Effect of Altering Potassium Concentration on the Action of Lidocaine and Diphenylhydantoin on Rabbit Atrial and Ventricular Muscle

Transcription

1 Effect of Altering Potassium Concentration on the Action of Lidocaine and Diphenylhydantoin on Rabbit Atrial and Ventricular Muscle By B. N. Singh and E. M. Vaughan Williams ABSTRACT AH previously studied antiarrhythmic drugs which also have local anaesthetic properties reduce the maximum rate of depolarization (MRD) of cardiac muscle. Recent evidence suggested that lidocaine and diphenylhydantoin (DPH) might have a different mode of action, because they did not reduce MRD except at high concentration. The latter evidence, however, was obtained from tissues nourished by solutions containing DIM potassium. In the present experiments, the effects of lidocaine and DPH were studied in solutions with and 3 mm KC1. In the former, both drugs reduced MRD at concentrations similar to those found in the blood of treated patients, but in low [KC1] higher concentrations were necessary. It was concluded that there was no reason to suppose that the mode of action of lidocaine and DPH on the cardiac membrane is fundamentally different from that of quinidine, procaine, procainamide and other compounds which interfere directly with depolarization. KEY WORDS cardiac potentials cardiac arrhythmias microeleclrodes antidysrhythmic action The actions of antidysrhythmic drugs may be classified into three main categories (1). The first class of action, possessed by quinidine, procaine, procainamide and many other compounds (2, 3), is a reduction in the maximum rate of depolarization (MRD) of cardiac muscle, in the absence of a change in resting potential or significant prolongation of the action potential. Drugs with such class 1 actions are also local anesthetics, though very much higher concentrations are required to depress conduction in nerve than in cardiac muscle (4, 5). The second class of action is antisympathetic, and compounds with such an action are naturally most effective against dysrhythmias associated with a high level of sympathetic activity. A complication arose when it was discovered that the /3-receptorblocking drug, pronethalol, protected against From the Department of Pharmacology, Oxford University, England. Received March 12, Accepted for publication July 16, ouabain-induced ventricular fibrillation (6). It was found, however, that pronethalol and many other /3-receptor-blocking drugs, including propranolol, alprenolol, and oxprenolol (5, 7-9) had class 1 actions also on cardiac muscle and were local anesthetics, and some authors maintained that this action alone could account for the protection against digitalis intoxication (10, 11). Bretylium, however, a sympatholytic drug devoid of class 1 action, also protects against ouabain-induced ventricular fibrillation (12), and more recent evidence (4, 13-15) has made it clear that antagonism to sympathetic action, whether by neuron blockade or competition for receptors, contributed to protection against dysrhythmias, however produced. Very recently a third class of antidysrhythmic action has been demonstrated, due to a prolongation of the duration of the cardiac action potential produced by drugs (18, 17) or by hypothyroidism (18), a condition in which dysrhythmias are rare and which has 286 CtrcuUlion Restsrcb, Vol. XXIX, Stpumber 1971

2 LIDOCAINE AND DPH AT DIFFERENT K LEVELS 287 been purposely induced to control tachycardias resistant to drug treatment (19). The question here at issue is whether it is necessary to propose that there is a fourth class of action in order to explain the antidysrhythmic effects of lidocaine and diphenylhydantoin. Since lidocaine is a powerful local anesthetic, it might have been supposed that its antidysrhythmic effects were due to a class 1 action on cardiac muscle. Davis and Temte (20) and Bigger and Mandel (21) found that lidocaine did reduce MRD in canine Purkinje fibers but at concentrations so high that they