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Does lindane (gamma-hexachlorocyclohexane) increase the rapid delayed rectifier outward K+ current (IKr) in frog atrial myocytes?

Sauviat MP, Colas A, Pages N - BMC Pharmacol. (2002)

Bottom Line: Under voltage-clamp conditions, lindane (1.7 microM) increased the amplitude of the outward current (Iout) which developed in Ringer solution containing TTX (0.6 microM), Cd2+ (1 mM) and TEA (10 mM).The lindane-increased Iout was not sensitive to Sr2+ (5 mM).It was blocked by subsequent addition of quinidine (0.5 mM) or E-4031 (1 microM).

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Affiliation: Laboratoire d'Optique et Biosciences, Unité INSERM 451, UMR CNRS 7645, Ecole Polytechnique-ENSTA, F-91128 Palaiseau Cedex, France. martin-pierre.sauviat@polytechnique.fr

ABSTRACT

Background: The effects of lindane, a gamma-isomer of hexachlorocyclohexane, were studied on transmembrane potentials and currents of frog atrial heart muscle using intracellular microelectrodes and the whole cell voltage-clamp technique.

Results: Lindane (0.34 microM to 6.8 microM) dose-dependently shortened the action potential duration (APD). Under voltage-clamp conditions, lindane (1.7 microM) increased the amplitude of the outward current (Iout) which developed in Ringer solution containing TTX (0.6 microM), Cd2+ (1 mM) and TEA (10 mM). The lindane-increased Iout was not sensitive to Sr2+ (5 mM). It was blocked by subsequent addition of quinidine (0.5 mM) or E-4031 (1 microM). E-4031 lengthened the APD; it prevented or blocked the lindane-induced APD shortening.

Conclusions: In conclusion, our data revealed that lindane increased the quinidine and E-4031-sensitive rapid delayed outward K+ current which contributed to the AP repolarization in frog atrial muscle.

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Effects of E-4031 (1 microM) and lindane (3.4 microM) on the action potential (AP). Superimposed traces of the AP recorded on frog auricle using intracellular microelectrodes. A. a): AP recorded before and after addition of E-4031 to the Ringer solution; b) further addition of lindane to the solution containing E-4031. B). AP recorded in the Ringer solution containing lindane before and after further addition of E-4031.
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Figure 4: Effects of E-4031 (1 microM) and lindane (3.4 microM) on the action potential (AP). Superimposed traces of the AP recorded on frog auricle using intracellular microelectrodes. A. a): AP recorded before and after addition of E-4031 to the Ringer solution; b) further addition of lindane to the solution containing E-4031. B). AP recorded in the Ringer solution containing lindane before and after further addition of E-4031.

Mentions: Intracellular recordings of transmembrane potentials show that the addition of lindane (3.4 microM) to the Ringer solution did not alter the RP, decreased the amplitude of the OS and shortened the plateau duration (Fig. 1). The effects of lindane on the AP were dose-dependent. Table 1 shows that lindane (0.34 microM to 6.8 microM) did not significantly modify RP; lindane (0.34 microM) slightly but significantly (P < 0.05) shortened APD40 and APD10 by 6% and 3%, respectively. APD40 and APD10 shortening was not significantly increased by increasing the lindane concentration to 6.8 microM. APD0 was only significantly shortened (P < 0.05) in the presence of lindane 3.4 microM in the Ringer solution (Table 1). Under voltage-clamp conditions, the remaining currents recorded in the Ringer solution containing TTX (0.6 microM), Cd2+ (1 mM) and TEA (10 mM) (control solution) mainly corresponded to the leak current and to the background inward rectifier K+ current (IK1) (Fig. 2A). Current-voltage relationships plotted for the current measured at the end of the clamp step potential (V) show that the current was inward (Iin) at V more negative than HP and outward (Iout) at V more positive than HP (Fig. 2B). The addition of lindane (1.7 microM) to the control solution increased Iout but did not alter the tail current (Fig. 2A). Current-voltage relationships of Fig. 2B show that lindane (1.7 microM) increased the amplitude of Iout which developed at membrane potentials more positive than -70 mV. Subsequent addition of Sr2+ (5 mM) to the control solution containing lindane (1.7 μM) decreased the amplitude of Iout in the membrane potential range of -120 mV to +30 mV (Fig. 2B), whereas further addition of quinidine (0.5 mM) to the solution containing both, lindane and Sr2+, suppressed the remaining Iout whatever the membrane potential tested (Fig. 2B). Lindane (1.7 microM) increased the magnitude of Iout which developed when IK1 was blocked by the addition of Ba2+ (2 mM) to the control solution (Fig. 3A). Current-voltage relationships show that the lindane-increased Iout developed at membrane potentials more positive than -20 mV (Fig. 3B). Subsequent addition of E-4031 (1 microM) to the control solution containing lindane blocked the lindane-increased Iout (Fig. 2A) whatever the membrane potential studied (Fig. 3B). The addition of E-4031 (2 microM) to the Ringer solution did not modify RP but prolonged APD (Fig. 4Aa) and further addition of lindane (3.4 microM) to the solution containing E-4031 (2 microM) did not modify the APD (Fig. 4Ab). Conversely, the addition of E-4031 (2 microM) to the Ringer solution containing lindane (3.4 microM) lengthened APD0, APD40 and APD10 (Fig. 4B).


