Comparison of the Action Potential Prolonging and Positive Inotropic Activity of DPI 201-106 and BDF 9148 in Human Ventricular Myocardium

Hoey, Andrew; Amos, Gregory; Ravens, Ursula

doi:10.1006/jmcc.1994.1119

Cited by 31 publications

(21 citation statements)

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“…[22][23][24] Studies using cardiac muscle have shown that the inhibition of repolarizing K + currents 25 and the stimulation of 1-, 26 1-, and 2-adrenoceptors 27 can produce an increase in muscle contraction as well as a prolongation of the action potential in the majority of mammalian species, including humans. 28 Although this correlation between the duration of the action potential and the contractility was also observed in the present study, the mechanisms for the positive inotropic effect by nifekalant have not yet been established. Possible mechanisms include increased Ca 2+ influx through voltagedependent Ca 2+ channels, 29 altered Ca 2+ extrusion by the Na + -Ca 2+ exchanger, 30 or a combination of both, 31 which could directly alter the Ca 2+ supply to the myofilaments or indirectly alter it by changing the SR Ca 2+ loading.…”

Section: Effect Of Nifekalant On Cellular Ca 2+ Loadingsupporting

confidence: 67%

Effect of Nifekalant, a Class III Anti-Arrhythmic Agent, on Ca2+ Waves in Rat Intact Trabeculae

Hirose

Miura

Wakayama

et al. 2005

Circ J

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S-551, a class III anti-arrhythmic agent, with a pyrimidinedione structure, inhibits the rapiddelayed rectifier K + currents (IKr) at therapeutic concentrations of 1-10 mol/L 1 and, furthermore, inhibits several other K + channels at concentrations above 10 mol/L. [2][3][4][5][6] The blocking of K + channels can prolong the duration of the action potential 4,7 and consequently prolong the myocardial refractory period, 4,[6][7][8][9] suggesting that the chief anti-arrhythmic action of nifekalant comes from the suppressive action against re-entrant arrhythmias. 7,9 By this blocking of K + channels, nifekalant exerts a clinically potent suppressive action against ventricular tachyarrhythmias. [9][10][11] To achieve optimal anti-arrhythmic effects with drugs, the clinician needs to avoid the pro-arrhythmic actions of the drug. In the case of nifekalant, one may anticipate that the drug will increase the cellular Ca 2+ load because of the prolongation of the action potential and thereby induce triggered premature beats and triggered arrhythmias. 12 been observed as a propagation of regional increases in intracellular Ca 2+ ([Ca 2+ ]i) with aftercontractions and delayed afterdepolarizations (DADs), 12 start from damaged regions within both rat ventricular 15 and human atrial cardiac muscle. 12 The velocity of Ca 2+ waves ranges from 0.34 to 5.47 mm/s, 12 depending on both [Ca 2+ ]i and Ca 2+ loading in the sarcoplasmic reticulum (SR). 14 The acceleration of Ca 2+ waves caused by the increase in the cellular Ca 2+ loading can increase the amplitude of DADs 16 and finally induce triggered arrhythmias. 17 Such triggered arrhythmias from DADs have been reported to play an important role in the occurrence of tachyarrhythmias in heart diseases such as heart failure, 18,19 cardiac hypertrophy 20 and digitalis intoxication.Therefore, in this study, we investigated: (i) the effect of nifekalant on the action potential, Ca 2+ transient, and developed force of rat myocardium to determine whether nifekalant increases muscle contraction with an increase in cellular Ca 2+ loading; and (ii) the effect of nifekalant on the velocity of Ca 2+ waves and aftercontractions to evaluate whether nifekalant can affect triggered arrhythmias as well as re-entrant arrhythmias. Methods Dissection and Mounting of Rat Ventricular TrabeculaeThe experiments were performed according to the guidelines for the care and use of laboratory animals of Tohoku University. Trabeculae were obtained as previously described. 14,17 Sprague -Dawley rats (250-300 g) were anesthetized and hearts were excised. Sixteen trabeculae (length = Background Nifekalant, a class III anti-arrhythmic agent, has been used clinically at serum concentrations of 1-10 mol/L in patients with ventricular arrhythmias. However, the effect of nifekalant on triggered arrhythmiashas not yet been established. Methods and ResultsTrabeculae were dissected from the right ventricles of 16 rat hearts. The force was measured using a silicon strain gauge, the membrane potential using ultra-complian...

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Section: Effect Of Nifekalant On Cellular Ca 2+ Loadingsupporting

confidence: 67%

Effect of Nifekalant, a Class III Anti-Arrhythmic Agent, on Ca2+ Waves in Rat Intact Trabeculae

Hirose

Miura

Wakayama

et al. 2005

Circ J

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“…By using an Na + -selective microelectrode, the racemic compound (±)BDF 9148 has been shown to increase the intracellular Na + -concentration in isolated human myocardium (Hoey et al 1994), which leads to a reduction of Ca 2+ -extrusion by the Na + ,Ca 2+ -exchanger and to an increase in intracellular Ca 2+ -concentration and force of contraction (Bers 1987;Ravens and Wettwer 1989). However, data on the influence of S(-)BDF 9196 on Na + -currents of human cardiomyocytes were not available to date.…”

Section: Discussionmentioning

confidence: 99%

“…An interaction with the sodium pump at high concentrations has also been found for racemic (±)BDF 9148 in guinea pig myocardial preparations (Herzig et al 1991). In human myocardium, it remains to be determined whether the increase in intracellular Na + -concentration by (±)BDF 9148 (Hoey et al 1994) might be the consequence of both increase in Na + -influx and inhibition of Na + ,K + -ATPase.…”

