[THE OPINION OF POPULATION CONCERNING ISSUE OF DRUG USE AS A SOCIAL HYGIENIC FACTOR].

The article indicates that in modern society the trends of reevaluation and redefinition of moral and social limits, regulating legitimate and non-legitimate pleasure. The popularity of programs of decreasing of narcotization harm is increasing to the prejudice of comprehensive conception of necessity of social prevention of drug abuse as a system of influence of public authorities and institutions of civil society with purpose to minimize drug effect. The modeling of such exposition pressure directing individual to "drug-independent" behavior by all totality of mechanisms society dispose is one of major tasks of drug abuse control. The article is targeted to reveal qualitative quantitative characteristics of public opinion in Russia and parameters of monitoring of public opinion on the basis of content analysis of secondary sources and qualitative analysis of sociological surveys. It is concluded that efforts information of public opinion are to be related to targets and tasks available in sphere of drug control and belonging to the structure of targets and tasks of public health and social hygiene. The core content of public opinion should not have a character of exclusively suggestion of drugs but is to reflect behavioral readiness of citizen to implement social control of narcotism.

Cardiac-specific external paths for lidocaine, defined by isoform-specific residues, accelerate recovery from use-dependent block.

Local anesthetic antiarrhythmic drugs block voltage-gated Na(+) channels from the cytoplasmic side. In addition, cardiac Na(+) channels can be also blocked by the membrane-impermeant local anesthetic QX via external paths not present in skeletal muscle or brain channels. Introduction of cardiac isoform-specific residues into wild-type skeletal muscle or brain channels creates access paths for external QX block. These paths should affect the characteristics of use-dependent block by influencing drug on- and off-rates. We investigated the effects of these external paths on drug kinetics of lidocaine, a lipophilic drug of clinical relevance, by studying use-dependent block using a two-electrode voltage clamp in Xenopus oocytes. Recovery from use-dependent block was slowed when cardiac isoform-specific residues important for external QX access were mutated to skeletal muscle or brain isoform-specific residues. As the fraction of charged lidocaine was decreased by raising external pH, differences in recovery kinetics diminished, indicating that these mutations mostly influenced block by charged lidocaine molecules. Data were fit into a model in which bound drug distributes into charged and neutral forms based on its pK(a) and external pH with separate dissociation paths and recovery-time constants. These isoform-specific mutations altered the recovery-time constants for the charged molecules with smaller effects on those for the neutral molecules. We conclude that the external egress paths created by isoform-specific residues influence the drug kinetics of lidocaine, and these residues define cardiac-specific external paths for local anesthetic drugs.

Structural and gating changes of the sodium channel induced by mutation of a residue in the upper third of IVS6, creating an external access path for local anesthetics.

Membrane-impermeant quaternary amine local anesthetics QX314 and QX222 can access their binding site on the cytoplasmic side of the selectivity filter from the outside in native cardiac Na(+) channels. Mutation of domain IV S6 Ile-1760 of rat brain IIA Na(+) channel or the equivalent (Ile-1575) in the adult rat skeletal muscle isoform (mu 1) creates an artificial access path for QX. We examined the characteristics of mutation of mu 1-I1575 and the resulting QX path. In addition to allowing external QX222 access, I1575A accelerated decay of Na(+) current and shifted steady-state availability by -27 mV. I1575A had negligible effects on inorganic or organic cation selectivity and block by tetrodotoxin (TTX), saxitoxin (STX), or mu-conotoxin (mu-CTX). It exposed a site within the protein that binds membrane-permeant methanethiosulfonate ethylammonium (MTSEA), but not membrane-impermeant methanethiosulfonate ethyltrimethylammonium (MTSET) and methanethiosulfonate ethylsulfonate (MTSES). MTSEA binding abolished the QX path created by this mutation, without effects on toxin binding. The mu-CTX derivative R13N, which partially occluded the pore, had no effect on QX access. I1575A exposed two Cys residues because a disulfide bond was formed under oxidative conditions, but the exposed Cys residues are not those in domain IV S6, adjacent to Ile-1575. The Cys mutant I1575C was insensitive to external Cd(2+) and MTS compounds (MTSEA, MTSET, MTSES), and substitution of Ile with a negatively charged residue (I1575E) did not affect toxin binding. Ile-1575 seems to be buried in the protein, and its mutation disrupts the protein structure to create the QX path without disturbing the outer vestibule and its selectivity function.