considered the antidysrhythmic action could not be attributed to this effect. Likewise, Bigger et al. (22) found that diphenylhydantoin (DPH) reduced MRD at a concentration of 5X1(HM (13.8 mg/liter), but at concentrations between IO^M and IO^M DPH increased MRD and reduced electrical threshold. These experiments were carried out in Tyrode's solution, which usually contains 2.7M K, but which was given as containing 3M K. Since MRD is a function of the resting potential at which the action potential takes off (23) and since the resting potential is a function of the external K concentration (24), the lower the external K, the faster the MRD. The present experiments were undertaken, therefore, to study the effect of external potassium concentration on the action of lidocaine and DPH on cardiac intracellular potentials, and to investigate whether the failure of low concentrations of these drugs to reduce the MRD might thus be explained. Methods The methods have been described in detail elsewhere (2, 3). Briefly small rabbits of either sex (about 1 kg) were killed by a blow on the head, and their atria, or strips of ventricle, dissected in freely flowing oxygenated modified Locke's solution. They were suspended horizontally in an organ bath through which nutrient fluid was circulated at 32 C by an oxygenator external to the bath. Fibers were penetrated with glass microelectrodes from the internal surface. Mean values were calculated from all records except those rejected according to defined criteria (24); i.e., if the resting potential was not the same at the beginning and end of the recording Circulation Rtstarcb, Vol. XXIX, Stpttmbtr 1971 run, or if there were gross irregularities in the repolarization record implying movement artifact. No records were rejected on the grounds of low values of any parameter. Contractions were recorded with an RCA 5734 transducer, and conduction velocity was calculated from the interval between a stimulus (1- msec square wave, strength at least twice threshold) and an action potential recorded with a surface bipolar electrode. The driving frequency was 60/min in ventricular strips and was adjusted to be about 10% faster than the spontaneous frequency in atria. Electrical thresholds and the maximum frequency at which the muscle would follow a stimulus were also measured. Records were displayed on a pair of Tektronix 502 oscilloscopes, and were photographed. All solutions contained (nfti): NaCl, 125; CaCln, 2.16; NaHCO 3, 25; glucose, 11; KC1, eidier 3 or ; and were gassed with 95* O 2 and 5% CO,, ph 7.4. The statistical significance of differences was calculated by Student's t-test. Drugs.-Phenytoin sodium, B.P. (Parke Davis) and lidocaine (lignocaine) hydrochloride, B.P. (Astra-Hewlett) were dissolved directly into the Locke solution to avoid the complication introduced by the use of special diluent (21). It may be presumed that at the two highest concentrations of DPH employed, the drug was not fully dissolved. If the actual concentrations were lower than those nominally given, this would only serve to reinforce the argument that very high concentrations of DPH were not necessary to reduce MRD. Dose-related responses were obtained up to the highest concentration used (Table 1). Results Control recordings were obtained after the isolated tissues had been set up for minutes. The muscle was then exposed to a low concentration of the drug being studied, and records were taken at intervals between 10 and 60 minutes later. It was found that the full effect of both drugs was established within minutes. After 1 hour, a higher concentration of the same drug was introduced into the bath, and the recording cycle was repeated. When a satisfactory doseresponse curve had been obtained, the tissue was exposed to drug-free solution, and a second set of control records was obtained at intervals. Complete recovery always occurred after minutes even when the tissue had been in the organ bath for 6 hours (8). The

