Hiroake Kume
Kindai University, Japan
Title: Involvement of allosteric GPCR modulation in synergistic effects of beta-adrenergic receptor agonists with muscarinic receptor antagonists in airway smooth muscle
Biography
Biography: Hiroake Kume
Abstract
Rationale: Long acting b2-adrenergic receptor agonists (LABAs) and muscarinic receptor antagonists (LAMAs), are used as bronchodilators to improve lung function, symptoms, and QOL in COPD. Since these agents may cause a desirable cross talk between b2-adrenergic and muscarinic receptors, combination of LABA with LAMA has pharmacological rationale as a bronchodilator therapy. This study was designed to determine mechanisms underlying synergistic interaction between these agents with a focus on allosteric modulation.
Methods: For record of isometric tension, the strips of tracheal smooth muscle of guinea pigs were placed in the organ bath and were perfused with the physiological solution. The responses to an agent under each condition were described as a percentage of the maximal response. Allosteric modulation was analyzed using concentration-inhibition curves.
Results: 1 nM tiotropium, LAMA, caused a modest inhibition (5.6%, n = 8) of 10 mM MCh-induced contraction. Relaxant action of 0.3 nM formoterol, LABA, was increased from 12.1 to 35.8 percent inhibition (P<0.01) in the presence of tiotropium (1 nM). When formoterol was cumulatively applied to the tissues pre contracted by 10 mM MCh, EC50 was 1.8 nM, and the maximal inhibition was 68.9% (intrinsic efficacy). In the presence of 1 nM tiotropium, concentration-inhibition curves for formoterol was shifted to the left, and moved to upper side. EC50 was decreased to 0.3 nM (P<0.05), and maximal inhibition was augmented to 92.4% (P<0.01).
Conclusions: Tiotropium synergistically enhances formoterol-induced relaxation against muscarinic contraction in airway smooth muscle. Since tiotropium reduces the EC50 and elevates the maximal inhibition in the concentration-inhibition curves for formoterol against MCh, tiotropium binds to allosteric sites on b2-adrenergic receptors, leading to enhancements of affinity and efficacy to formoterol via allosteric modulation. Therefore, allosteric modulation contributes to synergistic effects between LAMA and LABA, and combination of these agents may be beneficial to therapy for COPD.