Evaluation and Interpretation of Voltage- and Frequency-Dependent Electrophysiologic Effects of a New Class I Antiarrhythmic Agent (Nicainoprol) on Guinea Pig Papillary Muscle and Isolated Heart

Weirich, J.; Antoni, H.

doi:10.1097/00005344-198812000-00007

Cited by 5 publications

(13 citation statements)

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“…Although the effects of nicainoprol on MRD tended to be potentiated in the presence of simulated ischaemia, the difference was not statis-tically significant. It has, nevertheless, been reported that nicainoprol does preferentially bind to inactivated Na channels (Weirich & Antoni, 1988). The reason why a marked potentiation of its Class I effect was not observed in the present study is not known but it is perhaps of importance that the preferential binding of the drug to inactivated Na channels was noted with concentrations higher than those used in this study.…”

Section: Discussioncontrasting

confidence: 71%

Modification by hypoxia, hyperkalaemia and acidosis of the cardiac electrophysiological effects of a range of antiarrhythmic drugs

Pacini

Boachie-Ansah

Kane

1992

British J Pharmacology

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1 The electrophysiological effects of a series of drugs with Class I antiarrhythmic activity were examined in sheep Purkinje fibres, superfused in vitro with either a normal or hypoxic, hyperkalaemic and acidotic physiological salt solution (PSS). 2 In normal sheep Purkinje fibres, lignocaine, disopyramide, nicainoprol and propranolol all significantly reduced action potential height and the maximum rate of depolarization of phase zero (MRD) and abbreviated the action potential, without modifying resting membrane potential (RMP). 3 Verapamil at the highest concentration studied, 8 gM, significantly reduced MRD with an associated slight membrane depolarization and abbreviated action potential duration measured at 50% repolarization (APD50). 4 Superfusion of sheep Purkinje fibres with a hypoxic, hyperkalaemic and acidotic PSS resulted in marked reductions in resting membrane potential, upstroke and duration of the action potential. 5 In the presence of modified PSS, lignocaine, propranolol and verapamil all reduced MRD to a greater extent than in normal PSS. The effects of nicainoprol on MRD were not affected whereas those of disopyramide were significantly attenuated. 6 Under simulated ischaemic conditions, lignocaine, propranolol and nicainoprol did not produce a concentration-dependent reduction in action potential duration whereas disopyramide and verapamil, respectively, prolonged and abbreviated both APD50 and APD90.7 The Na+ channel blocking actions of the different subtypes of Class I antiarrhythmic agents studied, as well as their effects on action potential duration, were modified differently by simulated ischaemia.

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Section: Discussioncontrasting

confidence: 71%

Modification by hypoxia, hyperkalaemia and acidosis of the cardiac electrophysiological effects of a range of antiarrhythmic drugs

Pacini

Boachie-Ansah

Kane

1992

British J Pharmacology

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“…3.5 s at 10 pkf (28), and 51.6 2 9.4 s at 50 pkf (1 3); all of these values were comparable. Such large values of T~ indicate that nicainoprol should be classified "as Class-I antiarrhythmic drugs with slow kinetics (Ic)" (4,13,26,28). The relatively slow onset of the development of UDB (fairly long T, , ) also supports this notion.…”

Section: Use-dependent Block Of (Udb) Vmxmentioning

confidence: 70%

“…The difference between the Vm in the steady state and the Vmm of the first action potential was used as a measure of UDB. The amount of UDB was increased with increasing stimulation frequency (0.2-3.0 Hz) (13,28) or with increasing the drug concentration (3.3-10 pM) (28). The time course of development of UDB was also stimulation frequency as well as drug concentration dependent.…”

Section: Use-dependent Block Of (Udb) Vmxmentioning

confidence: 96%

“…0.7 s at 1.0 Hz, and 2.6 f 0.4 s a t 2.0 Hz (13). The rate of Vmn reduction per action potential (AP-I) during the stimulation train at 1.0 Hz was 0.053 k 0.007 AP-' at 3.3 p.M and 0.066 2 0.005 AP-' at 10 p.M (28). The onset kinetics of UDB expressed as either T, , or APwere affected by changes in the drug concentration and the stimulation frequency applied (13,28).…”