3 288 SINGH, VAUGHAN WILLIAMS Effects of Lidocaine and Diphenylhydantoin Concentrations Drug concn. (AM) 0 (Control) (Recovery) 0 (Control) <72.5 <145 0 (Recovery) [KC1] (mm) Reatinc potential (mv) 62.3 ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 1.4* 67.7 ± ± ± 2.2 TABLE 1 on Atrial IntraceUular Potentials at Normal and. Low Potassium Action potential Lidocaine 90.1 ± ± ± ± ±1.2* 91.8 ± ± 0.7f 90.5 ± ± 1.4t 85.9 ± ± ± ± 1.2 Diphenylhydantoin 88.7 ± ± ± ± ± ± ± 1.4* 89.2 ± ± ± ± ± 1.2* 89.2 ± ± 1.9 MRD (v/iec) ± ± ± ± ± ± ± ± ± ± 46.5 ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 6.9 Time for 90% ropobrixation (mtec) ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 1.2 from the con- Each figure is the mean result from five experiments. Statistical significance of any difference trol: *P < 0.01; +P < effects of a range of concentrations of diphenylhydantoin and lidocaine was studied in solutions containing 3 or HIM KC1. Lidocaine. The contrast between the effects of the drug in the different potassium solutions is apparent in Figure 1. Whereas a concentration of 3 mg/liter (11.2 /XM) caused a very big reduction in the MRD of atrial potentials in IBM KC1, 5 mg/liter (18.7 lidocaine had no effect in 3 rrim KCL It No. of records was necessary to raise the concentration of lidocaine to 30 mg/liter (112 /AM) to produce a substantial reduction of MRD (Fig. 2). A similar contrast was observed in records obtained from strips of ventricle (Fig. 3). The effects of lidocaine on atrial intracelrular potentials in nm and 3 mm KC1 have been summarized in Table 1. It is immediately apparent, as would be expected from previous work (24), that 3 mm KC1 caused a Circulation Rtsiarcb, Vol. XXIX, Septcmbir 1971

4 LIDOCAINE AND DPH AT DIFFERENT K LEVELS 289 CONTROL k K=5 6mM B K= 3 OmM LIMCAINE inig/lrtre (I \Z x ICPM) LIDOCAINE 5mg/lltre RECOVERY IO0ms«c loomsk slow,5msfc fast FIGURE 1 Effect of Udocaine on atrial intracellular potentials in and 3 m*r KCl. In each frame the traces depict the following: Left: horizontal trace, zero potential; middle traces, intracellular potentials at slow and fast sweep speeds; bottom trace; contractions. Right: upper trace, stimulus artifact from electrode on left atrium and action potential recorded from surface of right atrium; lower trace, differential of intracellular record, the depth of the spike being proportional to the maximum, rate of depolarization. In min KCl lidocaine 3 mg/liter greatly reduced MRD, whereas in 3 mm KCl lidocaine 5 mg/ltter had no effect on MRD. CONTROL LIDOCAINE lomg/htrt 100 mv k. K= mh B K =3-OmM FIGURE 2 Description as for Figure 1. Lidocaine did decrease MRD in 3 m«kcl, but the concentration required to produce comparable effects was higher than in mn KCl. Lidocaine did not affect the duration of the action potential in atrial muscle. CircnUtio* Research, Vol. XXIX, Stpfmber 1971

5 290 SINGH, VAUGHAN WILLIAMS A. K- 5-6 mm K - J-0 (rfl CONTROL 10 mg/lltre 0 ^ loomv FIGURE 3 Effect of lidocaine on ventricular intracellular potentials in 3 and VIXM KCl. Description as in previous figures. As with atrial mwcle, higher concentrations of lidocaine were required to reduce MRD in 3 than in mm KCl, but the duration of the action potential was reduced by similar concentrations of lidocaine in both solutions. hyperpolarization and increase in MRD throughout. This raised the threshold concentration of lidocaine required to reduce MRD by a factor of about ten. Very similar results were obtained from measurements of ventricular potentials, so far as the depression of MRD was concerned. In ventricular muscle MRD fell to one-third the control value with 37.3 fjlm. lidocaine in mm KCl, but was not reduced in 3 mm KCl. In atrial muscle, the duration of the action potential was not altered by lidocaine at even the highest concentrations in either of the potassium solutions. In ventricular muscle, however, lidocaine shortened the action potential at a concentration of 11.2 /XM, and the effect was similar in