Does lindane (gamma-hexachlorocyclohexane) increase the rapid delayed rectifier outward K+ current (IKr) in frog atrial myocytes?

Sauviat MP, Colas A, Pages N - BMC Pharmacol. (2002)

Effects of E-4031 (1 microM) and lindane (3.4 microM) on the action potential (AP). Superimposed traces of the AP recorded on frog auricle using intracellular microelectrodes. A. a): AP recorded before and after addition of E-4031 to the Ringer solution; b) further addition of lindane to the solution containing E-4031. B). AP recorded in the Ringer solution containing lindane before and after further addition of E-4031.
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Figure 4: Effects of E-4031 (1 microM) and lindane (3.4 microM) on the action potential (AP). Superimposed traces of the AP recorded on frog auricle using intracellular microelectrodes. A. a): AP recorded before and after addition of E-4031 to the Ringer solution; b) further addition of lindane to the solution containing E-4031. B). AP recorded in the Ringer solution containing lindane before and after further addition of E-4031.
Mentions: Intracellular recordings of transmembrane potentials show that the addition of lindane (3.4 microM) to the Ringer solution did not alter the RP, decreased the amplitude of the OS and shortened the plateau duration (Fig. 1). The effects of lindane on the AP were dose-dependent. Table 1 shows that lindane (0.34 microM to 6.8 microM) did not significantly modify RP; lindane (0.34 microM) slightly but significantly (P < 0.05) shortened APD40 and APD10 by 6% and 3%, respectively. APD40 and APD10 shortening was not significantly increased by increasing the lindane concentration to 6.8 microM. APD0 was only significantly shortened (P < 0.05) in the presence of lindane 3.4 microM in the Ringer solution (Table 1). Under voltage-clamp conditions, the remaining currents recorded in the Ringer solution containing TTX (0.6 microM), Cd2+ (1 mM) and TEA (10 mM) (control solution) mainly corresponded to the leak current and to the background inward rectifier K+ current (IK1) (Fig. 2A). Current-voltage relationships plotted for the current measured at the end of the clamp step potential (V) show that the current was inward (Iin) at V more negative than HP and outward (Iout) at V more positive than HP (Fig. 2B). The addition of lindane (1.7 microM) to the control solution increased Iout but did not alter the tail current (Fig. 2A). Current-voltage relationships of Fig. 2B show that lindane (1.7 microM) increased the amplitude of Iout which developed at membrane potentials more positive than -70 mV. Subsequent addition of Sr2+ (5 mM) to the control solution containing lindane (1.7 μM) decreased the amplitude of Iout in the membrane potential range of -120 mV to +30 mV (Fig. 2B), whereas further addition of quinidine (0.5 mM) to the solution containing both, lindane and Sr2+, suppressed the remaining Iout whatever the membrane potential tested (Fig. 2B). Lindane (1.7 microM) increased the magnitude of Iout which developed when IK1 was blocked by the addition of Ba2+ (2 mM) to the control solution (Fig. 3A). Current-voltage relationships show that the lindane-increased Iout developed at membrane potentials more positive than -20 mV (Fig. 3B). Subsequent addition of E-4031 (1 microM) to the control solution containing lindane blocked the lindane-increased Iout (Fig. 2A) whatever the membrane potential studied (Fig. 3B). The addition of E-4031 (2 microM) to the Ringer solution did not modify RP but prolonged APD (Fig. 4Aa) and further addition of lindane (3.4 microM) to the solution containing E-4031 (2 microM) did not modify the APD (Fig. 4Ab). Conversely, the addition of E-4031 (2 microM) to the Ringer solution containing lindane (3.4 microM) lengthened APD0, APD40 and APD10 (Fig. 4B).

Bottom Line: Under voltage-clamp conditions, lindane (1.7 microM) increased the amplitude of the outward current (Iout) which developed in Ringer solution containing TTX (0.6 microM), Cd2+ (1 mM) and TEA (10 mM).The lindane-increased Iout was not sensitive to Sr2+ (5 mM).It was blocked by subsequent addition of quinidine (0.5 mM) or E-4031 (1 microM).

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratoire d'Optique et Biosciences, Unité INSERM 451, UMR CNRS 7645, Ecole Polytechnique-ENSTA, F-91128 Palaiseau Cedex, France. martin-pierre.sauviat@polytechnique.fr

ABSTRACT

Background: The effects of lindane, a gamma-isomer of hexachlorocyclohexane, were studied on transmembrane potentials and currents of frog atrial heart muscle using intracellular microelectrodes and the whole cell voltage-clamp technique.

Results: Lindane (0.34 microM to 6.8 microM) dose-dependently shortened the action potential duration (APD). Under voltage-clamp conditions, lindane (1.7 microM) increased the amplitude of the outward current (Iout) which developed in Ringer solution containing TTX (0.6 microM), Cd2+ (1 mM) and TEA (10 mM). The lindane-increased Iout was not sensitive to Sr2+ (5 mM). It was blocked by subsequent addition of quinidine (0.5 mM) or E-4031 (1 microM). E-4031 lengthened the APD; it prevented or blocked the lindane-induced APD shortening.

Conclusions: In conclusion, our data revealed that lindane increased the quinidine and E-4031-sensitive rapid delayed outward K+ current which contributed to the AP repolarization in frog atrial muscle.

Show MeSH
Related in: MedlinePlus