A critical residue for isoform difference in tetrodotoxin affinity is a molecular determinant of the external access path for local anesthetics in the cardiac sodium channel.

Membrane-impermeant quaternary derivatives of lidocaine (QX222 and QX314) block cardiac Na(+) channels when applied from either side of the membrane, but they block neuronal and skeletal muscle channels poorly from the outside. To find the molecular determinants of the cardiac external QX access path, mutations of adult rat skeletal muscle (micro1) and rat heart (rH1) Na(+) channels were studied by two-electrode voltage clamp in Xenopus oocytes. Mutating the micro1 domain I P-loop Y401, which is the critical residue for isoform differences in tetrodotoxin block, to the heart sequence (Y401C) allowed outside QX222 block, but its mutation to brain type (Y401F) showed little block. mu1-Y401C accelerated recovery from block by internal QX222. Block by external QX222 in mu1-Y401C was diminished by chemical modification with methanethiosulfonate ethylammonium (MTSEA) to the outer vestibule or by a double mutant (mu1-Y401C/F1579A), which altered the putative local anesthetic binding site. The reverse mutation in heart rH1-C374Y reduced outside QX314 block and slowed dissociation of internal QX222. Mutation of mu1-C1572 in IVS6 to Thr, the cardiac isoform residue (C1572T), allowed external QX222 block, and accelerated recovery from internal QX222 block, as reported. Blocking efficacy of outside QX222 in mu1-Y401C was more than that in mu1-C1572T, and the double mutant (mu1-Y401C/C1572T) accelerated internal QX recovery more than mu1-Y401C or mu1-C1572T alone. We conclude that the isoform-specific residue (Tyr/Phe/Cys) in the P-loop of domain I plays an important role in drug access as well as in tetrodotoxin binding. Isoform-specific residues in the IP-loop and IVS6 determine outside drug access to an internal binding site.

Sodium channel selectivity filter regulates antiarrhythmic drug binding.

Local anesthetic antiarrhythmic drugs block Na+ channels and have important clinical uses. However, the molecular mechanism by which these drugs block the channel has not been established. The family of drugs is characterized by having an ionizable amino group and a hydrophobic tail. We hypothesized that the charged amino group of the drug may interact with charged residues in the channel's selectivity filter. Mutation of the putative domain III selectivity filter residue of the adult rat skeletal muscle Na+ channel (micro1) K1237E increased resting lidocaine block, but no change was observed in block by neutral analogs of lidocaine. An intermediate effect on the lidocaine block resulted from K1237S and there was no effect from K1237R, implying an electrostatic effect of Lys. Mutation of the other selectivity residues, D400A (domain I), E755A (domain II), and A1529D (domain IV) allowed block by externally applied quaternary membrane-impermeant derivatives of lidocaine (QX314 and QX222) and accelerated recovery from block by internal QX314. Neo-saxitoxin and tetrodotoxin, which occlude the channel pore, reduced the amount of QX314 bound in D400A and A1529D, respectively. Block by outside QX314 in E755A was inhibited by mutation of residues in transmembrane segment S6 of domain IV that are thought to be part of an internal binding site. The results demonstrate that the Na+ channel selectivity filter is involved in interactions with the hydrophilic part of the drugs, and it normally limits extracellular access to and escape from their binding site just within the selectivity filter. Participation of the selectivity ring in antiarrhythmic drug binding and access locates this structure adjacent to the S6 segment.

Blockade of cardiac Na+ channels by a charged class I antiarrhythmic agent, bisaramil: possible interaction of the drug with a pre-open closed state.