both potassium solutions (from 189 msec control, to 174 in mm and to 164 in 3 mm KCl); 37.3 /AM lidocaine caused a further shortening to 144 msec in mm and to 129 in 3 mm KCl. Effects of Lidocaine on Spontaneous Frequency, Maximum Driven Frequency, Electrical Threshold, Conduction Velocity and Contractions. Here again, the effects of lidocaine were greatly reduced by the presence of 3 mm external potassium, and the results are summarized in Figure 4. Diphenylthydantoin. The effects of DPH at different potassium concentrations were studied in exactly the same way as those of lidocaine. The results of the atrial intracellular recordings are summarized in Table 1. The only difference from the results with lidocaine is that in 3 mm KCl the lowest concentration of DPH caused an increase in MRD. Although it was statistically significant, the increase amounted to only 10%. The effects of DPH on ventricular potentials at different Circulation Rtstanb, Vol. XXIX, Stpttmbtr 1971

6 LIDOCAINE AND DPH AT DIFFERENT K LEVELS we-.so- ' ' JO M- -KX> no- Latecoitw Cere (mj/l> > C^hO K-3o«b - 5 0^7 * CT-'M) c-10 H-Tii ffi'a) d / ir'm) n 1H Contmotron H amphtujc SpontanKafi drmn Coniidtai ^. b c d rate frtqjmcy [~ ^M vrtxny ^Bj n h r rt ^B abed ^ B b C ^ H 1 n^ ^B abed Ekctrtccl 1 - FIGURE 4 Ml LI Effects of lidocaine in 3 and min KCl solutions on the spontaneous frequency, maximum frequency at which a stimulus toas followed, electrical threshold, conduction velocity and contraction amplitude of isolated rabbit atria. Lidocaine was less effective in 3 than in vut KCl. potassium concentrations were again very similar to those of lidocaine. The duration of the action potential was shortened by 18 /AM DPH from a control value of 193 to 187 msec in mm and to 180 msec in 3 mm potassium solutions. The highest concentration of DPH caused a further shortening to 103 msec in both potassium solutions. The effects of DPH on other parameters of atrial function are presented in Figure 5. Discussion The results have shown that reducing the external potassium concentration raised the threshold concentrations at which lidocaine and DPH decreased the MRD in rabbit atrial and ventricular muscle and shifted the whole dose-response curve to the right. If the responses of canine cardiac muscle are similar, these findings could explain why the results of Bigger et al. (22) and of Strauss et al. (25) with DPH appeared to be at variance with CircuUiion Research, Vol. XXIX, September 1971 those of other authors (26) and would resolve also the difference between our own investigations with lidocaine (1) and those of Davis and Temte (20) and of Mandel and Bigger (21, 27). Since the resting potential of cardiac muscle is a function of the ratio of extracellular to intracellular potassium concentrations, a decrease of extracellular potassium makes the intracellular potential more negative, and this is itself responsible for increasing the MRD (23, 24). Consequently, drugs which act by reducing MRD, such as quinidine and compounds with class 1 actions (1) on cardiac muscle analogous to the action of local anesthetics on nerve, would be much less effective in low potassium solutions (28). In Hodgkin-Huxley terms, such drugs interfere with depolarization by altering the voltage at which the sodium depolarizing system can be reactivated after repolarization. The factor "h" is prevented by the drugs from returning to its normal high value at the resting potential (29), but this effect can be counteracted by hyperpolarizing the membrane, or by increasing the ratio of extracellular to intracellular sodium (30-32). "I f I H30 OPH ConcenlnUion (mq^fitrt) o-l (3 62 x Kf^H) b-5 (1-81 i PUKP) d-20 (7 25x0"^).-40 (1 45x10"^) Contraction Anpftudt obedt K-J-OmM FIGURE 5 Effects of DPH in 3 and mm KCl solutions on the spontaneous frequency, maximum driven frequency, electrical threshold, conduction velocity and contractions of isolated rabbit atria. The drug teas less effective in 3 mm K than in mm KCl.

