Effects of Formoterol on Contraction and Ca²⁺ Signaling of Mouse Airway Smooth Muscle Cells

Abstract

Formoterol, a long-acting b 2 -receptor agonist, is used to relieve bronchial constriction. However, formoterol is often a racemic formulation, and contains both (R,R)-and (S,S)-enantiomers. Because the activity of each isomer is poorly defined, the mechanisms by which formoterol relaxes smooth muscle cells (SMCs) of intrapulmonary airways are not well understood. Consequently, we compared the effects of (S,S)-, (R,R)-, and racemic formoterol, as well as (R)-albuterol, on the contraction and Ca 21 signaling of airway SMCs in mouse lung slices with phase-contrast and confocal microscopy. Small airways were contracted with methacholine and the associated SMCs displayed sustained Ca 21 oscillations and an increase in Ca 21 sensitivity. These contracted airways displayed a substantial, concentration-dependent relaxation in response to (R,R)-formoterol. Racemic formoterol had a similar potency as (R,R)-formoterol for relaxing airways. By contrast, (S,S)-formoterol only induced a small relaxation. In conjunction with relaxation, (R,R)-and racemic formoterol stopped and decreased the methacholineinduced Ca 21 oscillations and Ca 21 sensitivity of the SMCs, respectively, whereas (S,S)-formoterol only decreased the Ca 21 sensitivity. In these studies, (R,R)-and racemic formoterol had a similar, but much greater, potency than (R)-albuterol for relaxing mice airways. This action was quickly initiated at high concentrations by decreasing the frequency of Ca 21 oscillations, but was more usually mediated at lower concentrations by decreasing the Ca 21 sensitivity of the SMCs.

Human Airway Contraction and Formoterol-Induced Relaxation Is Determined by Ca2+ Oscillations and Ca2+ Sensitivity

“…The transient induction of Ca 21 oscillations indicates that IP 3 is rapidly metabolized. Similar results were found in mouse airways (35).…”

“…However, the specifics of this action vary with species and agonist. Isoproterenol appears to slow Ca 21 oscillations by inhibiting the open probability of the IP 3 R, whereas formoterol appears to act initially on Ca 21 sensitivity of mouse airways (35).…”

“…This implies either a high affinity of formoterol for the b 2 -receptor or, perhaps, a substantial partition of formoterol into the membrane of the airway SMCs (34). Interestingly, this longevity of action was not observed in mouse airways (35), implying that human b-receptors or membrane proteins are more susceptible to formoterol than are mouse receptors.…”

Association between Polymorphisms in Bitter Taste Receptor Genes and Clinical Features in Korean Asthmatics

“…Recently, Tan and Sanderson [46] have demonstrated that TAS2R agonists reversed bronchoconstriction by reducing the frequency of calcium oscillations and calcium sensitivity using mouse lung tissues. A similar mechanism has been reported in β 2 AR-induced bronchodilation as shown in previous research [2,45,46]. Taken together, the results in the current study implied that genetic variation in the TAS2R gene affects the airway reversibility by varying the degree of calcium oscillation and sensitivity of lung tissues.…”

“…Asthma is a chronic inflammatory disorder characterized by variable airflow obstruction and hyperresponsiveness of bronchi to different stimuli [1,2,3]. Most asthma types can be well controlled by current asthma medication, including inhaled corticosteroid with or without long-acting β 2 -agonists, leukotriene antagonists, theophylline, tiotropium, and even omalizumab; however, approximately 5−10% of all patients fail to achieve control despite the availability of optimal asthma treatments [4], leading to a great burden on health costs [5].…”