Section: Use-dependent Block Of (Udb) Vmxmentioning

confidence: 99%

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Nicainoprol

Imanishi

Kimura

Arita

1991

Cardiovascular Drug Reviews

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Nicainoprol is a newly synthesized antiarrhythmic agent, which can be categorized as a class I drug with slow kinetics; it has a minor, but significant class IV effect. Its chemical name is 8-(3-isopropylamino-2-hydroxy-propoxy)-I-nicotinoyl-1,2,3,4-tetrahydroquinoline (Fig. 1); other names are CAS-924 and RU-42924; its empirical formula is C,,H,,N,O,; the molecular weight is 370.2; it is a white powder; readily soluble in water at room temperature; pKa value of 9.0 (determined in Roussel-Uclaf) or 9.50 (27); and log P value of 1.03 (measured in our laboratory, see ref. 13) or 2.050 (27). IN VITRO EFFECTS Effects on Action Potential CharacteristicsElectrophysiologic studies on isolated dog Purkinje fibers and dog and guinea pig ventricular muscles indicated, that nicainoprol decreases the maximal upstroke velocity (Vmm) of the action potential in a concentration-dependent manner (3.3 to 100 pM) without changing the resting potential (6,13,20,28). In addition, the drug shortened the action potential duration (APD) and effective refractory period (ERP) of the dog Purkinje fiber (6,20). However, the effects of this drug on the APD of ventricular muscles are controversial (6,13,20,28). Nicainoprol produced statistically significant increases in the APD of dog and guinea pig ventricular muscles at concentrations of 3 and 10 pM, respectively (6,20). In other reports, the agent, at relatively low concentrations (1, 3.3, 5, and 10 pM), tended to increase the APD and ERP of the guinea pig ventricle, albeit the changes were not significant (13,28). In contrast, the drug, at higher concentrations (50 and 100 pM), significantly decreased the APD in guinea pig ventricular muscles ( 13,20).Based on these cellular electrophysiological effects, the most consistent and prominent effect of nicainoprol is considered to be a concentration-dependent reduction in the 6' -of action potentials, a measure of Na+ channel availability. Such depression of Vmm is a common property of class I type antiarrhythmic action as proposed by Vaughan Williams

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“…Because these assumptions of APD shortening had little influence on shape and position of the calculated relationship between AG and steady cycle length, the respective curves in Figure 5 are superimposed, giving the impression of a single curve for each dosage of tocainide. Also shown in Figure 5 (Weirich & Antoni, 1988). On the other hand, resting membrane potential, an important modulator of sodium channel block, can only be controlled in vitro.…”

Section: Statisticsmentioning

confidence: 99%

Kinetics of rate‐dependent slowing of intraventricular conduction by the class Ib antiarrhythmic agent tocainide in vivo

Todt

Zojer

Raberger

1993

British J Pharmacology

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1 The effects of the class I antiarrhythmic agent, tocainide, on intraventricular conduction were assessed in guinea-pigs, anaesthetized with pentobarbitone sodium 60 mg kg', i.p. 2 After electrical ablation of the sinus node, heart rate was controlled by atrial pacing. His bundle electrograms were recorded by means of an epicardial bipolar electrode. administration of 30 mg kg-' tocainide, and 28.04 ± 0.64 ms versus 36.24 ± 1.31 ms (P<0.001), after addition of 20 mg kg-' tocainide. Thus, tocainide caused HV intervals to increase in a strictly ratedependent fashion. 4 In order to characterize the rate-dependent class I activity of tocainide in terms of its binding kinetics to sodium channels, fractional sodium channel block was estimated from drug induced reductions of intraventricular conduction velocity (AO). On abruptly changing the drive cycle length from 500 ms to 250 ms, AO reached a new steady state with rate constants of 1.23 ± 0.09 beat-' and 1.28 ± 0.09 beat ', after administration of 30 mg kg-' and addition of 20 mg kg-' tocainide, respectively. At a basic drive cycle length of 250 ms AO recovered with time constants of 250.29 ± 23.32 ms and 183.04 ± 8.03 ms after administration of 30 mg kg-' and addition of 20 mg kg-tocainide, respectively. 5 The experimentally determined kinetic parameters were implemented into a mathematical model that assumes drug binding to sodium channels in terms of a periodical two-state process. Rate-dependent reductions in conduction velocity during continuous stimulation after administration of tocainide were closely approximated by steady state reductions in sodium channel availability as calculated on the basis of the aforementioned model. 6 In agreement with previously published in vitro studies, our data, obtained in vivo, confirm the classification of tocainide as a class I antiarrhythmic agent with fast onset and offset kinetics. The kinetic parameters obtained in vivo can be used in order to predict steady state reductions in conduction velocity at a wide range of frequencies.

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Evaluation and Interpretation of Voltage- and Frequency-Dependent Electrophysiologic Effects of a New Class I Antiarrhythmic Agent (Nicainoprol) on Guinea Pig Papillary Muscle and Isolated Heart

Cited by 5 publications

References 0 publications

Modification by hypoxia, hyperkalaemia and acidosis of the cardiac electrophysiological effects of a range of antiarrhythmic drugs

Modification by hypoxia, hyperkalaemia and acidosis of the cardiac electrophysiological effects of a range of antiarrhythmic drugs

Nicainoprol

Kinetics of rate‐dependent slowing of intraventricular conduction by the class Ib antiarrhythmic agent tocainide in vivo

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