The mechanism of cardiac Na+ channel block by a charged class I antiarrhythmic agent, bisaramil, was studied in guinea-pig ventricular myocytes using patch-clamp techniques of whole-cell, cell-attached and inside-out configurations. Bath application of bisaramil caused the use-dependent block of whole cell Na+ current (INa) in a concentration-dependent manner and EC30 value was 2.0 microM. At 5 microM bisaramil, the degree of the use-dependent block of INa with a short (5 ms) pulse protocol (44.9 +/- 5.7% of the first pulse INa) was comparable to that with a long (200 ms) pulse protocol (42.8 +/- 5.9%). In cell-attached patches, bisaramil applied to the bath solution (external application) concentration dependently blocked macropatch Na+ currents (50.3 +/- 3.1% inhibition with 10 microM bisaramil). Internal application of bisaramil decreased the inside-out macropatch currents (82.6 +/- 1.3% inhibition with 10 microM bisaramil). Blocking effects of bisaramil applied to the bath solution were greater than those seen on the pipette application in all of the whole-cell, cell-attached and inside-out configurations. In cell-attached patches containing a single active channel, bath application of 10 microM bisaramil increased the null sweeps with a significant (P < 0.001) nonrandom clustering and decreased the total number of openings, whereas no changes in the number of openings per active sweep, unitary current amplitude, mean open time and mean closed time were observed. While the peak average current was decreased by 51.0 +/- 5.6% with 10 microM bisaramil, the number of active sweeps was decreased by 31.4 +/- 6.2%. In the presence of 10 microM bisaramil, the mean values of first latencies were significantly (P < 0.05) increased and the peak value of the first latency density function was decreased by 15.8 +/- 3.6%. From these results, we conclude that a charged tertiary amine, bisaramil interacts with cardiac Na+ channels preferentially in the activated state. Interactions with pre-open closed states might contribute to the activated channel block by the drug.

Interaction between external Na+ and mexiletine on Na+ channel in guinea-pig ventricular myocytes.

To assess the modulation of Na+ channel block with local anaesthetics by the change of external Na+ concentration ([Na+]o), we examined the block by mexiletine at different [Na+]o using the whole-cell and the cell-attached configurations of the patch-clamp technique. Lowering [Na+]o increased the degree of use-dependent block of the whole-cell Na+ current. The external Na+ dependence of the Na+ current block was caused by the interaction of mexiletine with the activated Na+ channel, but not with the inactivated channel. In single-Na+ channel current recordings at a reduced [Na+]o of 70 mM, mexiletine shortened the mean open time of the channels (1.32 +/- 0.06 ms in the control vs. 0.86 +/- 0.12 ms with the drug, P < 0.05) without changes in the unitary current amplitude, whereas the drug did not affect mean open time at a [Na+]o of 140 mM. Moreover, the open time distributions during drug exposure at the reduced [Na+]o were better fitted to a double exponential than to a single exponential in four out of six experiments. These data suggest that mexiletine induces two conductive states: the native open state and a state representing the first step of open channel block. The transition from the former to the latter is dependent on [Na+]o, suggesting an antagonistic interaction of external Na+ with mexiletine.

Voltage- and frequency-dependent modulation of L-type Ca2+ channel by MPC-1304, a novel calcium antagonist in guinea-pig hearts.

The electrophysiological effects of MPC-1304, a novel calcium antagonist, were examined using the conventional microelectrode and whole-cell patch-clamp techniques in guinea-pig hearts. MPC-1304, at 100 nM or higher concentrations, produced a dose-dependent reduction in the action potential duration of guinea-pig papillary muscles, without changes in resting membrane potentials and maximum rate of rise of action potentials. In guinea-pig ventricular myocytes, MPC-1304 (1-100 nM) dose-dependently depressed the initial inward currents induced by depolarizing pulses from a holding potential of -30 mV in the external Tyrode solution, as did nifedipine, whereas the late outward current was not changed by MPC-1304. In the presence of 100 nM of MPC-1304 or 100 nM of nifedipine, the first depolarizing pulse from a holding potential of -80 mV caused a depression of the isolated L-type Ca2+ current (I(Ca)) by 29.5 % and 29.4 % of the control, respectively (tonic block), and successive pulses further suppressed I(Ca) in a use-dependent manner (use-dependent block). The degree of steady state use-dependent block of I(Ca) by 100 nM of MPC-1304 was 25.5 % at the stimulus frequency of 1 Hz and further increased to 34.0 % at 2 Hz (frequency-dependent block), which were significantly larger than those by 100 nM of nifedipine at both frequencies. The onset rate of use-dependent block by 100 nM MPC-1304 was significantly smaller than that by 100 nM nifedipine. MPC-1304 (100 nM) and nifedipine (100 nM) shifted the steady state inactivation curve of I(Ca) toward the negative potential by 3.3 mV and 9.1 mV in the mid-potential of the curve, respectively. The estimated dissociation constants of MPC-1304 were 137.7 and 49.9 nM for the resting and inactivated states of the L-type Ca2+ channel, respectively, and those of nifedipine were 113.9 and 18.1 nM, respectively. We conclude that MPC-1304 suppress the L-type Ca2+ channel with slow kinetics in a voltage- and frequency-dependent manner, which might be caused by its high affinity to the activated as well as to the inactivated state of the channel.

