Effect of Antiasthma Drugs on Microvascular Leakage in Guinea Pig Airways

Abstract

We have studied the effect of intravenous epinephrine, albuterol, verapamil, and aminophylline on airway microvascular leakage in guinea pigs. Microvascular leakage was induced by platelet-activating factor (PAF; 50 ng/kg intravenously), which acts directly on venular endothelial cells, and measured by quantifying extravasation of Evans blue (EB) dye. Epinephrine (20 micrograms/kg) inhibited PAF-induced changes in dye leakage in larynx and main bronchi; at 80 and 160 micrograms/kg, significant inhibition was observed in all airways studied. This effect was reversed by phentolamine (2.5 mg/kg) or prazosin (100 micrograms/kg). By contrast, albuterol (20 to 320 micrograms/kg) and aminophylline (12.5 to 50 mg/kg) failed to inhibit dye leakage at any dose studied. Verapamil inhibited PAF-increased leakage in larynx, main bronchi, and intrapulmonary airways at the lowest dose tested (125 micrograms/kg), although inhibition was not dose dependent. These results suggest that the antiedema effect of epinephrine may be due to vasoconstriction rather than to a direct effect on endothelial cell contractility and that neither beta-agonists nor theophylline have an inhibitory effect. The inhibitory effect of epinephrine on airway microvascular leakage may have therapeutic implications for asthma.

Quantitative assessment of increased airway microvascular permeability to 125I‐labelled plasma fibrinogen induced by platelet activating factor and bradykinin

“…For example, PAF-induced tracheal leakage was virtually abolished in the presence of the PAF receptor antagonist WEB 2086, but was not significantly altered in the presence of histamine H -receptor antagonists, the leukotriene receptor antagonist SKF 104353, or the BK2-receptor antagonist, NPC 349. Similarly, the BK-induced response was significantly reduced by the receptor subtype-selective antagonist, NPC 349 and was therefore apparently mediated via BK2 receptors (Jin et al, 1989;Ichinose & Barnes., 1990 (Boschetto et al, 1989) and to blunt the microvascular leakage response to other inflammatory mediators including histamine (Persson & Erjefalt, 1979). In the present study, the leakage response to BK was significantly reduced by adrenaline, but only when the pretreatment time was reduced to 5 min and the concentration raised to 1001jg kg-1.…”

“…Studies to the present time have largely concentrated on measurement of mediator-induced plasma leakage from tracheal microvessels and have used readily diffusable plasma markers such as FITC-dextran, albumin (radiolabelled or associated with Evans blue dye) (Persson, 1987;Boschetto et al, 1989), or colloidal carbon particles (O'Donnell & Barnett, 1987). In the present study, we were interested in establishing the microvascular sites throughout the respiratory tree at which increased permeability was induced in response to PAF and BK.…”

Formoterol protects against platelet-activating factor-induced effects in asthma

“…Likewise, LABAs reduce the adhesion of inflammatory eosinophils and neutrophils to endothelial cells [21] and restrain their traffic from the vascular to the airway compartment [18,22]. b 2 agonists are efficacious when given by inhalation in animal models, suggesting inhibition of airway plasma exudation [22]. In normal subjects, salmeterol (50 mg b.i.d.…”

Theophylline in the management of asthma: time for reappraisal?

“…Data on the effect of theophylline on plasma exudation in asthmatic airways are lacking, but the observations on some of the effects of theophylline on the late asthmatic reaction could be explained in this way. Data obtained in guinea-pig tracheobronchial mucosa demonstrate that theophylline reduces the local airways inflammatory stimulus-induced plasma exudation, although this effect may be dependent on the strength of the stimulus [103][104][105][106].…”