The relation between the effects of veratridine on action potential and contraction in mammalian ventricular myocardium

Honerjäger, P; Reiter, M.

doi:10.1007/bf00498026

Cited by 75 publications

(33 citation statements)

References 26 publications

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“…12 To achieve this result in guinea pig papillary muscle micromolar concentrations are necessary. 6 As one would expect, the excitation threshold increases in the presence of TTX. 6 Therefore, TTX-treated preparations were stimulated with pulses of 5-msec duration and 2-3 times the rheobasic strength determined in the absence of TTX.…”

Section: Experiments With Tetrodotoxinmentioning

confidence: 94%

“…6 As one would expect, the excitation threshold increases in the presence of TTX. 6 Therefore, TTX-treated preparations were stimulated with pulses of 5-msec duration and 2-3 times the rheobasic strength determined in the absence of TTX. For the experiments carried out at a high (1 Hz) contraction frequency the muscles were taken from guinea pigs pretreated with reserpine (5 mg/kg, ip) 24 hours prior to the experiment.…”

Section: Experiments With Tetrodotoxinmentioning

confidence: 94%

“…4 The tetrodotoxin-sensitive prolongation of the cardiac action potential by veratrine 5 or veratridine 6 indicates that a drug-induced increase of P,\ a occurs during each excitation. If an increased sarcolemmal P,va causes a positive inotropic effect via accumulation of Na ions inside the cell, the inotropic response should lag behind the increase in P Na .…”

mentioning

confidence: 99%

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Sarcolemmal sodium permeability and contractile force of guinea pig papillary muscle: effects of germitrine.

Honerjäger¹,

Reiter²

1977

Circulation Research

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SUMMARY The action potential of guinea pig papillary muscle exposed to the ceveratrum alkaloid germitrine (2 J*M) is followed by a long-lasting after-depolarization (maximal amplitude, 8 mV; half-time of decay, 32 seconds; total duration, -75 seconds). This after-depolarization interrupts the terminal phase of repolarization. During repetitive stimulation (0.1-1.0 Hz; 80 nM germitrine) the after-depolarizations that follow consecutive action potentials are summed, causing persistent depolarization of up to 10 mV. The after-depolarization is reversibly abolished by tetrodotoxin (TTX). Test contractions evoked at various times during or after the germitrine-induced after-depolarization reveal a phase during which the ability of the muscle to develop force is transiently increased. This positive inotropic influence reaches its maximum 1 minute after the conditioning stimulus and thereafter decays with a half-time 4.8 times longer than the half-time of decay of the after-depolarization. It is reversibly abolished by TTX and augmented by dihydro-ouabain (DHO). We conclude: Germitrine induces an after-depolarization by prolonging dramatically the Na permeability component which is mediated by the fast Na channels and normally restricted to the first few milliseconds of the action potential. The germitrine-induced selective and persistent increase of sarcolemmal sodium permeability (P Na ) causes a positive inotropic effect, probably because intracellularly accumulating Na ions exchange for extracellular Ca ions.TWO DIFFERENT mechanisms are currently thought to play a major role in determining the inotropic state of the cardiac muscle cell: inward Ca current during depolarization, and Na-Ca exchange across the sarcolemma.1 The latter concept predicts that a change in the Na concentration gradient across the cell membrane alters the transsarcolemmal distribution of Ca. For instance, an increase of [Na]i at constant [Na] 0 should increase [Ca]|. Changes of [Na]j, by their effect on Na-Ca exchange, may be responsible for the positive inotropic response of cardiac muscle to increased stimulation rates or to cardiac glycosides. With regard to the functional significance of Na-Ca exchange it seemed desirable to test how an intervention which selectively increases the Na permeability (P Na ) of the sarcolemma affects contractile force.The ceveratrum alkaloid veratridine increases P Na of excitable membranes by a specific interaction with the (fast) Na channels. 4 The tetrodotoxin-sensitive prolongation of the cardiac action potential by veratrine 5 or veratridine 6 indicates that a drug-induced increase of P,\ a occurs during each excitation. If an increased sarcolemmal P,va causes a positive inotropic effect via accumulation of Na ions inside the cell, the inotropic response should lag behind the increase in P Na . The test of this prediction is complicated, however, by the relatively short duration of the Na permeability increase associated with veratrine or veratridine. The present publication shows that the germine triest...

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Section: Experiments With Tetrodotoxinmentioning

confidence: 94%

Section: Experiments With Tetrodotoxinmentioning

confidence: 94%

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Sarcolemmal sodium permeability and contractile force of guinea pig papillary muscle: effects of germitrine.

