, is still best represented by the prototype drug theophylline. After a brief review of the chemical history of antiasthma xanthines (the first limited attempts to develop novel derivatives 30 to 40 years ago), and some recent structure-activity findings, this article discusses the pharmacology of a selected xanthine derivative, enprofylline (3-propylxanthine). In various experimental systems and in patients, enprofylline shares antiasthmatic effects with theophylline; however, enprofylline is the more potent of the two (greater than 1 to 2 micrograms/ml plasma are effective concentrations of enprofylline). At present, enprofylline, which lacks diaphragmatic and central nervous system stimulatory actions, has been shown to be at least as clinically efficacious as theophylline in obstructive lung disease. Further work is needed to elucidate the target cells and mechanism(s) of action involved in bronchodilatory and anti-inflammatory effects of the xanthines. Growing numbers of animal and human pharmacologic studies show that enprofylline is without many of theophylline's extrapulmonary effects--in particular the excitatory ones. Perhaps most significantly, enprofylline does not produce central nervous system stimulant behavioral effects, including seizures. If and when enprofylline becomes available as an alternative drug, increased attention will probably be focused on the significance of other theophylline actions (gastric secretion, release of free fatty acids, vasoconstriction, diuresis, etc.) that are not shared by enprofylline.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1986

Leakage of macromolecules from guinea-pig tracheobronchial microcirculation. Effects of allergen, leukotrienes, tachykinins, and anti-asthma drugs.

The tracheobronchial mucosa of anaesthetized guinea-pigs (normal or sensitized with ovalbumin to produce IgE and IgG antibodies) was superfused (0.02 ml min-1, 5 min) with saline, mediators, and (in sensitized animals) ovalbumin via a catheter atraumatically introduced orally. The intravascular blood pool and amount of macromolecules in excised trachea and adjoining main bronchi were quantified by measuring erythrocytes, that had been labelled in vivo with 99Tcm, and analysing for FITC-dextran, MW = 70,000, that had been given i.v. Extravasation of macromolecules was determined as the analysed total content minus the calculated intravascular content of FITC-dextran. Capsaicin 0.1 nmol extravasated 223 micrograms of FITC-dextran per g wet weight of airway tissue (P less than 0.001). Substance P 0.1 nmol, 41 micrograms g-1 (P greater than 0.05); substance P 0.3 nmol, 142 micrograms g-1 (P less than 0.001); eledoisine 0.1 nmol, 101 micrograms g-1 (P less than 0.01); ovalbumin 0.1 microgram, 179 micrograms g-1 (P less than 0.001); LTC4 0.2 pmol, 180 micrograms g-1 (P less than 0.001); LTD4 0.2 pmol 223 micrograms ml-1 (P less than 0.001). Bronchi and trachea were similarly affected by these agents. Prior superfusion (0.02 ml min-1, 30 min) with terbutaline 0.06 nmol, enprofylline 12 nmol, or lidocaine 6 nmol significantly reduced the effect of capsaicin. Enprofylline also reduced significantly the effect of LTC4. The degree of extravasation in this study was smaller than could be detected by changes in tissue wet to dry weight ratios. The present data support the view that tracheobronchial vascular permeability to macromolecules is subject to physiological and pharmacological control.

Adrenergic beta-Agonists↗
PubMed1986

Lung mechanics of the guinea-pig isolated perfused lung.

