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Background: Cigarette smoking has been associated with diminished vasodilatory function in the airway circulation. It is possible that cigarette smoking similarly affects the pulmonary circulation before resting pulmonary circulatory abnormalities become manifested. The aim of this study was to compare the acute effect of inhaled albuterol on airway and pulmonary hemodynamic function as an index of β2-adrenoceptor-mediated vasodilation in smokers and never smokers.Methods: In 30 adults, airway and pulmonary vascular function was assessed before and 15 min after albuterol inhalation (270 μg). From mean systemic arterial pressure, cardiac output, airway blood flow, and mean pulmonary arterial pressure, airway vascular resistance (AVR) and pulmonary vascular resistance (PVR) were derived.Results: Albuterol induced a substantial drop in mean (± SE) PVR (-67.2% ± 5%), with no difference between groups. In contrast, the albuterol-induced decrease in AVR was significantly greater in never smokers than in smokers (-28.6% ± 3% vs -3.1% ± 6%; P < .02).Conclusions: These results are consistent with a dysfunction in a β2-adrenergic signaling pathway mediating vasorelaxation in the airway circulation of current smokers. The vasodilatory deficit in the airway circulation but not in the pulmonary circulation could be related to local differences in the impact of cigarette smoke on the vascular endothelium. [ABSTRACT FROM AUTHOR]

Exercise-related hyperventilation is associated with cooling and drying of the airway mucosa. A compensatory increase in the blood perfusion of the airway (Qaw) theoretically could counteract this effect. Subjects with asthma have been shown to have a blunted endothelium-dependent vasodilation in their airway, and this could attenuate their Qaw response to exercise. We measured the Qaw response to a 5-min exercise challenge in 15 subjects with mild asthma and 10 controls. Baseline mean(±SE) Qaw was 39.6±3.5 µl·min-1·ml-1 in asthmatics and 37.7±4.1 µl·min-1·ml-1 in controls (P=NS), but asthmatics had a blunted vasodilator response to inhaled albuterol (consistent with endothelial dysfunction). Mean Qaw increased significantly in both groups after exercise, reaching a peak of 48±14% at 15 min in asthmatics and 35±10% at 60 min in controls, respectively (P=NS between the groups). In the asthmatics, mean Qaw returned to baseline level by 30 min, whereas in the non-asthmatics, mean Qaw remained high through the 90 min measurement point. Since mean arterial pressure, the driving pressure for Qaw, did not change after exercise in either group, the increase in Qaw reflected local vasodilation in the airway. Thus, brief exercise led to a transient increase in the blood perfusion of the airway without a difference between asthmatics and controls, despite the presence of a blunted endotheliumdependent vasodilation in asthmatics. This suggests that the exerciserelated increase in Qaw was not endothelium dependent. [ABSTRACT FROM AUTHOR]

Abstract: Corticosteroids inhibit organic cation transporters (OCTs) that play an important role in drug absorption, tissue distribution and elimination. Corticosteroid sensitivity of bronchodilator trafficking in the airway tissue, however, is poorly understood. To assess the effects of inhaled corticosteroids on airway absorption and disposal mechanisms of long-acting β2-agonists, human airway epithelial and smooth muscle cell uptake of tritiated formoterol and salmeterol was measured in vitro. Corticosteroids caused a rapid, concentration-dependent inhibition of uptake of the cationic formoterol by airway smooth muscle cells, but not airway epithelial cells. Uptake of the non-charged lipophilic salmeterol was corticosteroid-insensitive in both cell types. In smooth muscle cells, inhaled corticosteroids inhibited formoterol uptake with a novel potency rank order: des-ciclesonide > budesonide > beclomethasone 17-monopropionate > beclomethasone dipropionate > ciclesonide > fluticasone. The inhibitory action was rapidly reversible, and was not enhanced by prolonged corticosteroid exposure or sensitive to a transcription inhibitor. Suppression of OCT3 expression using lentivirus-mediated production of shRNA reduced corticosteroid sensitivity of formoterol uptake by smooth muscle cells. Our data support a corticosteroid insensitive absorption and a corticosteroid-sensitive disposition mechanism for cationic long-acting β2-agonist bronchodilators in the airway. Potency rank order and other ‘classical’ features of anti-inflammatory effects do not apply to inhaled corticosteroids’ rapid drug transport actions. [Copyright &y& Elsevier]