Honerjäger¹,

Reiter²

1977

Circulation Research

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“…In order to test this hypothesis the influence of R 56865 was studied on calcium-dependent slow action potentials and on the calcium current in ventricular myocytes. The possible interference of R 56865 with the sodium influx was tested indirectly by exposing the cardiac tissue to either veratridine or Anemonia sulcata toxin ATX II, compounds known to increase the intracellular sodium load (Honerjager & Reiter, 1975;Ravens, 1976). Furthermore, the effect of R 56865 on the sodium current was assessed in isolated ventricular myocytes of the guinea-pig.…”

Section: Introduction Methodsmentioning

confidence: 99%

Characterization of the interaction of R 56865 with cardiac Na‐ and L‐type Ca channels

Wilhelm

Himmel

Ravens

et al. 1991

British J Pharmacology

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1 In isolated cardiac muscle, submicromolar concentrations of R 56865 (N-[1-[4-(4-fluorophenoxy)butyl]-4-piperidinyl]-N-methyl-2-benzothiazolamine) have been shown to attenuate the toxicity of cardiac glycosides. 2 We studied the influence of R 56865 on calcium and sodium currents in single isolated ventricular cardiomyocytes. The effect of R 56865 on action potential and contractile force in the presence of increased sodium load was also tested by exposing papillary muscles to veratridine or Anemonia sulcata toxin ATX II. 3 The calcium current was not affected by R 56865 as assessed in slow action potentials of papillary muscles and current measurements in ventricular cardiomyocytes. 4 In papillary muscles, R 56865 (1,umol I-) abolished veratridine-induced aftercontractions and afterdepolarizations without affecting the profound prolongation of the action potential. When pretreated with R 56865, the occurrence of afterdepolarizations was prevented and the decline of the resting membrane potential was attenuated.5 Pretreatment with R 56865 (1,pmol -') did not counteract the ATX II-induced prolongation of the action potential.6 The sodium current (Na0 30mmoll-') was concentration-dependently decreased by R 56865 (0.1-1Opmol 1 -l). The blocking effect was more pronounced at less negative holding potentials. 7 Our results demonstrate that the protective effect of R 56865 against veratridine-induced electrical and mechanical oscillations is not due to a direct effect on the calcium current. A potential-dependent inhibition of the sodium current may contribute. Additional sites of action, like interference with intracellular calcium release and inhibition of potassium currents, remain to be investigated.

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“…prolongation by okadaic acid was preserved even when the fast Na+ channel was inactivated in the high-K+ medium, or partially blocked by TTX at 2 x 10-6 M. These facts may indicate that a.p.d. prolongation induced by okadaic acid is not mediated by a mechanism similar to veratrine (Horackova & Vassort, 1973), veratridine (Honerjager & Reiter, 1975), anthopleurin-A (Kodama, Shibata, Toyama & Yamada, 1981;Shibata & Norton, 1982) and ATX II (Isenberg & Ravens, 1984), which were reported to inhibit the inactivation process of the fast Na+ current of cardiac muscles. A contribution of Na+ window current is also unlikely.…”

Section: Effects Of Okadaic Acid On Membrane Currentsmentioning

confidence: 97%

Electromechanical effects of okadaic acid isolated from black sponge in guinea‐pig ventricular muscles.

Kodama¹,

Kondo²,

Shibata³

1986

The Journal of Physiology

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Okadaic acid is a monocarboxylic acid with a unique molecular structure of C44H66O13. Okadaic acid, at concentrations above 10(‐5) M, caused a dose‐dependent increase of contractile force in guinea‐pig isolated ventricular muscles. The increase of contractile force by okadaic acid (1‐4 X 10(‐5) M) was accompanied by a prolongation of action potential duration (a.p.d.), while a.p.d. was shortened by okadaic acid at above 10(‐4) M. The okadaic‐acid‐induced changes in contractile force and a.p.d. were abolished by pre‐treatment with verapamil (2 X 10(‐6 M) or nifedipine (10(‐6) M). In a low‐Ca2+ medium (0.12 mM), the contractile response to okadaic acid (4 X 10(‐5) M) was inhibited, whereas the a.p.d. was more prolonged by the drug than in a control medium (containing 1.2 mM‐Ca2+). In a low‐Na+ (70 mM) medium or in a low‐Na+ (70 mM) and low‐Ca2+ (0.12 mM) medium both the contractile force and a.p.d. were unaffected by okadaic acid (4 X 10(‐5) M). The positive inotropic effect of okadaic acid (4 X 10(‐5) M) was not inhibited by treatment with tetrodotoxin (TTX, 2 X 10(‐6) M) or with ryanodine (2 X 10(‐6) M). In voltage‐clamp experiments using a single sucrose‐gap technique, okadaic acid (4 X 10(‐5) M), caused a significant increase of slow inward current, while it did not affect the net outward current. These findings suggest that okadaic acid has a positive inotropic effect on the heart, probably due to the enhancement of slow Ca2+ and/or Na+ inward current through the cell membrane.

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The relation between the effects of veratridine on action potential and contraction in mammalian ventricular myocardium

Cited by 75 publications

References 26 publications

Sarcolemmal sodium permeability and contractile force of guinea pig papillary muscle: effects of germitrine.

Sarcolemmal sodium permeability and contractile force of guinea pig papillary muscle: effects of germitrine.

Characterization of the interaction of R 56865 with cardiac Na‐ and L‐type Ca channels

Electromechanical effects of okadaic acid isolated from black sponge in guinea‐pig ventricular muscles.

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