[Stimulus-dependent effects of the sodium channel blockers in the C-fiber sensory units]. / Stimulozavisimye éffekty pri deistvii blokatorov natrievykh kanalov na sensornye C-edinitsy.

The data obtained suggest a use-dependent inhibition in the skin terminals of the C-fibre sensory units. The terminals are discussed in respect to search of efficient local anaesthetising agents as well as cardiac anti-arrhythmic agents with obvious neurotropic effects.

Arritmias por Reperfusion Coronaria: Mecanismos Fisiopatologicos y Estudio Farmacologico / Coronary reperfusion arrhythmias: Physiopathologic mechanisms and pharmacological study

Las arritmias que aparecen despues de la recirculacion sanguinea de una arteria coronaria previamente obstruida, han sido objeto de estudio de multiples investigadores desde finales de la decada de los 70 hasta nuestros dias, debido a la posibilidad de que estos tipos de trastornos del ritmo cardiaco pueden llevar a la muerte a pacientes en los que se libera un espasmo coronario o se produce la lisis de un trombo coronario. Con el presente trabajo tuvimos la oportunidad de profundizar en el conocimiento fisiopatologico de estas arritmias ventriculares, para ello utilizamos un modelo experimental animal de probada eficacia en este tipo de estudio. En el empleamos tres antiarritmicos clase I: prajmalina, lidocaina y mexiletine con el objetivo de conocer y analizar los efectos de estas drogas sobre la tension arterial, la frecuencia cardiaca y la incidencia de las arritmias por reperfusion coronaria. Nuestra investigacion arrojo una disminucion notable del por ciento de incidencia de arritmias en el grupo de animales tratados con mexiletine a diferencia de los resultados obtenidos con el resto de las series. Tambien en todos los grupos experimentales se registraron hipotension y bradicardia significativas al ser comparadas con su control: se emplearon para este analisis estadistico la "t" de Student para muestras pareadas (p < 0,05)

Chemically modified cardiac Na+ channels and their sensitivity to antiarrhythmics: is there a hidden drug receptor?

Elementary Na+ currents were recorded at 19 degrees C in inside-out patches from cultured neonatal rat cardiocytes. In analyzing the sensitivity of chemically modified Na+ channels to several class 1 antiarrhythmic drugs, the hypothesis was tested that removal of Na+ inactivation may be accompanied by a distinct responsiveness to these drugs, open channel blockade. Iodate-modified and trypsin-modified cardiac Na+ channels are noninactivating but strikingly differ from each other by their open state kinetics, a O1-O2 reaction (tau open(1) 1.4 +/- 0.3 msec; tau open(2) 5.4 +/- 1.1 msec; at -40 mV) in the former and a single open state (tau open 3.0 +/- 0.5 msec; at -40 mV) in the latter. Lidocaine (150 mumol/liter) like propafenone (10 mumol/liter), diprafenone (10 mumol/liter) and quinidine (20 mumol/liter) in cytoplasmic concentrations effective to depress NPo significantly can interact with both types of noninactivating Na+ channels to reduce the dwell time in the conducting configuration. Iodate-modified Na+ channels became drug sensitive during the O2 state. At -40 mV, for example, lidocaine reduced tau open(2) to 62 +/- 5% of the control without detectable changes in tau open(1). No evidence could be obtained that these inhibitory molecules would flicker-block the open Na+ pore. Drug-induced shortening of the open state, thus, is indicative for a distinct mode of drug action, namely interference with the gating process. Lidocaine proved less effective to reduce tau open(2) when compared with the action of diprafenone. Both drugs apparently interacted with individual association rate constants, a(lidocaine) was 0.64 x 10(6) mol-1 sec-1 and a(diprafenone) 13.6 x 10(6) mol-1 sec-1. Trypsin-modified Na+ channels also appear capable of discriminating among these antiarrhythmics, the ratio a(diprafenone)/a(lidocaine) even exceeded the value in iodate-modified Na+ channels. Obviously, this antiarrhythmic drug interaction with chemically modified Na+ channels is receptor mediated: drug occupation of such a hypothetical hidden receptor that is not available in normal Na+ channels may facilitate the exit from the open state.