7 292 SINGH, VAUGHAN WILLIAMS X no Vcnlrkular Alriol f 60 a = 'Therapeutic* Lignocoine Concentration (mg/litre) x Range Theroprulic Range FIGURE 6 Dose-response curves for lidocaine (left) and DPH (right) on the maximum rate of depolarization of atrial and ventricular muscle in 3 and in TUM KCl solutions. Evidence for therapeutic concentrations taken from Bigger et al. (46) and from Harrison et al. (48). Davis and Temte employed a [K] of only 2.7 mm, and the other authors who failed to observe a reduction of MRD by DPH and lidocaine except at high concentrations also employed solutions containing only mm K. To assess the significance of such experiments, two questions have to be considered. (1) What is a "normal" potassium concentration? (2) How closely do drug concentrations with pharmacological actions in vitro correspond to those occurring in the plasma of successfully treated patients? Spector (33) stated that normal concentrations for serum potassium were 5.5 mm in the rabbit, and 5 mm in man. Since potassium may be released in clotting, plasma levels are perhaps more relevant, and Hoffman (34) quoted normal values for man of meq/liter (mean 4.7). Ninety-nine percent of healthy adults have a plasma [K] above 3.5 meq/liter (35). In the survey of Wootton and King (36), 98% of humans had serum and plasma [K] between 3.5 and meq/liter. Singer (37) gives the normal human plasma level of potassium as 4.2 meq/liter. There can be little doubt, therefore, that a [K] of meq/liter must be considered abnormally low. The clinical relevance of hypokalemia in the treatment of dysrhythmias is illustrated by a patient with a ventricular tachycardia and a serum [K] of 3.1 meq/liter who failed to respond to 2 mg propranolol i.v mg lidocaine i.v.+ 2 mg/min lidocaine i.v., but in whom, after the serum [K] had been raised to 4.4 meq/liter by an injection of 60 meq KCl, sinus rhythm was restored by lidocaine, 2 mg/min (38). So far as diphenylhydantoin is concerned, our results have merely confirmed those of Jensen and Katzung (31, 32), though we have studied a wider range of concentrations. In addition, we have shown that the effect on MRD of lidocaine also is greatly reduced by lowering the external potassium concentration. Conduction velocity and MRD are both depressed at increased driving frequency (39, 40), and Jensen and Katzung (31) demonstrated that the higher the frequency the greater the effect of DPH on MRD. This explains the relatively greater effect of DPH on the Circulation Research, Vol. XXIX, September 1971

8 LIDOCAINE AND DPH AT DIFFERENT K LEVELS 293 conduction velocity of extrasystoles (41) than of sinus beats. At low concentrations (up to 5 mg/liter), DPH produced a small increase (10%) in MKD in isolated rabbit atrial fibers, in agreement with the observations of Bigger et al. on canine Purkinje fibers (22). Bigger et al. (42) found that 5-10 mg/kg DPH also shortened AV conduction in dogs. Such effects (Fig. 4) are normally associated with sympathetic activation (43), which increases liability to dysrhythmias, and it may be questioned whether they play any part in the antidysrhythmic action of DPH, or, indeed, whether they are due to any direct action of DPH on the cardiac membrane. Bigger et al. observed that the shortening of AV conduction by DPH was attenuated by pretreatment with atropine (1 mg/kg) and propranolol (0.2 mg/kg) and did not occur at all in reserpinized rabbits (42). Sasyniuk and Dresel (44) found that the shortening by DPH of AV conduction reported by Rosati et al. (45) in unanesthetized dogs did not occur in isolated blood-perfused canine hearts. In any case, all authors agree that it is only in the presence of small amounts of DPH that MRD is increased or AV conduction accelerated, and that at higher concentrations DPH is purely depressant, so that it is important to know the plasma concentrations at which DPH exerts an antidysrhythmic effect in man. Bigger et al. (46) measured the plasma concentrations of DPH in patients treated for various types of cardiac dysrbythmia, and reported that "70% of the arrhythmias which responded to DPH did so at a plasma level between 10 and 18 mg/1." A further 10% responded at a concentration higher than 18 mg/liter. On the other hand, no cases of atrial fibrillation (out of 12) or of atrial flutter (out of 5) responded, in spite of plasma concentrations of and mg/liter, respectively. Manifestations of toxicity