4^thInternational Conference on Chronic Obstructive Pulmonary Disease May 29-31, 2017 Osaka,Japan

Biography:

Hiroaki Kume obtained his MD from Toyama Medical and Pharmaceutical University in 1982.  He has completed his PhD in Department of Medicine (II), Nagoya University School of Medicine in 1990, and postdoctoral studies from School of Veterinary Medicine, University of Pennsylvania (Dr. Michael I. Kotlikoff’s Lab).  Currently, he works at Department of Respiratory Medicine and Allergology, Kindai University Faculty of Medicine, and focuses on investigating the characteristics of airway smooth muscle using physiological methods, with the goal of identifying therapeutic targets for asthma and COPD. 

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.