Mechanisms of Verapamil Inhibition of Action Potential Firing in Rat Intracardiac Ganglion Neurons1
- 1Department of Physiology and Pharmacology, University of Queensland, Brisbane, Queensland, Australia (R.C.H., D.J.A.); and2Dipartmento Biologia Cellulare e Molecolare, Universita’ di Perugia, Perugia, Italy (C.T., L.C., A.P., F.F.)
Abstract
The effects of verapamil and related phenylalkylamines on neuronal excitability were investigated in isolated neurons of rat intracardiac ganglia using whole-cell perforated patch-clamp recording. Verapamil (≥10 μM) inhibits tonic firing observed in response to depolarizing current pulses at 22°C. The inhibition of discharge activity is not due to block of voltage-dependent Ca2+channels because firing is not affected by 100 μM Cd2+. The K+ channel inhibitors charybdotoxin (100 nM), 4-aminopyridine (0.5 mM), apamin (30–100 nM), and tetraethylammonium ions (1 mM) also have no effect on firing behavior at 22°C. Verapamil does not antagonize the acetylcholine-induced inhibition of the muscarine-sensitive K+ current (M-current) in rat intracardiac neurons. Verapamil inhibits the delayed outwardly rectifying K+ current with an IC50 value of 11 μM, which is approximately 7-fold more potent than its inhibition of high voltage-activated Ca2+ channel currents. These data suggest that verapamil inhibits tonic firing in rat intracardiac neurons primarily via inhibition of delayed outwardly rectifying K+ current. Verapamil inhibition of action potential firing in intracardiac neurons may contribute, in part, to verapamil-induced tachycardia.
Footnotes
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Send reprint requests to: Dr. David J. Adams, Department of Physiology and Pharmacology, University of Queensland, Brisbane, Queensland 4072, Australia. E-mail: dadams{at}plpk.uq.edu.au
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↵1 This work was supported by National Health and Medical Research Council of Australia Grant 961138 (to D.J.A.) and Grant 92.689.CT04 from Italian Consiglio Nazionale Ricerch (to F.F.).
- Abbreviations:
- ACh
- acetylcholine
- IK(DR)
- delayed rectifier K+ currents
- IM
- muscarine-sensitive K+ current
- TTX
- tetrodotoxin
- TEA
- tetraethylammonium ions
- D600
- methoxyverapamil hydrochloride
- 4-AP
- 4-aminopyridine
- ChTX
- charybdotoxin
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- Received February 22, 1999.
- Accepted February 22, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