Section: Introductionmentioning

confidence: 99%

Na+-channel modulating effect of the inotropic compound S(-)BDF 9196 in human myocardium

Müller‐Ehmsen

Näbauer

Schwinger

1999

Naunyn-Schmiedeberg's Arch Pharmacol

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S(-)BDF 9196, the active enantiomer of racemic (+/-)BDF 9148, has been shown to increase force of contraction in myocardium from different species including humans. The present study aimed to investigate the mechanism of the positive inotropic action of the active enantiomer S(-)BDF 9196 in human myocardium. In electrically driven human left ventricular papillary muscle strips (dilated cardiomyopathy, NYHA IV, cardiac transplantation, n=9), S(-)BDF 9196 increased force of contraction concentration-dependently. The maximal positive inotropic effect remained unchanged after the addition of carbachol (1 mmol/l, indicating a cAMP-independent mode of action of S(-)BDF 9196. While [3H]ouabain binding in human myocardial membranes was not influenced by S(-)BDF 9196 up to 10 micromol/l, the inward Na(+)-current in isolated human left ventricular myocytes was increased significantly by S(-)BDF 9196 (1 micromol/l, n=5). These results provide evidence that S(-)BDF 9196 increases force of contraction in human myocardium primarily by enhancing Na(+)-influx, while cAMP-dependent or Na(+),K(+)-ATPase blocking effects do not seem to play a role.

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“…Parts of the effects of BDF and LIDO on FFR that have been observed in the present study might also be secondary to alterations of action potential duration followed by an altered Ca 2+ influx. Thus, BDF has been shown previously to prolong action potential duration (Brasch and Iven 1991;Hoey et al 1994), whereas LIDO decreased action potential duration in cardiac tissue (Sheu and Lederer 1985).…”

Section: Na + Influx and Force-frequency Relationshipmentioning

confidence: 99%

“…Therefore, FFRs were obtained in human right auricular trabeculae in the absence and presence of (±)BDF 9148, an agent that increases intracellular Na + concentration by inhibiting inactivation of Na + channels (Hoey et al 1994;Ravens et al 1991), and lidocaine, a local anaesthetic that inhibits Na + influx via Na + channels (Payet 1985) and thereby reduces intracellular Na + concentration (Sheu and Lederer 1985).…”

Section: Introductionmentioning

confidence: 99%

Na+ channel modulation and force-frequency relationship in human myocardium

Müller‐Ehmsen

Brixius

Schulze

et al. 1997

Naunyn-Schmiedeberg's Arch Pharmacol

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The enhancement of force of contraction (FOC) following increasing frequencies of stimulation is an important mechanism of positive inotropy in human myocardium. The present study aimed to investigate the influence of alterations in Na+ influx on FFR in human myocardium. Isometric FOC of electrically stimulated right auricular trabeculae (AUT, n = 12) from human non-failing hearts (n = 8) was measured at different stimulation rates (0.5-3 Hz) under control conditions, after increasing Na+ influx by the addition of (+/-)BDF 9148 (BDF, 3 mumol l-1) and after decreasing Na+ influx by the addition of lidocaine (LIDO, 10 mumol l-1). Additionally, the rate dependent changes in diastolic tension (DT) were measured in all experiments. Under control conditions FOC increased with increasing frequencies of stimulation. The rate at which maximal FOC was observed (SFmax) was 2.0 +/- 0.2 Hz and maximal increase in FOC (PIEmax) by increasing frequency of stimulation was +1.5 +/- 0.5 mN. After increase of Na+ influx by BDF (3 mumol l-1) SFmax was decreased to 0.8 +/- 0.1 Hz (p < 0.05 versus control) and PIEmax was +0.1 +/- 0.3 mN (p < 0.05). When Na+ influx was diminished by LIDO (10 mumol l-1) SFmax and PIEmax were increased compared to control (2.4 +/- 0.1 Hz and +4.1 +/- 0.9 mN, p < 0.05 versus control). The diastolic tension (DT) of AUT at 3 Hz was not changed at higher rates in the control group and after application of LIDO (10 mumol l-1), whereas after enhancement of Na+ influx by BDF there was an increase in DT of +0.7 +/- 0.2 at 3 Hz (p < 0.05 versus control and LIDO). An enhanced Na+ influx leads to a decrease in the optimal frequency and to a smaller force potentiation by higher stimulation rates which could be at least partly due to incomplete relaxation at higher frequencies, whereas a reduced Na+ influx is followed by opposite alterations. It is concluded that besides Ca2+ handling also Na+ influx and Na+ homeostasis might determine the frequency-induced force potentiation in human myocardium. Thus, the negative FFR in diseased human myocardium might result from changes in cellular Ca2+ or Na+ regulatory sites.

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Comparison of the Action Potential Prolonging and Positive Inotropic Activity of DPI 201-106 and BDF 9148 in Human Ventricular Myocardium

Cited by 31 publications

References 0 publications

Effect of Nifekalant, a Class III Anti-Arrhythmic Agent, on Ca2+ Waves in Rat Intact Trabeculae

Effect of Nifekalant, a Class III Anti-Arrhythmic Agent, on Ca2+ Waves in Rat Intact Trabeculae

Na+-channel modulating effect of the inotropic compound S(-)BDF 9196 in human myocardium

Na+ channel modulation and force-frequency relationship in human myocardium

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