Effects of disopyramide on the maximum rate of rise of action potential (Vmax) in guinea-pig papillary muscles.

Kojima, Michio; Ban, Takashi; Sada, Hideaki

doi:10.1254/jjp.32.91

Cited by 13 publications

(8 citation statements)

References 24 publications

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“…(2) A similar conclusion can be reached from experiments in which the duration of a repetitive depolarization was prolonged from 10 ms to 500 ms without causing any important change of the use-dependent block. This confficts with the data of Kojima et al (1982), based on the increased effect of disopyramide in preparations bathed in low K concentrations when combined with low rates of stimulation (0.1 Hz). They interpreted their results to be due to a promoted inactivation block, caused by a lengthening of the action potential duration in low potassium solution.…”

Section: Blockade Ofopen Channelssupporting

confidence: 88%

“…In published studies (Kus & Sasyniuk, 1978;Kojima et al, 1982) the duration of the depolarizing step (Figure lc,d) or by changing the holding potential preceding the test depolarization ( Figure 2). As shown in Figure 1, prolongation of the depolarizing step from lOis to 500 ms had no effect on the amplitude of the block in steady-state.…”

Section: Absence Of Inactivation Blockmentioning

confidence: 99%

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The activation gate of the sodium channel controls blockade and deblockade by disopyramide in rabbit Purkinje fibres

Gruber¹,

Carmeliet²

1989

British J Pharmacology

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1 The effect of disopyramide on the maximum upstroke velocity (V,,,,) and the sodium current of rabbit cardiac Purkinje fibres was studied with the two-microelectrode voltage-clamp technique. 2 In the absence of stimulation the drug did not cause block at membrane potentials ranging from -100 to -65 mV. Use-dependent block of V.. was most pronounced at -75 mV. At hyperpolarized membrane potentials development of use-dependent block was faster than at depolarized membrane potentials. The time course of development of use-dependent block was not significantly influenced by the duration of the depolarizing pulse. These results strongly suggest that disopyramide predominantly blocks activated sodium channels. 3 The relative decrease of the sodium current at the beginning of a 2s depolarizing clamp to -45 mV was almost the same as at the end, implying a rapid blockade of activated sodium channels. The Hill plots were linear with slopes ranging from 0.98 to 1.08 indicating a first order reaction; the dissociation constant for activated channels was 70 /LM. 4 Recovery of V.. from use-dependent block during rest was strongly voltage-dependent, the time constant of recovery increasing upon hyperpolarization. When the fraction of charged molecules was reduced by changing the pH of the external solution, the voltage-dependence of recovery was decreased. In contrast, recovery of V.. for a change in holding potential from -80 to -95 mV was very fast during repetitive stimulation. 5 It is concluded that disopyramide blocks the sodium channel during activation and is trapped in the channel when the activation gate closes.

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Section: Blockade Ofopen Channelssupporting

confidence: 88%

Section: Absence Of Inactivation Blockmentioning

confidence: 99%

The activation gate of the sodium channel controls blockade and deblockade by disopyramide in rabbit Purkinje fibres

Gruber¹,

Carmeliet²

1989

British J Pharmacology

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“…6B). Such an upward shift of the normalized VmaX Vm curve by disopyramide was also reported by other investigators (20).…”

supporting

confidence: 88%

“…This inconsistency might stem from differences in experimental conditions. Kojima et al (20) Fig. 6B).…”

Section: Discussionmentioning

confidence: 89%

Frequency- and Voltage-Dependent Depression of Maximum Upstroke Velocity of Action Potentials by Pirmenol in Guinea Pig Ventricular Muscles

Nakaya

Tohse

Kanno

1988

Japanese Journal of Pharmacology

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Abstract-The frequency-dependency and voltage-dependency of the suppressing effect of pirmenol, a novel antiarrhythmic agent, on the maximum upstroke velocity (Vmax) of action potentials were examined and compared with those of disopyramide in guinea pig papillary muscles. Pirmenol in concentrations higher than 3 ,M decreased Vmax with a slight increase in action potential duration. The reduction of Vmax by pirmenol was enhanced in a frequency-dependent manner over the range of 0.1-2.0 Hz. Pirmenol (30 uM) produced a small resting block (5.5%), whereas disopyramide (100 fM) produced a greater one (25.8%). The onset of frequency dependent Vmax reduction at 2.0 Hz followed a monoexponential function with a slow rate constant (0.308±0.055 AP-1). The time constant for the recovery from the frequency-dependent block by pirmenol was also slow (33.5±5.4 sec), but faster than that of disopyramide (82.5±12.3 sec). At 1.0 Hz, pirmenol caused a shift (9.5 mV) of the curve relating the resting membrane potential and Vmax along the voltage axis in the hyperpolarizing direction. Thus, pirmenol is a Class la drug that has frequency and voltage-dependent inhibitory actions on Vmax, and its onset and offset kinetics are relatively slow.

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“…The molecular mode ofaction ofdisopyramide Several studies of the actions of disopyramide on the cardiac action potential have been reported (Danilo et al, 1977;Kus & Saszniuk, 1978;Kojima et al, 1982;Yamada et al, 1982). These studies have involved measurement of monophasic action potentials by intracellular electrodes.…”

Section: Discussionmentioning

confidence: 99%

The effects of external and internal application of disopyramide on the ionic currents of the squid giant axon

Elliott

Hendry

1987

British J Pharmacology

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1 The actions of the class I anti-arrythmic agent, disopyramide, on the ionic currents of the voltageclamped squid axon have been investigated, by use of both extra-axonal and intra-axonal routes of application. 2 Extra-axonal application of0.1 mM disopyramide produced no significant effects on the membrane currents. External disopyramide at 1.0 mM caused small, poorly reversible inhibition of both sodium and potassium currents. This block was use-dependent and was enhanced by use of test stimuli to more positive membrane potentials. 3 Intra-axonal application of 0.1 mM disopyramide caused a 40% reduction in the first-pulse sodium current (tonic block) and an additional use-dependent block. Analysis offirst-pulse currents in terms of the Hodgkin-Huxley formalism indicated that the block resulted mainly from a reduction in the maximum available sodium conductance (gNa); there were no effects on the voltage dependence of the steady-state activation and inactivation parameters, m,, and h,. 4 The use-dependent actions of disopyramide were investigated with a double voltage-clamp pulse protocol. The significant use-dependent effects of the drug were a further reduction in ga and an increase in the time constant of inactivation (Th).5 Disopyramide appears to enter a blocking site in the sodium channel which is only readily accessible from the axoplasmic phase. Partition to the site depends on membrane voltage and on the state of the channel gates. Disopyramide binds at a significant rate to both open and inactivated forms of the sodium channel.

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Effects of disopyramide on the maximum rate of rise of action potential (Vmax) in guinea-pig papillary muscles.

Cited by 13 publications

References 24 publications

The activation gate of the sodium channel controls blockade and deblockade by disopyramide in rabbit Purkinje fibres

The activation gate of the sodium channel controls blockade and deblockade by disopyramide in rabbit Purkinje fibres

Frequency- and Voltage-Dependent Depression of Maximum Upstroke Velocity of Action Potentials by Pirmenol in Guinea Pig Ventricular Muscles

The effects of external and internal application of disopyramide on the ionic currents of the squid giant axon

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