Synthesis and biological activity of the metabolites of syn-3-ethyl-7-methyl-3,7-diazabicyclo[3.3.1]non-9-yl 4-chlorobenzoate hydrochloride.

Five metabolites of syn-3-ethyl-7-methyl-3,7-diazabicyclo[3.3.1]non-9-yl 4-chlorobenzoate hydrochloride (YUTAC) (1) were prepared and examined for Na+ current blocking activity in guinea pig ventricular myocytes. These metabolites showed lower inhibitory activities than the parent compound or were inactive.

External pH modifies sodium channel block by mexiletine in guinea pig ventricular myocytes.

OBJECTIVE: The aim was to examine the kinetics and the degree of Na+ channel block by mexiletine under different values of external pH to produce a fractional variation of charged and uncharged forms of mexiletine. METHODS: The Na+ current (INa) was recorded using the patch clamp technique of whole cell configuration in guinea pig ventricular myocytes. RESULTS: In the presence of 20 microM mexiletine, INa block developed with a single exponential when depolarising pulse trains of 5 ms were applied to -30 mV from a holding potential of -100 mV at a diastolic interval of 500 ms. At the 30th pulse, the degree of use dependent block of INa was 12.3(SEM 0.41)% (n = 4) of the 1st pulse. When the duration of pulses was prolonged to 200 ms, the degree of use dependent block was increased to 25.6(4.7)%, which had the block development of two exponentials with fast and slow rate constants. The slow component at the 200 ms pulses was comparable to the single exponential component at the 5 ms pulses. Drug binding to the inactivated channel was increased by external alkalinisation, which increased the uncharged form of mexiletine, whereas the block at the 5 ms pulses was not affected by the change of external pH. CONCLUSIONS: Uncharged mexiletine caused use dependent block with a fast rate constant having affinity for the inactivated state of the Na+ channel, while the charged form produced a slow component of the block having affinity for the activated state. Therefore the fraction of the uncharged to the charged form of mexiletine could be one of the important determinants in the development and mechanism of INa block.

Use-dependent block of Na+ currents by mexiletine at the single channel level in guinea-pig ventricular myocytes.

1. The mechanism of use-dependent block of Na+ current by mexiletine was studied at the single channel level in guinea-pig ventricular myocytes by the patch-clamp techniques. All experiments were performed using stimulation protocols to enable us to analyze the strict dependence of changes in channel properties on channel use. 2. In cell-attached patches, bath or pipette application of mexiletine (40 microM) produced a use-dependent reduction of the peak average current without changes in single channel conductance. Null sweeps were increased and the number of openings per sweep decreased with successive pulses, whereas no significant change in the mean open time was detected during the train. 3. Block by mexiletine became greater when pulse duration was extended beyond the period in which channels were open, suggesting that block progressed without channel opening. 4. At near threshold potentials, mexiletine decreased the later occurrence of first openings. Additionally, late openings were reduced in a use-dependent way. 5. We conclude that mexiletine binds to the inactivated closed states of the Na+ channel and then causes a failure of late openings as well as early, which results in null sweeps on subsequent depolarization.

Use-dependent block of Ca2+ current by moricizine in guinea-pig ventricular myocytes: a possible ionic mechanism of action potential shortening.