Background: Long-term glucocorticoid therapy has been suggested to improve airway and airway vascular smooth muscle responsiveness to inhaled β2-agonists in patients with asthma. Objective: We sought to assess whether a single dose of an inhaled glucocorticoid acutely potentiates β2-adrenergic airway and airway vascular smooth muscle reactivity in asthma. Methods: In 10 asthmatic and 10 healthy subjects, airway blood flow and FEV1 were measured before and 30 minutes after fluticasone or placebo inhalation and 15 minutes after the subsequent inhalation of racemic albuterol (0.6 mg or 1.25 mg) or (R)-albuterol (0.3 mg or 0.6 mg). Results: In healthy subjects all albuterol formulations increased airway blood flow equally after placebo or fluticasone pretreatment. In asthmatic subjects airway blood flow response was blunted after placebo and acutely restored after fluticasone pretreatment. Fluticasone pretreatment did not increase FEV1 responses to any albuterol formulation, except 0.6 mg racemic albuterol. Conclusion: A single dose of an inhaled glucocorticoid restores β2-adrenergic airway vasodilator responses in patients with mild asthma. The mechanism of this rapid glucocorticoid effect remains to be clarified. [Copyright &y& Elsevier]

Background: Organic cation transporters (OCTs) have an important role in tissue distribution and elimination of cationic drugs. Carrier-mediated disposal of cationic bronchodilators in the airway tissue, however, is incompletely understood. Objectives: We sought to assess the uptake of long-acting β2-agonist bronchodilators by bronchial and vascular smooth muscle cells. Methods: Human airway cells and tissues obtained from organ donors were evaluated for cationic drug transporter expression by means of quantitative RT-PCR and immunofluorescence. For in vitro functional studies, tritiated formoterol and tritiated salmeterol uptake by bronchial and vascular smooth muscle cells was measured. Results: Quantitative RT-PCR analysis revealed high mRNA levels for the corticosteroid-sensitive OCT3 in bronchial and vascular smooth muscle cells. Immunofluorescence staining of airway sections confirmed OCT3 expression in these cells. In bronchial smooth muscle cells, uptake of the cationic formoterol was inhibited with OCT inhibitors. Corticosteroids also inhibited formoterol uptake through a rapid (within 15 minutes) nongenomic action, with the following rank order for inhibitory potency: corticosterone > budesonide > fluticasone. The corticosteroid-induced inhibition was significantly higher in vascular than bronchial smooth muscle cells. In comparison with formoterol, uptake of the noncharged lipophilic salmeterol was approximately 10-fold higher and insensitive to all OCT inhibitors and corticosteroids. Conclusions: Our findings suggest that corticosteroids, through OCT3 inhibition, rapidly interfere with the disposal of cationic drugs by smooth muscle cells in the airway. Clinical implications: This novel immediate interaction between corticosteroids and cationic β2-agonist bronchodilators supports the use of such combinations in the pharmacotherapy of asthma. [Copyright &y& Elsevier]

Background: Long-term glucocorticoid therapy has been suggested to improve airway and airway vascular smooth muscle responsiveness to inhaled beta(2)-agonists in patients with asthma., Objective: We sought to assess whether a single dose of an inhaled glucocorticoid acutely potentiates beta(2)-adrenergic airway and airway vascular smooth muscle reactivity in asthma., Methods: In 10 asthmatic and 10 healthy subjects, airway blood flow and FEV(1) were measured before and 30 minutes after fluticasone or placebo inhalation and 15 minutes after the subsequent inhalation of racemic albuterol (0.6 mg or 1.25 mg) or (R)-albuterol (0.3 mg or 0.6 mg)., Results: In healthy subjects all albuterol formulations increased airway blood flow equally after placebo or fluticasone pretreatment. In asthmatic subjects airway blood flow response was blunted after placebo and acutely restored after fluticasone pretreatment. Fluticasone pretreatment did not increase FEV(1) responses to any albuterol formulation, except 0.6 mg racemic albuterol., Conclusion: A single dose of an inhaled glucocorticoid restores beta(2)-adrenergic airway vasodilator responses in patients with mild asthma. The mechanism of this rapid glucocorticoid effect remains to be clarified.

Inhaled glucocorticosteroids (corticosteroids) continue to be the standard treatment for nonexacerbated asthma because of their anti-inflammatory actions. These include effects on the airway vasculature, which participates in the inflammatory process. Corticosteroids are now known to have genomic as well as nongenomic effects that involve different mechanisms of action. The genomic vascular effects of inhaled corticosteroids include a decrease in airway wall hypervascularity (inhibition of angiogenesis), reversal of the increased airway blood flow, and inhibition of vascular hyperpermeability and leukocyte recruitment. In addition, inhaled corticosteroids decrease airway blood flow acutely (within minutes) and reversibly through a nongenomic action that involves noradrenergic neurotransmission. This effect is likely related to the binding of inhaled corticosteroids to the plasma membrane of and the inhibition of the extraneuronal monoamine transporter on airway vascular smooth muscle cells, thereby increasing norepinephrine concentrations at alpha(1)-adrenoceptors and causing airway vascular smooth muscle contraction and a decrease in airway blood flow. Inasmuch as vascular hyperperfusion is a manifestation of airway inflammation, the acute vasoconstriction could also be considered an anti-inflammatory effect of inhaled corticosteroids.