become apparent at mg/liter (47). Harrison et al. (48) stated that "venous blood levels of lidocaine between 1.2 and 6.0 mg/1 represent the effective blood level in patients following acute myocardial infarction." The CiraUatio* Resurcb, Vol. XXIX, Seplemitr 1971 effects of lidocaine and DPH on MRD in atrial and ventricular muscle at 3 and mm KC1 have been plotted in Figure 6 against the background of these therapeutic levels. It may be argued that the activity of DPH in plasma may be less than that of the equivalent concentration in vitro as a consequence of binding to protein, but this objection would be less applicable to the more water-soluble lidocaine. This is certainly a factor to be considered, but, to paraphrase the words of William of Occam, if a simple hypothesis can account for the facts there is no need for a complicated one. There would seem to be little convincing evidence at present for the proposal that the existence of a special fourth class of antidysrhythmic action is necessary to explain the effects of DPH and lidocaine. This is not to imply that there are no differences between the actions of DPH and lidocaine and of other antidysrhythmic drugs with local anesthetic properties, but that such differences may be attributable to extracardiac (e.g., autonomic) factors or to inequalities in the relative sensitivity of atrial, ventricular or Purkinje tissue, rather than to any fundamental difference in their mode of action on the cardiac membrane. References 1. VAUCHAN WILLIAMS, E.M.: Classification of anti-arrhythmic drugs. In Symposium on Cardiac Arrhythmias, Edited by E. Sandfte, E. Flensted-Jensen, and K.H. Olesen. Sweden, AB ASTRA, Sodertalje, 1970, pp VAUCHAN WILLIAMS, E.M.: Mode of action of quinidine in isolated rabbit atria interpreted from intracellular records. Br J Pharmacol Chemother 13: , SZEKERES, L., AND VAUGHAN WILLIAMS, E.M.: Antiflbrillatory action. J Physiol (Lond) 160: 47CM82, DOHADWALLA, A.N., FREEDBERG, A.S., AND VAUGHAN WILLIAMS, E.M.: Relevance of - receptor blockade to ouabain-induced cardiac arrhythmias. Br J Pharmacol 36: , SINGH, B.N., AND VAUGHAN WILLIAMS, E.M.: Local anaesthetic and anti-arrhythmic actions of alprenolol relative to its effect on intracellular potentials and other properties of isolated cardiac muscle. Br J Pharmacol 38: , 1970.

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10 LIDOCAINE AND DPH AT DIFFERENT K LEVELS 295 cine. Chicago, Year Book Medical Publishers, Inc., 1970, p WRONG, O.: Incidence of hypokalaemia in severe hypertension. Br Med J 2: , WOOTTON, I.D.P., AND KING, E.J.: Normal values for blood constituents. Lancet 1: , SINGER, R.B.: Biology Data Book. Washington D. C, Am Soc Exp Biol 1964, p PAMTNTUAN, J.C., DRETFUS, L.S., AND WATANABE, Y.: Comparative mechanisms of anti-arrhythmic drugs. Am J Cardiol 26: , VAUGHAN WILLIAMS, E.M.: Some observations concerning the mode of action of acetylcholine in isolated rabbit atria. J Physiol (Lond) 140: , VLEHSMA, J.W., BOUMAN, L.N., AND MATER, M.: Frequency, conduction velocity and rate of depolarization in rabbit auricle. Nature 217: , RUSSELL, J.M., AND HARVEY, S.C.: Effects of diphenylhydantoin on canine atria and A-V conduction system. Arch Int Pharmacodyn Thei 182: , BIGGER, J.T., STRAUSS, H.C., AND HOFFMAN, B.F.: Effects of diphenylhydantoin on atrioventricular conduction. Fed Proc 27:406, HUTTKR, O., AND TRAUTWEIN, W.: Vagal and sympathetic effects on the pacemaker fibres in the sinus venosus of the heart. J Gen Physiol 39: , SASYNIUK, B.I., AND DRESEL, P.E.: Effect of diphenylhydantoin on conduction in isolated, blood perfused hearts. J Pharmacol Exp Ther 161: , ROSATT, R.A., ALEXANDER, J.A., SCHAAL, S.F., AND WALLACE, A.G.: Influence of diphenylhydantoin on electrophysiological properties of canine heart. Circ Res 21: , BIGCER, J.T., SCHMIDT, D.N., AND KUTT, H.: Relationship between the plasma level of diphenylhydantoin sodium and its cardiac antiarrhythmic effects. Circulation 38: , KUTT, H., WINTERS, W., KOKENGE, R., AND MCDOWELL, F.: Diphenylhydantoin metabolism, blood levels and toxicity. Arch Neurol 11: , HABBISON, D.C., STENSON, R.L., AND CONSTAN- TINO, R.T.: Relationship of blood levels, infusion ratio and metabolism of lidocaine to its anti-arrhythmic action. Symposium on Cardiac Arrhythmias, edited by E. Sand0e, E. Flensted- Sensen, and K.H. Olesen. AB ASTRA, Sodertalje, Sweden, 1970, pp CircuUliun Rtsturcb, Vol. XXIX, Soplembor 1971