1. Whole cell patch clamp techniques were used to study the effects of moricizine on membrane currents in guinea-pig ventricular myocytes. 2. Application of moricizine caused reversible depression of the time-dependent outward K+ current. 3. The Na+/Ca2+ exchange current was not directly affected by moricizine. 4. Although moricizine hardly affected the L-type Ca2+ current when cells were stimulated at a frequency of 0.1 Hz, it suppressed the current at depolarized holding potentials in a use-dependent manner at 1 Hz. 5. Developments of use-dependent block of the Ca2+ current in the presence of moricizine were best expressed by two exponentials. Binding to both activated and inactivated states of the Ca2+ channel were supported from the binding kinetics study. 6. We concluded that moricizine suppressed the L-type Ca2+ current in a use-dependent manner and this might explain, at least in part, action potential shortening by the drug.

Properties of veratridine-modified single Na+ channels in guinea pig ventricular myocytes.

Modification of single Na+ channels by the alkaloid neurotoxin veratridine was investigated in guinea pig ventricular myocytes using the cell-attached configuration of the patch-clamp technique. Pipette application of veratridine (50 microM) induced long-lasting openings with two different single-channel conductances of 7.6 and 3.0 pS, in addition to normal type of short openings with a single-channel conductance of 16 pS. The veratridine-modified high- and low-conductance channels appeared commonly, and they could coexist with the normal one in the same patch. The open-time distributions for the high- and low-conductance channels could be fitted by a single exponential. The mean open time for the high- and low-conductance events ranged between 19.1 ms at -120 mV and 86.0 ms at -10 mV and between 4.5 ms at -120 mV and 16.2 ms at -10 mV, respectively. The closed-time distributions for the two conductance channels consisted of at least two components, and their values and voltage dependence were similar. External Ca2+ block resulted in an apparent reduction of unitary current amplitudes with a similar voltage dependence and affinity for Ca2+ in the high- and low-conductance channels. However, the low-conductance channel was more resistant to tetrodotoxin than the high one. The probability of simultaneous occurrence of the high and low events was equal to the product of the probabilities of occurrence of the high event times that of the low event. Furthermore, we observed modified channel openings after a normal opening for the two conductance channels and a modified one turning into a normal one for the high-conductance channel. It is concluded that veratridine induces the two different types of modified Na+ channels in cardiac myocytes and these are correlated with normal openings.

Combined class I antiarrhythmic agents have differential effects on tonic and use dependent block of maximum rate of depolarisation of action potentials in guinea pig cardiac muscle.

OBJECTIVE: The aim was to study the difference between tonic and use dependent block of the cardiac sodium channel produced by the combined application of the same subclass of antiarrhythmic agents (class Ia or Ib). METHODS: Conventional glass microelectrode technique was used to record the maximum rate of depolarisation (dV/dtmax) of action potentials reflecting sodium channel availability, before and after the combined application of quinidine plus disopyramide, aprindine plus lignocaine, aprindine plus mexiletine, and lignocaine plus mexiletine. Guinea pig papillary muscles (n = 4-8 per experiment) were used for the study. RESULTS: All combinations increased tonic block additively compared to use of a single drug. On the other hand, use dependent block was increased by the combination of quinidine 10 microM plus disopyramide 30 microM compared to a single drug, and was not changed by lignocaine 50 microM plus mexiletine 20 microM, whereas it was decreased by aprindine 3 microM plus lignocaine 50 microM or mexiletine 20 microM. When concentrations of mexiletine and lignocaine were increased, both tonic and use dependent block in a single drug were increased dose dependently, whereas the combination produced an additive increase in tonic block but no change in use dependent block compared to a single drug. CONCLUSIONS: The results suggested that the binding and unbinding process of the drug to produce tonic block was different from that to produce use dependent block, and that combination of different drugs produced diverse effects on use dependent block even though state dependent affinity of individual drugs seemed similar. These two factors must be born in mind in evaluating the combination therapy.

States and sites of actions of flecainide on guinea-pig cardiac sodium channels.

