β-adrenergic augmentation of flecainide-induced conduction slowing in canine purkinje fibers

Kevin T. Cragun, Susan B. Johnson, Douglas L Packer

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Background: This study was undertaken to test the hypothesis that β- adrenergic stimulation in the setting of membrane depolarization will potentiate flecainide-induced conduction slowing. Methods and Results: To elucidate the potential mechanism for the flecainide proarrhythmia observed in CAST, the voltage dependence of β-adrenergic modulation of impulse propagation in eight flecainide-superfused canine Purkinje fibers was examined with a dual-microelectrode technique. At physiological membrane potentials (V(m)) (K +](o)=5.4 μmol), 1 μmol flecainide decreased V(max) from 698±55 to 610±72 V/s (P=.003) and squared conduction velocity (Θ 2) from 2.11±1.1 to 1.72±0.9 (m/s) 2 (P=.001). With K + depolarization to V(m)=-70 mV, flecainide further reduced V(max) from 306±101 to 245±65 V/s and Θ 2 from 1.12±0.4 to 0.99±0.6 (m/s) 2, producing a 2.0-mV hyperpolarizing shift of apparent Na + channel availability curves derived from Θ 2. The addition of 1 μmol isoproterenol to flecainide-superfused fibers at physiological V(m) increased Θ 2 by 8% to 1.84±0.6 (m/s) 2 (P<.01) without altering V(max). At -70 mV, the addition of isoproterenol magnified the flecainide-induced reduction of V(max) an additional 24% to 185 ±52 V/s (P<.01) and Θ 2 by 17% to 0.82±0.5 (m/s) 2 (P=.04), producing an additional 1.8-mV (P=.002) and 1.9-mV (P=.002) hyperpolarizing shift in the apparent Na + channel inactivation curves generated from V(max) and Θ 2, respectively. At physiological V(m), the action potential duration (APD 95) was reduced from 307±35 to 269±27 ms (P<.001) by flecainide and subsequently to 217±4 ms (P<.001) with isoproterenol addition. With 12 mmol/L K +, APD 95 decreased from 198±23 to 182±17 ms (P=.005) with flecainide and to 164±10 ms (P=.004) with isoproterenol. Conclusions: At depolarized V(m), isoproterenol amplified the flecainide-induced reduction of V(max) and Θ 2, suggesting a further adrenergic-mediated reduction of Na + current. Consequently, the synergy between catecholamines and flecainide at depolarized V(m) and the shortened APD 95 could facilitate arrhythmogenesis in the presence of underlying ischemia.

Original languageEnglish (US)
Pages (from-to)2701-2708
Number of pages8
JournalCirculation
Volume96
Issue number8
StatePublished - Oct 21 1997

Fingerprint

Flecainide
Purkinje Fibers
Adrenergic Agents
Canidae
pamidronate
Isoproterenol
Microelectrodes
Membrane Potentials
Action Potentials
Catecholamines
Ischemia

Keywords

  • Flecainide
  • Isoproterenol
  • Receptors, adrenergic, beta
  • Sodium

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

β-adrenergic augmentation of flecainide-induced conduction slowing in canine purkinje fibers. / Cragun, Kevin T.; Johnson, Susan B.; Packer, Douglas L.

In: Circulation, Vol. 96, No. 8, 21.10.1997, p. 2701-2708.

Research output: Contribution to journalArticle

Cragun, Kevin T. ; Johnson, Susan B. ; Packer, Douglas L. / β-adrenergic augmentation of flecainide-induced conduction slowing in canine purkinje fibers. In: Circulation. 1997 ; Vol. 96, No. 8. pp. 2701-2708.
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T1 - β-adrenergic augmentation of flecainide-induced conduction slowing in canine purkinje fibers

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AU - Johnson, Susan B.

