Effects of quinidine on action potentials and ionic currents in isolated canine ventricular myocytes.

Salata, Joseph J.; Wasserstrom, J. Andrew

doi:10.1161/01.res.62.2.324

Cited by 116 publications

(68 citation statements)

References 40 publications

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“…The proarrhythmic effects of class I antiarrhythmic agents or other local anaesthetics are associated with Na+ channel blockade, which slows conduction velocity and favours re-entrant phenomena. Action potential amplitude was also attenuated by the above opioids and quinidine, which is consistent with other studies (Salata & Wasserstrom, 1988;Kawamura, Kodama, Toyama, Hayashi, Saito & Yamada, 1990 Mechanisms of negative inotropic effects of opioids: Na+-dependent mechanisms It has been proposed that the negative inotropic effects of opioids and quinidine result from inhibition of Na+ channel function. In the above contractile measurements, suprathreshold stimulation was applied so that contractile activation was not affected by alterations to myocardial excitability associated with Na+ channel depression.…”

Section: Discussionsupporting

confidence: 91%

“…The opioids depressed the stimulation-induced rise of both intracellular Ca2' and ICa The depression by local anaesthetics, including quinidine, of ICa (Carmeliet et al 1986;Josephson, 1988;Salata & Wasserstrom, 1988) and the Ca2+ transient (Stewart, Rubin & Thomas, 1991) has been reported, as well as a potentiation of their negative inotropic effects by calcium antagonists (Herzig, Ruhnke & Wulf, 1994). The plots in Fig.…”

Section: Discussionmentioning

confidence: 86%

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The mode of action of several opioids on cardiac muscle

Wu¹,

Fry²,

Henry³

1997

Experimental Physiology

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SUMMARYThe objective of the experiments was to investigate the cellular basis of the inotropic effect on myocardium of several opioids which have been implicated in producing cardiotoxic effects in human poisioning. Opioids exerted negative inotropic effects, with half-maximal concentrations between 10 /LM (dextropropoxyphene) and 118 /,M (pethidine); all agents reduced the magnitude of the intracellular Ca2+ transient and the L-type Ca2+ current, ICa, over a similar concentration range to that which reduced twitch tension. The depression of ICa correlated positively with the value of the opioid oil-water partition coefficient. Effects were not antagonized by the opioid receptor antagonist naloxone. Action potential upstroke rate was also reduced but at significantly higher concentrations. Resting potential and action potential duration were not consistently affected; none of the opioids tested altered intracellular pH. These data suggest that opioids exert a negative inotropic effect by their action on ICa; blockade of the Na+ current is not great enough to exert a significant action. The lack of effect of naloxone implies the actions are independent of the opioid receptor. The correlation of effects with the oil-water partition coefficient implies a nonspecific effect dependent on the hydrophobicity of the agent.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 86%

The mode of action of several opioids on cardiac muscle

Wu¹,

Fry²,

Henry³

1997

Experimental Physiology

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“…Voltage, current, and cell-length signals were digitized by a TL-1 DMA interface (Axon Instruments Inc.) at 7 to 10 kHz and channeled into the Clampex data acquisition program, for later analysis using the Clampfit program (pCLAMP6). Additional details of the use of the switch clamp with high-resistance electrodes can be found in previous publications (see Salata and Wasserstrom, 1988;Wasserstrom and Salata, 1988).…”

Section: Methodsmentioning

confidence: 99%

Effect of Cardiac Glycosides on Action Potential Characteristics and Contractility in Cat Ventricular Myocytes: Role of Calcium Overload