The states and sites of actions of flecainide on sodium channels were investigated in guinea-pig single cardiac cells, using the whole-cell voltage-clamp technique at 22 degrees C. External application of flecainide caused tonic and use-dependent block of the sodium current (INa). The tonic block and the steady state use-dependent block increased with increasing drug concentrations. The dose-response curve for the use-dependent block was fitted by the equation for 1:1 drug-receptor binding and yielded a KD of 7.0 microM flecainide. At 5 microM flecainide, the use-dependent block of INa with 10 and 200 ms depolarizing pulses at an interpulse interval of 400 ms was 31.1 +/- 2.7 (mean +/- S.E.) and 36.8 +/- 2.7%, respectively. The two values were not significantly different. The block developed as a single exponential function with onset rate of 0.041 +/- 0.005/pulse. Recovery from flecainide block consisted of two components as reported previously. The mean time constant of the initial fast component was 48 +/- 17 ms, which was comparable but significantly longer than that in the absence of the drug. The late slow component was only seen after drug application and the time constant was 26 +/- 7 s at -100 mV. Internal application of 5 and 50 microM flecainide for 30 min after rupture of the cell membrane produced a non-significant block and values of 1.7 +/- 0.8 and 6.9 +/- 2.4%, respectively, for the use-dependent block of INa.(ABSTRACT TRUNCATED AT 250 WORDS)

Multiple ionic mechanisms of early afterdepolarizations in isolated ventricular myocytes from guinea-pig hearts.

Ionic mechanisms of early afterdepolarization (EAD) induced by the K(+)-free solution or veratridine were studied with guinea-pig ventricular myocytes using the patch-clamp technique of whole-cell and cell-attached patch configurations. In the K(+)-free solution, myocytes exhibited prolonged action potential duration with humps on the final repolarization phase, which eventually turned into EAD starting around -70 mV and induced triggered activity. Application of 0.5 mM Cd2+ inhibited the development of EAD and caused depolarization of maximum diastolic potentials around -30 mV, although Cd2+ did not prevent prolongation of the action potential. Application of 50-100 microM Ni2+ or 30 microM tetrodotoxin had little effects on EAD and diastolic potentials. The background current-voltage relation examined by a ramp voltage clamp showed inhibition of the inward rectifier K+ current, induction of steady inward current between -40 and -10 mV, and increase in the outward tail current upon repolarization in the K(+)-free solution. Cd2+ completely blocked the steady inward current at the plateau level and partially depressed the delayed outward K+ current, while Ni2+ had no effects on the background I-V relation. Tetrodotoxin showed a mild inhibitory effect on the inward component of the background current negative to -50 mV, but left the steady inward current at the plateau level. Therefore, EAD in the K(+)-free condition is mainly formed by decreased inward rectifier K+ current, activation of the L-type Ca2+ current, and time-dependent decay of the delayed outward K+ current upon repolarization. Application of 25-100 microM veratridine caused marked prolongation of action potential with appearance of regenerative EADs. Action potential prolongation and EADs were partially abolished by Cd2+ and completely eliminated by tetrodotoxin. The single channel current recordings showed a decreased current amplitude, and prolonged and delayed openings of the Na+ channel currents by veratridine. Thus, an ensemble average current showed markedly prolonged decay time constant of 609 msec in veratridine from 3.6 msec in the control. These results indicate that veratridine-induced EAD is mainly formed by altered properties of the Na+ channel current and partly by the L-type Ca2+ current due to slowed repolarization. Thus, EAD can be induced by different ionic mechanisms depending on the basal conditions.

The catalytic subunit of cyclic AMP-dependent protein kinase directly inhibits sodium channel activities in guinea-pig ventricular myocytes.

We investigated the effects of the purified catalytic subunit (C subunit) of the cAMP-dependent protein kinase (A-kinase) on the cardiac Na+ channel currents. Single Na+ channel currents in guinea-pig ventricular myocytes were recorded using the patch clamp technique of the inside-out configuration. Application of C subunit decreased the peak average current and slowed the current decay, effects which were caused by decrease in the open probability of Na+ channels and increase in the first latency, whereas the unitary current amplitude and mean open times were not affected. We conclude that the cardiac Na+ channel is directly modulated by phosphorylation process through A-kinase.

Electrophysiological properties of a new antiarrhythmic agent, bisaramil on guinea-pig, rabbit and canine cardiac preparations.