In the isolated perfused guinea-pig lung, lung resistance (RL) and dynamic compliance (CDYN) as well as flow, pH, PO2 and PCO2 of the perfusate were recorded. The baseline values were stable up to 2.5 h. Mean values (+/- SEM) for RL and CDYN were 0.36 cm H2O ml-1 s-1 +/- 0.04 and 0.27 ml cm-1 H2O +/- 0.02, respectively, which agree with in vivo values reported for unanaesthetized guinea-pigs. The pH was always slightly raised and the PCO2 always lowered in the effluent compared to the inflowing medium (P less than 0.001), indicating that the lung had an operative ventilation. Intravascularly administered acetylcholine, histamine and adenosine caused reproducible dose-dependent bronchoconstrictions recorded as increased RL and decreased CDYN. It is noteworthy that adenosine in this model and in vivo consistently produced bronchoconstriction which is in contrast to findings in other in vitro airway preparations. We conclude that this isolated perfused guinea-pig lung preparation has stable in vivo-like characteristics offering interesting possibilities for combining studies of respiratory effects with, for example, metabolism, pharmacokinetic and vascular reactivity studies.

Acetylcholine↗
PubMed1985

Tachykinin antagonists have potent local anaesthetic actions.

Contrary to what would have been expected, an antagonist of substance P (SP) [Arg5,D-Trp7,9]SP-(5-11) inhibited the neurogenic contraction of isolated guinea-pig hilus bronchi more readily than a contraction produced by exogenous SP. Furthermore, it has previously been shown that a tachykinin antagonist given intrathecally produced motor blockade as do local anaesthetic drugs. We therefore examined whether tachykinin antagonists had a depressant action on axonal neurotransmission. The compound action potential (APc) of the frog isolated sciatic nerve was suppressed in a concentration-dependent manner by the tachykinin antagonists [D-Pro2,D-Trp7,9]SP and [Arg5,D-Trp7,9]Sp-(5-11), both being about 4 times more potent than lidocaine. SP itself was without effect. Similarly in the rat isolated sciatic nerve [D-Pro2,D-Trp7,9]SP suppressed the APc. It was more potent in the A alpha- than in the C-fibres. SP did not affect conduction in either fibre type. In conscious guinea-pigs [D-Pro2,D-Trp7,9]SP injected adjacent to the sciatic nerve was found to block motor but not sensory functions of the limb. Thus, commonly used tachykinin antagonists, but not SP itself, have potent local anaesthetic properties. This should be considered when these agents are employed as pharmacological tools.

Action Potentials↗
PubMed1985

Anti-asthma drugs and capsaicine-induced microvascular effects in lower airways.

Substance P, capsaicine and bicervical vagal stimulation may increase microvascular permeability to macromolecules in lower airways. In previous studies techniques were employed that could have adversely affected the microvasculature. An atraumatic method of exposing the guinea-pig trachea to constant concentrations of drugs followed by quantitation of the blood-pool (in vivo 99Tcm-labelled erythrocytes) and extravasated macromolecules (Fitc.-dextran) has now been developed. Capsaicine produced marked extravasation of Fitc.-dextran while substance P in the concentration tested merely had vasodilator properties. Pretreatment with lidocaine, the beta-receptor agonist, terbutaline, or the adenosine non-blocking xanthine, enprofylline, inhibited the capsaicine induced inflammatory response.

Animals↗
PubMed1985

The effect of theophylline and enprofylline on allergen-induced bronchoconstriction.

The effect on the allergen-induced immediate and late bronchoconstriction of theophylline and enprofylline (3-propylxanthine), a new xanthine derivative with negligible ability to antagonize adenosine, was studied in nine patients with asthma. The patients were challenged three times at weekly intervals with the same dose of allergen. FEV1 and SGaw were followed up to 6 hours after challenge. The drugs were administered intravenously. Placebo was always administered on the first occasion. Theophylline and enprofylline were administered on test days 2 and 3 with a double-blind, randomized crossover technique. One hour before the allergen challenge, a loading dose was administered during 60 minutes followed by a constant infusion during 6 hours. The loading infusion was 7.2 mg/kg of theophylline and 2.7 mg/kg of enprofylline. The maintenance dose was 74 mg/hr and 71 mg/hr, respectively. Both theophylline and enprofylline caused a minor initial bronchodilatation. Theophylline and enprofylline slightly but significantly attenuated the immediate bronchoconstricting reaction after allergen inhalation. Theophylline and enprofylline had a significant attenuating effect on the late bronchial reaction. The mean plasma level of theophylline was 0, 10.8, 10.5, and 10.5 mg/L at 0, 1, 4, and 7 hours after the start of the loading infusion, respectively. The corresponding mean plasma levels of enprofylline were 0, 2.6, 2.7, and 2.7 mg/L. Theophylline and enprofylline caused headache in one patient. Two patients developed nausea and vomiting during the enprofylline infusion. The present data suggest that adenosine receptor antagonism may not be the main mode of action of xanthines in inhibiting bronchoconstriction after single dose antigen challenge.