Ruch¹,

Nishio²,

Wasserstrom³

2003

J Pharmacol Exp Ther

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There is increasing evidence that cardiac glycosides act through mechanisms distinct from inhibition of the sodium pump but which may contribute to their cardiac actions. To more fully define differences between agents indicative of multiple sites of action, we studied changes in contractility and action potential (AP) configuration in cat ventricular myocytes produced by six cardiac glycosides (ouabain, ouabagenin, dihydroouabain, actodigin, digoxin, and resibufogenin). AP shortening was observed only with ouabain and actodigin. There was extensive inotropic variability between agents, with some giving full inotropic effects before automaticity occurred whereas others produced minimal inotropy before toxicity. AP shortening was not a result of alterations in calcium current or the inward rectifier potassium current, but correlated with an increase in steady-state outward current (I ss ), which was sensitive to KB-R7943, a Na ϩ -Ca 2ϩ exchange (NCX) inhibitor.Interestingly, I ss was observed following exposure to ouabain and dihydroouabain, suggesting that an additional mechanism is operative with dihydroouabain that prevents AP shortening.Further investigation into differences in inotropy between ouabagenin, dihydroouabain and ouabain revealed almost identical responses under AP voltage clamp. Thus all agents appear to act on the sodium pump and thereby secondarily increase the outward reverse mode NCX current, but the extent of AP duration shortening and positive inotropy elicited by each agent is limited by development of their toxic actions. The quantitative differences between cardiac glycosides suggest that mechanisms independent of sodium pump inhibition may result from an altered threshold for calcium overload possibly involving direct or indirect effects on calcium release from the sarcoplasmic reticulum.

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“…In addition, a long diastolic interval may allow the quinidine block of sodium channels to dissipate, augmenting the inward sodium "window" current during the subsequent action potential and tending to prolong its duration. 28 …”

Section: Effect Ofabrupt Changes Ofapdmentioning

confidence: 99%

Frequency-dependent effects of quinidine on the ventricular action potential and QRS duration in humans.

et al. 1990

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We studied the frequency-dependent effects of quinidine on the right ventricular action potential and QRS duration in 10 patients (nine men and one woman; mean age, 57±+14 years) undergoing electrophysiologic studies for clinical indications. The right ventricular monophasic action potential, electrocardiographic, and conventional intracardiac electrical signals from various sites were recorded at different pacing cycle lengths from 30 seconds to 1 minute before and after a 10-mg/kg i.v. quinidine infusion. We used the extrastimulus technique to determine the effects of quinidine on ventricular refractory periods at different pacing cycle lengths and on the abrupt changes of the action potential duration. The action potential duration progressively decreased as the ventricular pacing rate increased at baseline and after quinidine infusion. Quinidine significantly increased the action potential duration from that of control by 25 msec (p<0.02) at the relatively slow pacing cycle lengths of 600, 500, and 400 msec. Quinidine's effect on the action potential duration was attenuated at the pacing cycle length of 350 msec and became negligible at 300 msec. In contrast, quinidine progressively lengthened the QRS duration as the pacing rate increased (20,18, 37, 46, and 34 msec at pacing cycle lengths of 600, 500, 400, 350, and 300 msec, respectively;p <0.05). There were no rate-dependent changes in the QRS duration during the control period. The relation between the ventricular refractory periods and the action potential duration at different pacing cycle lengths was also determined before and after quinidine infusion. Quinidine uniformly increased the ventricular refractory periods by about 9-11% above the control values regardless of the pacing cycle lengths and the action potential durations. Although quinidine generally had no effect on the ratio of ventricular effective refractory period to the action potential duration, a strong trend emerged showing that quinidine increased the ratio as the pacing cycle lengths shortened (p=0.07). Our data demonstrate that at slower heart rates quinidine has a significant effect on the action potential duration, repolarization, and voltage-dependent refractory period. As the heart rate increased, quinidine's effect on these variables diminished, but its effect on the time-dependent refractory period became more pronounced. In contrast to quinidine's effect on the action potential duration, the drug prolonged the QRS duration in a use-dependent manner. (Circulation 1990;81:790-796) C hanges in heart rate affect many facets of cardiac electrical activity.' In particular, the repolarization phase of the cardiac action Presented in part at the 61st Scientific Sessions of the American Heart Association, Washington, DC, November 14-17, 1988

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Effects of quinidine on action potentials and ionic currents in isolated canine ventricular myocytes.

Cited by 116 publications

References 40 publications

The mode of action of several opioids on cardiac muscle

The mode of action of several opioids on cardiac muscle

Effect of Cardiac Glycosides on Action Potential Characteristics and Contractility in Cat Ventricular Myocytes: Role of Calcium Overload

Frequency-dependent effects of quinidine on the ventricular action potential and QRS duration in humans.

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