Effect ofβ(in2)-adrenoceptor agonists against platelet-activating factor-induced airway microvascular leakage and bronchoconstriction in the guinea pig

Abstract

We have investigated the effect of inhaled formoterol (0.75 mg/ml, 60 breaths) and salbutamol (25 mg/ml, 60 breaths) against airway microvascular leakage and bronchoconstriction induced by inhaled platelet-activating factor (PAF) and histamine in anaesthetized guinea pigs. Lung resistance (RL) was measured for 6 min after challenge, followed by measurement of extravasation of Evans blue dye into airway tissues, used as an index of airway microvascular leakage. PAF (0.1, 0.4 and 1 mM; 30 breaths) caused a significant increase in RL and extravasation of dye, but the responses were smaller than those induced by histamine (5 mM, 30 breaths). Both formoterol and salbutamol caused a small but significant inhibition of extravasation in the distal intrapulmonary airways induced by PAF (0.1 and 0.4 mM for formoterol and 0.1 mM for salbutamol), and only formoterol reduced the increase in RL induced by 1 mM PAF. These drugs also inhibited both airway effects of histamine to a higher degree. In conclusion, formoterol and salbutamol can partly inhibit airway microvascular leakage and bronchoconstriction induced by inhaled PAF and histamine. The inhibitory potency of beta 2-adrenoceptor agonists may be dependent on the inflammatory mediator inducing the airway effects.

Decreased Serum Levels of P-Selectin and Eosinophil Cationic Protein in Patients with Mild Asthma after Inhaled Salbutamol

“…A statistically significant decrease in ECP was also recorded after salbutamol inhalation in the asthmatics. One may speculate that events leading to lower amounts of serum ECP may include ‘sealing’ of eosinophil membranes in vitro in a manner similar to that reported in other tissue membranes exposed to a β-2-receptor agonist [7]. We did not measure eosinophil counts in peripheral blood, and the reduction of P-selectin and ECP observed after salbutamol in this study could theoretically be related to increased margination of leukocytes.…”

“…Mechanisms of action, apart from relaxation of bronchial smooth muscle, also include multiple systemic effects such as a presumed anti-inflammatory effect, expressed as lessened plasma protein leakage from mucosal membranes [7, 8]and reduced plasma protein extravasation induced by bradykinin [9]. Furthermore, decreased number and activity state of circulating eosinophils as well as inhibited eosinophil recruitment to bronchial tissue have also been reported after β-2-receptor agonists [10].…”

Acute severe asthma: pathophysiology and pathobiology of gas exchange abnormalities

“…Although this contention also concurs with the inhibitory effects of β 2 -agonists, in the guinea-pig, on PAFinduced [74,75] and histamine-induced [76] disrupted airway permeability and acute plasma exudation, the efficacy of its potent airway relaxant influence on smooth muscle cannot be overlooked. The prevention of vascular leakage provoked by some drugs cannot be expected to have a rapid reversal, possibly because the rate of resolution of interstitial fluid is dependent mainly on the relatively slow lymphatic drainage.…”

“…Similarly, in the rat trachea, acute inhalation of a long-acting β 2 -agonist induced a similar effective antioedema effect, whether plasma exudation was increased by cell-mediated mediators (PAF) or neuron-mediated mediators (SP) [75]. In contrast, another long-acting β 2 -agonist, salmeterol, given over a 1 week period, did not inhibit the effects of PAF inhalation in normal individuals, possibly because of the induction of tachyphylaxis related to repeated dosing [77].…”

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

“…Moreover, formoterol reversed methacholine-induced bronchoconstriction as rapidly as salbutamol, and more rapidly than salmeterol [25]. Formoterol showed slightly greater potency over salbutamol against PAF-induced extravasation and bronchoconstriction in guinea pigs [26]. However, compared with formoterol, both salmeterol and salbutamol exhibited the greatest inhibition on neutrophil accumulation at a lower dose [27].…”