Inhibition of autonomic nerve-mediated inotropic responses in guinea pig atrium by bafilomycin A.
Neurosecretory vesicles actively accumulate neurotransmitter by consuming proton motive force generated by vacuolar H+-ATPase (V-ATPase). The effects of bafilomycin A, a macrolide antibiotic that inactivates V-ATPase, on nerve stimulation-mediated inotropic responses of the left atrium were studied to explore the role of the enzyme in the cholinergic and adrenergic neurotransmissions. On field stimulation, the contractility of paced atrium exhibited initial atropine-sensitive depression followed by propranolol-sensitive facilitation. Both the negative and positive inotropic effects were abolished by bafilomycin A. The inhibitions were irreversible and followed a similar time course and the inhibitory effects were accelerated by intense nerve stimulation. In contrast, bafilomycin A had no effect on the inotropic responses produced by muscarinic acetylcholine or alpha-adrenergic receptor agonist. Stimulation of neuronal nicotinic acetylcholine receptor also elicited biphasic changes of contractile force, which were depressed by bafilomycin A. Compared with the inhibitory effects on field stimulation, the depressions progressed slowly and incompletely. The results suggest that inhibition of V-ATPase depressed the synaptic transmissions at autonomic nerve-muscle junctions. Furthermore, bafilomycin A preferentially inhibited neurotransmitter release emanating from the immediately releasable pool.
Department of Pharmacology, College of Medicine, National Taiwan University, No. 1, Sec. 1, Taipei, Taiwan, ROC. sjhong@ha.mc.ntu.edu.tw
S J
SJ
Hong
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D016275:Atrial Function; D017776:Autonomic Pathways / Q000187:drug effects* / Q000502:physiology; D002304:Cardiac Pacing, Artificial; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004246:Dimethylphenylpiperazinium Iodide / Q000494:pharmacology; D005731:Ganglionic Stimulants / Q000494:pharmacology; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects / Q000294:innervation; D066298:In Vitro Techniques; D018942:Macrolides; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D009433:Neural Inhibition / Q000187:drug effects* / Q000502:physiology; D018722:Nicotinic Agonists / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D002316:Cardiotonic Agents; D005731:Ganglionic Stimulants; D018942:Macrolides; D018722:Nicotinic Agonists; C057620:bafilomycin A; D004246:Dimethylphenylpiperazinium Iodide