Mechanism of action of antifibrillatory drugs

Heistracher, P.

doi:10.1007/bf01003037

Cited by 115 publications

(34 citation statements)

References 20 publications

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“…The relative independence from drug concentration, exhibited by Tre, has also been noted by others (Heistracher, 1971;Kojima & Ban, 1979;Courtney, 1980a,c;Oshita, Sada, Kojima & Ban, 1980;Sada & Ban, 1981a;Sada, Grant, Trantham, Brown & Strauss, 1982).…”

Section: Kinetics Of Offset Ofrdb (Rre)supporting

confidence: 71%

Importance of physico‐chemical properties in determining the kinetics of the effects of Class I antiarrhythmic drugs on maximum rate of depolarization in guinea‐pig ventricle

Campbell

1983

British J Pharmacology

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1The effects of Class I antiarrhythmic drugs on the maximum rate of depolarization (Vmax) of guinea-pig ventricular action potentials were studied by standard microelectrode techniques. 2 The ability of seven different drugs to depress V'max in unstimulated tissue ('resting block') was found to correlate poorly with the lipophilicity (log P) of the compounds and only a little better with their molecular weights. 3 Depression of Vmax in stimulated tissue was studied for 11 drugs and found, in all cases, to increase with stimulation frequency ('rate-dependent block'). 4 The rapidity of onset of rate-dependent block (at approximately equipotent concentrations) varied markedly between drugs. It correlated well with molecular weight (r= 0.83; P< 0.01). 5The time constant of recovery from rate-dependent block (Tre) also correlated very well with molecular weight (r= 0.94; P< 0.001) for the seven drugs thus studied. 6 A simplified model for the interaction of Class I drugs with the fast sodium channel is proposed in which the drugs all act as 'inactivation enhancers' (as suggested by other workers) but in which their molecular weight plays a central role in determining the kinetics of this interaction.

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Section: Kinetics Of Offset Ofrdb (Rre)supporting

confidence: 71%

Importance of physico‐chemical properties in determining the kinetics of the effects of Class I antiarrhythmic drugs on maximum rate of depolarization in guinea‐pig ventricle

Campbell

1983

British J Pharmacology

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“…We have recently reported that ketamine decreased the maximum rate of rise of action potential upstroke ( max) in isolated guinea pig papillary muscles, suggesting that ketamine also exerts an inhibitory action on cardiac sodium (Na) channels [12]. It is wellknown that Na channel blockers such as lidocaine and quinidine produce inhibition of max in a use-dependent manner (use-dependent block, UDB) where its inhibition is enhanced with repetition of evoking action potential [13,16]. In our previous study [12] ketamine markedly depressed V · max of the first action potential after a long pulse-free period and failed to produce a further decrease in max during the subsequent train of stimuli.…”

Section: Methodsmentioning

confidence: 99%

Tonic Block of the Sodium and Calcium Currents by Ketamine in Isolated Guinea Pig Ventricular Myocytes.

