Activation of endogenous GABAA channels on airway smooth muscle potentiates isoproterenol-mediated relaxation.
Reactive airway disease predisposes patients to episodes of acute smooth muscle mediated bronchoconstriction. We have for the first time recently demonstrated the expression and function of endogenous ionotropic GABA(A) channels on airway smooth muscle cells. We questioned whether endogenous GABA(A) channels on airway smooth muscle could augment beta-agonist-mediated relaxation. Guinea pig tracheal rings or human bronchial airway smooth muscles were equilibrated in organ baths with continuous digital tension recordings. After pretreatment with or without the selective GABA(A) antagonist gabazine (100 muM), airway muscle was contracted with acetylcholine or beta-ala neurokinin A, followed by relaxation induced by cumulatively increasing concentrations of isoproterenol (1 nM to 1 muM) in the absence or presence of the selective GABA(A) agonist muscimol (10-100 muM). In separate experiments, guinea pig tracheal rings were pretreated with the large conductance K(Ca) channel blocker iberiotoxin (100 nM) after an EC(50) contraction with acetylcholine but before cumulatively increasing concentrations of isoproterenol (1 nM to 1 uM) in the absence or presence of muscimol (100 uM). GABA(A) activation potentiated the relaxant effects of isoproterenol after an acetylcholine or tachykinin-induced contraction in guinea pig tracheal rings or an acetylcholine-induced contraction in human endobronchial smooth muscle. This muscimol-induced potentiation of relaxation was abolished by gabazine pretreatment but persisted after blockade of the maxi K(Ca) channel. Selective activation of endogenous GABA(A) receptors significantly augments beta-agonist-mediated relaxation of guinea pig and human airway smooth muscle, which may have important therapeutic implications for patients in severe bronchospasm.
Gallos
George
G
Dept. of Anesthesiology, College of Physicians and Surgeons of Columbia Univ., 650 W. 168 St., P&S Box 46, New York, NY, USA. gg2125@columbia.edu
Gleason
Neil R
NR
Zhang
Yi
Y
Pak
Sang-Woo
SW
Sonett
J R
JR
Yang
Jay
J
Emala
Charles W
CW
D000109:Acetylcholine / Q000494:pharmacology; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D018756:GABA Antagonists / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology*; D009126:Muscle Relaxation / Q000187:drug effects*; D009130:Muscle, Smooth / Q000378:metabolism*; D015288:Neurokinin A / Q000031:analogs & derivatives / Q000494:pharmacology; D009924:Organ Culture Techniques; D010446:Peptide Fragments / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000378:metabolism*; D014132:Trachea / Q000378:metabolism*; D014665:Vasodilator Agents / Q000494:pharmacology
D000318:Adrenergic beta-Agonists; D018756:GABA Antagonists; D010446:Peptide Fragments; D010455:Peptides; D011724:Pyridazines; D011963:Receptors, GABA-A; D014665:Vasodilator Agents; C064218:neurokinin A (4-10), beta-Ala(8)-; C064719:iberiotoxin; D015288:Neurokinin A; C049853:gabazine; D000251:Adenosine Triphosphatases; C029321:calcium potassium ATPase; D007545:Isoproterenol; D000109:Acetylcholine
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