Prejunctional GABA-B inhibition of cholinergic, neurally-mediated airway contractions in guinea-pigs.
GABA is a known inhibitory neurotransmitter in the CNS. Recent studies have also demonstrated the presence of GABA in peripheral tissue, including lung. To delineate a role for GABA in lung, the effect of GABA and selective GABA agonists and antagonists on neuronally-induced airway contractions in guinea pigs were studied. In vitro, tracheal contractions induced by electrical field stimulation (EFS) were inhibited by tetrodotoxin and atropine indicating that the contractions were mediated by neuronal release of acetylcholine. The contractions caused by EFS, but not those by exogenous acetylcholine, were inhibited by GABA (EC50 = 4.5 microM) and the selective GABA-B agonist baclofen (EC50 = 9 microM), but not by the GABA-A agonist, muscimol. The inhibitory effect of baclofen was not affected by the GABA-A antagonist, bicuculline, but was significantly reversed with the GABA-B antagonists, 3-aminopropylphosphonic acid (3-APPA) (pA2 = 4.5) and 2-hydroxysaclofen (pA2 = 4.1). In vivo, vagal nerve stimulation (5 V, 20 Hz, 0.5 ms, 5 s) in anesthetized, mechanically ventilated guinea-pigs caused cholinergic-dependent bronchospasms that were inhibited by intravenous GABA (3 and 10 mg/kg) and baclofen (1-10 mg/kg), but not by muscimol. The inhibitory effects of GABA and baclofen against vagal bronchospasm were blocked by 3-APPA (5 mg/kg, i.v.), but not by bicuculline. Responses to the GABA-B agonists were unaltered after the treatment of animals with phentolamine or propranolol to block alpha-adrenergic and beta-adrenergic receptors, respectively. Bronchospasm due to intravenous methacholine was also unchanged by GABA and baclofen.(ABSTRACT TRUNCATED AT 250 WORDS)
Chapman
R W
RW
Schering-Plough Research, Department of Allergy, Bloomfield, New Jersey 07003.
Danko
G
G
Rizzo
C
C
Egan
R W
RW
Mauser
P J
PJ
Kreutner
W
W
D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects / Q000294:innervation; D001986:Bronchial Spasm / Q000503:physiopathology; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D004558:Electric Stimulation; D058787:GABA-A Receptor Antagonists; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects / Q000294:innervation* / Q000502:physiology; D010275:Parasympathetic Nervous System / Q000502:physiology*; D011437:Propylamines / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects / Q000294:innervation; D014630:Vagus Nerve / Q000502:physiology
D016085:Bronchoconstrictor Agents; D058787:GABA-A Receptor Antagonists; D011437:Propylamines; C011649:3-aminopropylphosphonic acid; D001640:Bicuculline