Adult↗
PubMed1985

A method for studies of tracheobronchial microvascular permeability to macromolecules.

Probably because of methodological problems, little is known about permeability to macromolecules and edema formation in the tracheobronchial microcirculation. A novel atraumatic technique of exposing the guinea pig airway mucosa to mediators has been developed. The intralumenal surface of the trachea and main bronchus is superfused (0.02 ml/min) via a thin plastic tubing introduced into the trachea through the mouth in anesthetized, tilted, and spontaneously breathing guinea pigs. Erythrocytes were labelled in vivo with Technetium 99m and individual hematocrit values and plasma concentrations of Fitc-dextran were determined. By quantification of content of a macromolecular tracer (Fitc-dextran MW 70,000) and blood pool in excised airway tissue the amount of extravasated macromolecules was calculated. In control animals where airways were superfused with saline (0.02 ml/min) during 30 min the extravasated amount of tracer was 0 +/- 14 micrograms/g trachea (n = 15), which was similar to what was found in animals without any superfusion (n = 6). Capsaicin 10(-6) M (total dose 0.1 nmol), probably by activating nerves, produced an extravasation of Fitc-dextran of 223 +/- 32 micrograms/g, n = 8, (p less than 0.005). In guinea pigs intubated for artificial respiration and prepared for vagal stimulation the base-line microvascular values were deranged, and large amounts of macromolecules leaked from the vascular compartment. Still, vagal stimulation in these animals produced further extravasation of macromolecules. It is suggested that atraumatic techniques such as the present superfusion method should be employed in studies of physiological and pharmacological control of permeability to macromolecules in the tracheobronchial microvasculature.

Animals↗
PubMed1985

Effects of bronchoconstrictors and bronchodilators on a novel human small airway preparation.

Human lung bronchiolar segments (about 2 mm long and with a diameter of 0.6-1.5 mm) were dissected and circular muscle tension recorded. Airways were identified by histology and in some preparations by relaxant responses to noradrenaline (0.1-10 microM). Adenosine (1-100 microM) produced only very weak contractions, whereas carbachol (EC50 = 0.40 microM), histamine (EC50 = 0.63 microM), prostaglandin D2 (EC50 = 0.50 microM), substance P (EC50 = 4.6 microM) and ATP (1-100 microM) produced much greater ones. The contractions generally developed rapidly and were stable. The mean maximum increase in tension achieved with the most efficient constrictor, carbachol, was 0.5 g. ATP was the least efficient producing only about 40% of carbachol's maximum. Terbutaline, theophylline and enprofylline relaxed carbachol (2.0 microM = EC70)-contracted preparations. Terbutaline (3-3000 nM) relaxed 4 out of 11 bronchioles. Theophylline (10-4000 microM) and enprofylline (1-400 microM) consistently relaxed the bronchiolar preparations including those exhibiting little responsiveness to the beta 2-adrenoceptor agonist. Since enprofylline (which does not block adenosine receptors) was a five times more potent relaxant than theophylline and since adenosine produced only weak contractions, antagonism of adenosine receptors is probably not involved in relaxation of the small airways. It is suggested that the present data, which apparently differ from those obtained with lung parenchymal strips, are of relevance for human small airways responsiveness.

Adenosine↗