Hara

Chugun

Nakaya

et al. 1998

The Journal of Veterinary Medical Science

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ABSTRACT. Effects of ketamine on the sodium (I Na ) and L-type calcium currents (I Ca ) were examined by using whole-cell patch clamp techniques in guinea pig single ventricular myocytes. The mode of action of ketamine was compared with those of quinidine, a sodium channel blocker, and verapamil, a calcium channel blocker. Ketamine (30-300 µM) inhibited both I Na and I Ca in a concentrationdependent manner. Quinidine (30 µM) and verapamil (0.1 µM) produced use-dependent depression of I Na and I Ca , respectively. The amplitude of I Na elicited by the first depolarizing pulse after a long quiescent period was slightly decreased by quinidine. During a train of depolarizing pulse the current amplitude decreased gradually, and reached a steady state level in the quinidine-treated cells (use-dependent block, UDB). Verapamil produced a similar mode of inhibition of I Ca , i.e., UDB. In contrast, ketamine produced significant decrease in I Na and I Ca elicited by the first depolarizing pulses and the decreases of both currents were not augmented during a train of depolarizing pulses. From these results, it can be concluded that ketamine produces tonic block of the cardiac sodium and calcium channels and the mode of inhibition is clearly different from UDB by quinidine and verapamil. -KEY WORDS: calcium current, cardiac myocyte, ketamine, sodium current, tonic block.J. Vet. Med. Sci. 60(4): 479-483, 1998 MATERIALS AND METHODSCell preparations: Guinea pigs, weighing 200-350 g, were used in this study. Single ventricular cells were isolated by an enzymatic dispersion, as previously described [11]. Briefly, the heart was removed from the open-chest guinea pig anesthetized with pentobarbital Na, and mounted on a modified Langendorff perfusion system for retrograde perfusion of the coronary circulation with a normal HEPESTyrode solution. The perfusion medium was then changed to a nominally Ca-free HEPES-Tyrode solution and then to a solution containing 0.02% w/v collagenase (Wako, Osaka, Japan). After digestion, the heart was perfused with a high K + and low Cl -solution (modified Kraftbrühe (KB) solution) [17,22]. Ventricular tissue was cut into small pieces in the modified KB solution and gently shaken to isolate cells. Dispersed cells were stored in the KB solution at 4°C and used over the next 7-10 hr.Recording techniques: Whole-cell membrane currents were recorded by patch clamp method [9]. Single ventricular cells were placed in a recording chamber (1-ml volume) attached to an inverted microscope (Olympus IMT-2, Tokyo, Japan) and superfused with the HEPES-Tyrode solution at a rate of 3 ml/min. The temperature of the external solution was kept constant at 36 ± 1°C. Glass patch pipettes with a diameter of 1.5 mm were filled with a pipette solution. The resistance of the patch pipette filled with the pipette solution was 2-3 MΩ. The tight-seal, whole cell voltage clamp technique was used. After the gigaohmseal between the tip of the electrode and the cell membrane was established, the membrane patch was disrupted by K...

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“…In these studies, 9-16% tonic block was present. Although several quantitative analyses have assumed that tonic block was zero (13,23,28) AM. 4% tonic block in the presence of QUIN has also been described in simple propagating systems (5).…”

Section: Resultsmentioning

confidence: 99%

Direct quantification of apparent binding indices from quinidine-induced in vivo conduction delay in canine myocardium.

Haugland

Johnson

Packer³

1994

J. Clin. Invest.

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To characterize quantitatively the quinidine (QUIN)-induced conduction delay (CD) in vivo, canine ventricular activation times were examined with an epicardial mapping technique. A high-resolution index of normalized (N) QUIN CD, derived from all 56 recording sites, was used to quantify QUIN effect. Repetitive stimulation elicited monoexponential increases in CD(N), the rates of which were a linear function of interpulse recovery interval, t,. Steady-state CD(N) was also linearly related to an exponential function of tr and drug uptake rates. The frequency-dependent properties of QUIN in 14 dogs were characterized by apparent binding and unbinding rates of k. = 7.1±3.5 x 106 M-1 s-l, 1a = 81±51 s-1 for activated, and kr = 12.6±11.3 X 103 M-l s51, 4r = 0.51±0.26 s-1 for resting states. k. and 4, were similar to values previously derived in canine Purkinje fibers. Drug unbinding at resting potentials was faster in vivo than previously observed in vitro. The time constant of recovery from QUIN block extracted from the interpulse recovery rate was also identical to that determined from post-mature stimulus diastolic scanning. As predicted by the two-state model, similar binding rates were also derived from declining CD(N) elicited by step decreases in heart rate. These findings represent a complete quantitative description of use-dependent QUIN CD in vivo and provide a firm foundation for characterizing antiarrhythmic drug action under physiologic and pathologic conditions. (J. Clin. Invest. 1994.

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Mechanism of action of antifibrillatory drugs

Cited by 115 publications

References 20 publications

Importance of physico‐chemical properties in determining the kinetics of the effects of Class I antiarrhythmic drugs on maximum rate of depolarization in guinea‐pig ventricle

Importance of physico‐chemical properties in determining the kinetics of the effects of Class I antiarrhythmic drugs on maximum rate of depolarization in guinea‐pig ventricle

Tonic Block of the Sodium and Calcium Currents by Ketamine in Isolated Guinea Pig Ventricular Myocytes.

Direct quantification of apparent binding indices from quinidine-induced in vivo conduction delay in canine myocardium.

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