Electrophysiological effects of bisaramil, a novel antiarrhythmic agent, were examined using the conventional microelectrode technique applied to cardiac multicellular preparations from guinea-pigs, rabbits and dogs and the whole-cell patch-clamp technique applied to guinea-pig ventricular myocytes. Bisaramil at 10(-6) M or higher concentrations produced a dose-dependent decrease in the maximum rate of rise (Vmax) of action potentials of guinea-pig papillary muscles without changes in resting membrane potentials. In the presence of bisaramil, trains of stimuli at rates greater than 0.1 Hz led to the use-dependent block of Vmax, which was enhanced at higher frequencies. At a concentration of 3 x 10(-6) M, the degree of use-dependent block was about 35% at 3.3 Hz, of which degree was comparable to those of 10(-4) M disopyramide and lidocaine. The development of Vmax block by bisaramil was expressed by a single exponential function in the same manner as flecainide, whereas the time courses of the block development by disopyramide and lidocaine were described by two exponentials. Recovery time constants from Vmax block were 44.1 +/- 3.4 s and 20.3 +/- 2.3 s for bisaramil and flecainide, respectively. Bisaramil at 10(-6) and 3 x 10(6) M did not change the action potential duration of guinea-pig papillary muscles and rabbit atrial muscles with a significant reduction of Vmax. No change in action potential duration can be explained by depression of both the Ca2+ and the delayed outward K+ currents by bisaramil. On the other hand, 10(-6) M bisaramil shortened action potential duration of canine Purkinje fibers at 50% and 90% of repolarization.(ABSTRACT TRUNCATED AT 250 WORDS)

Combined effects of different class I antiarrhythmic agents on maximum rate of depolarization (Vmax) of action potentials in guinea-pig papillary muscles.

The combination of two different kinds of class I antiarrhythmic agents (class Ia, Ib, or Ic) was examined with regard to their effects on the maximum rate of depolarization (Vmax) of action potentials in guinea-pig papillary muscles. The combinations of disopyramide plus lidocaine, disopyramide plus mexiletine, mexiletine plus flecainide, and disopyramide plus flecainide were employed to study their effects on use-dependent block of Vmax. All the combinations increased the percent of use-dependent block at most of the frequencies employed (0.1-3.3 Hz) as compared to the effects of the single use of either drug, but no decrease in use-dependent block was found with any of the combinations. The time courses of the development of use-dependent block by disopyramide, lidocaine, and mexiletine were best expressed by two exponential functions, whereas those by flecainide were expressed by a single exponential function. Disopyramide plus lidocaine and disopyramide plus mexiletine produced increases in the time constant of the fast component of the block (tau f), the fast fraction of the block (Af), and the ratio of the fast to the slow fraction (Af/As). Mexiletine plus flecainide increased tau f, Af, and As; whereas disopyramide plus flecainide caused no changes in the kinetic parameters of use-dependent block. These results suggest that there may be diverse modes of interaction between the drug and the Na+ channel, and the combination of two different types of the drug may sometimes provide different effects on the fast and slow components of the use-dependent block of Vmax.

Two components of use-dependent block of Na+ current by disopyramide and lidocaine in guinea pig ventricular myocytes.

We studied the kinetics of the use-dependent block of the Na+ current (INa) by disopyramide and lidocaine. INa was recorded from isolated guinea pig ventricular myocytes by using the whole-cell patch-clamp technique. The use-dependent block of INa by disopyramide with 20- and 200-msec depolarizing pulses developed in two exponential functions. The degree of the use-dependent block and the amplitude of the fast (Af) and slow (As) components with the short (20-msec) pulse protocol were comparable to those with the long (200-msec) pulse protocol. When pH was raised from 7.3 to 8.0, disopyramide increased Af without a change in As. At pH 6.5, INa block developed with a single exponential function revealing only the slow component. The fast and slow components of INa block by disopyramide could be explained by binding of the uncharged and charged forms, respectively, to the activated state of the channel. Development of INa block by lidocaine also was expressed by two exponentials at all pulse durations (5-200 msec). As pulse durations were prolonged or holding potentials were depolarized, the degree of the use-dependent block and Af increased. When pH was lowered to 6.5, the short pulse produced only the slow component, whereas the long pulse caused two exponentials with decreased Af and increased As. Internal application of QX-314, a permanently charged lidocaine analogue, produced a single exponential block of INa with a very slow onset rate.(ABSTRACT TRUNCATED AT 250 WORDS)