AU - Packer, Douglas L

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N2 - Background: This study was undertaken to test the hypothesis that β- adrenergic stimulation in the setting of membrane depolarization will potentiate flecainide-induced conduction slowing. Methods and Results: To elucidate the potential mechanism for the flecainide proarrhythmia observed in CAST, the voltage dependence of β-adrenergic modulation of impulse propagation in eight flecainide-superfused canine Purkinje fibers was examined with a dual-microelectrode technique. At physiological membrane potentials (V(m)) (K +](o)=5.4 μmol), 1 μmol flecainide decreased V(max) from 698±55 to 610±72 V/s (P=.003) and squared conduction velocity (Θ 2) from 2.11±1.1 to 1.72±0.9 (m/s) 2 (P=.001). With K + depolarization to V(m)=-70 mV, flecainide further reduced V(max) from 306±101 to 245±65 V/s and Θ 2 from 1.12±0.4 to 0.99±0.6 (m/s) 2, producing a 2.0-mV hyperpolarizing shift of apparent Na + channel availability curves derived from Θ 2. The addition of 1 μmol isoproterenol to flecainide-superfused fibers at physiological V(m) increased Θ 2 by 8% to 1.84±0.6 (m/s) 2 (P<.01) without altering V(max). At -70 mV, the addition of isoproterenol magnified the flecainide-induced reduction of V(max) an additional 24% to 185 ±52 V/s (P<.01) and Θ 2 by 17% to 0.82±0.5 (m/s) 2 (P=.04), producing an additional 1.8-mV (P=.002) and 1.9-mV (P=.002) hyperpolarizing shift in the apparent Na + channel inactivation curves generated from V(max) and Θ 2, respectively. At physiological V(m), the action potential duration (APD 95) was reduced from 307±35 to 269±27 ms (P<.001) by flecainide and subsequently to 217±4 ms (P<.001) with isoproterenol addition. With 12 mmol/L K +, APD 95 decreased from 198±23 to 182±17 ms (P=.005) with flecainide and to 164±10 ms (P=.004) with isoproterenol. Conclusions: At depolarized V(m), isoproterenol amplified the flecainide-induced reduction of V(max) and Θ 2, suggesting a further adrenergic-mediated reduction of Na + current. Consequently, the synergy between catecholamines and flecainide at depolarized V(m) and the shortened APD 95 could facilitate arrhythmogenesis in the presence of underlying ischemia.

AB - Background: This study was undertaken to test the hypothesis that β- adrenergic stimulation in the setting of membrane depolarization will potentiate flecainide-induced conduction slowing. Methods and Results: To elucidate the potential mechanism for the flecainide proarrhythmia observed in CAST, the voltage dependence of β-adrenergic modulation of impulse propagation in eight flecainide-superfused canine Purkinje fibers was examined with a dual-microelectrode technique. At physiological membrane potentials (V(m)) (K +](o)=5.4 μmol), 1 μmol flecainide decreased V(max) from 698±55 to 610±72 V/s (P=.003) and squared conduction velocity (Θ 2) from 2.11±1.1 to 1.72±0.9 (m/s) 2 (P=.001). With K + depolarization to V(m)=-70 mV, flecainide further reduced V(max) from 306±101 to 245±65 V/s and Θ 2 from 1.12±0.4 to 0.99±0.6 (m/s) 2, producing a 2.0-mV hyperpolarizing shift of apparent Na + channel availability curves derived from Θ 2. The addition of 1 μmol isoproterenol to flecainide-superfused fibers at physiological V(m) increased Θ 2 by 8% to 1.84±0.6 (m/s) 2 (P<.01) without altering V(max). At -70 mV, the addition of isoproterenol magnified the flecainide-induced reduction of V(max) an additional 24% to 185 ±52 V/s (P<.01) and Θ 2 by 17% to 0.82±0.5 (m/s) 2 (P=.04), producing an additional 1.8-mV (P=.002) and 1.9-mV (P=.002) hyperpolarizing shift in the apparent Na + channel inactivation curves generated from V(max) and Θ 2, respectively. At physiological V(m), the action potential duration (APD 95) was reduced from 307±35 to 269±27 ms (P<.001) by flecainide and subsequently to 217±4 ms (P<.001) with isoproterenol addition. With 12 mmol/L K +, APD 95 decreased from 198±23 to 182±17 ms (P=.005) with flecainide and to 164±10 ms (P=.004) with isoproterenol. Conclusions: At depolarized V(m), isoproterenol amplified the flecainide-induced reduction of V(max) and Θ 2, suggesting a further adrenergic-mediated reduction of Na + current. Consequently, the synergy between catecholamines and flecainide at depolarized V(m) and the shortened APD 95 could facilitate arrhythmogenesis in the presence of underlying ischemia.

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KW - Isoproterenol

KW - Receptors, adrenergic, beta

KW - Sodium

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