Effect of Ba 679 BR, a novel long-acting anticholinergic agent, on cholinergic neurotransmission in guinea pig and human airways.
We investigated the effect of Ba 679 BR, a novel long-acting antimuscarinic agent, on cholinergic neural responses in guinea pig and human airways. Ba 679 BR, atropine, and ipratropium bromide inhibited electrical field stimulation (EFS)-induced contraction with IC50 values of 0.17, 0.74, and 0.58 nM, respectively, in guinea pig trachea. Ba 679 BR had a slower onset and longer duration of action than atropine or ipratropium bromide (the times required to attain 50% of the maximum response were 34.8, 3.8, and 7.6 min, respectively, and the times required for 50% recovery of the response were 540, 31.6, and 81.2 min, respectively). Ba 679 BR, as well as atropine and ipratropium bromide, facilitated evoked [3H]acetylcholine release (an inhibitory effect on prejunctional muscarinic M2 receptors). The facilitation of acetylcholine release by Ba 679 BR was lost 2 h after washout, however, when there was still complete blockade of cholinergic contractile responses evoked by EFS (an effect on airway smooth muscle M3 receptors), confirming binding studies that suggest that Ba 679 BR shows "kinetic receptor subtype selectivity" for M3 over M2 receptors. The high potency, slow onset, and long duration of action of Ba 679 BR were also observed in human bronchi, suggesting that Ba 679 BR may be a useful drug to provide convenient therapy for patients with obstructive airway disease.
Department of Thoracic Medicine, Royal Brompton National Heart and Lung Institute, London, United Kingdom.
T
T
Takahashi
M G
MG
Belvisi
H
H
Patel
J K
JK
Ward
S
S
Tadjkarimi
M H
MH
Yacoub
P J
PJ
Barnes
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001980:Bronchi / Q000187:drug effects / Q000294:innervation; D001993:Bronchodilator Agents / Q000494:pharmacology*; D018680:Cholinergic Antagonists / Q000494:pharmacology*; D002799:Cholinergic Fibers / Q000187:drug effects* / Q000502:physiology; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000294:innervation; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology; D012602:Scopolamine Derivatives / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects*; D013997:Time Factors; D000069447:Tiotropium Bromide; D014132:Trachea / Q000187:drug effects* / Q000294:innervation
D001993:Bronchodilator Agents; D018680:Cholinergic Antagonists; D011976:Receptors, Muscarinic; D012602:Scopolamine Derivatives; D000109:Acetylcholine; D000069447:Tiotropium Bromide