Prajmalium, an antiarrhythmic with positive inotropic effect: mechanism of action in rabbit single cardiomyocytes.

The propyl derivative of ajmaline, N-n-propylajamaline (prajmalium), is an antiarrhythmic compound that lacks the commonly reported negative inotropic effects of all others under clinical use. The present study was undertaken to establish and understand its effects at the cellular level in mammalian preparations. Electrical and mechanical activities were recorded from right ventricular strips and Na and L-type Ca currents (INa and ICaL, respectively) were recorded with the whole-cell patch-clamp technique in right ventricular myocytes freshly dissociated from rabbit hearts. Prajmalium decreased the maximal rate of depolarization of the action potential in a dose-dependent manner with an EC50 of 3 microM. This effect was use and frequency dependent. Action potential duration was increased by 1 microM prajamalium but decreased on applying higher concentrations. The force of contraction was slightly (15%) increased at 0.1 microM, not affected at all at 1 microM and depressed by 30% at 20 microM. In single cardiomyocytes maintained at negative holding potentials, INa was slightly depressed by prajmalium at 10 nM and reduced by 75% at 10 microM. ICaL was increased by 30 and 20% on applying prajmalium at 1 and 10 microM, respectively; on the other hand, ICaL was reduced by these two concentrations of prajmalium at less negative holding potentials. A higher prajmalium concentration (100 microM) decreased ICaL at all holding potentials studies and this effect was enhanced with depolarization. The increase in ICaL induced by prajmalium (1 microM) was also observed after ICaL had been fully beta-adrenergic and P2-purinergic stimulated by isoproterenol (1 microM) in the presence of IBMX (100 microM) and ATP (10 microM). It is concluded that prajmalium is able to increase ICaL in rabbit ventricular cells in a voltage-dependent manner, an effect that could account in part for the observed lack of negative inotropism of this antiarrhythmic in clinics.

[Use-dependent inhibition of C-axon multimodal units of cat skin by lidocaine and N-propyl-ajmaline]. / Zavisimoe ot primeneniia ingibirovanie C-aksonnykh polimodal'nykh edinits kozhi koshki lidokainom i N-propil-aimalinom.

Subcutaneous application of local anesthetic drug lidocaine and cardiac antiarrhythmic n-propyl-ajmaline produced the reversible use-dependent inhibition of feline polymodal mechano-heat C-fiber cutaneous sensory units (CMH-units) excited by moderate noxious mechanical stimulus. The discharge rate as well as the number of evoked spikes of polymodal sensory units treated with the drugs decreased below the values observed under noxious chemical excitation of CMH-units. The repeated mechano-stimulation with 5 to 30 sec interval between stimuli produced complete though a reversible block of the treated units. Quaternary amine n-propyl-ajmaline induced use-dependent inhibition of CMH-units in lower concentrations than tertiary amine lidocaine. The use-dependent inhibition of CMH-units is discussed in connection with nociception and local analgesia.

Antiarrhythmic drugs impair hepatic uptake and secretory function by different mechanisms in the isolated perfused rat liver.

In the present study the effect of various antiarrhythmic drugs on hepatic perfusion parameters, uptake capacity of organic anions and biliary secretion using the isolated perfused rat liver was examined. Infusion of verapamil (VP), diltiazem, N-propyl-ajmaline (NPAB), and quinidine at pharmacological doses induced consistently a 1.4-1.6-fold increase in portal pressure accompanied by a approximately 60% decrease in bile flow and a approximately 65% inhibition of biliary taurocholate (TC) excretion. Furthermore, hepatic uptake of oxygen, bromosulphthalein (BSP), and TC was significantly reduced. All these effects were dose-dependent and reversible upon withdrawal of the drugs. Studies of the hepatic circulation using a Trypan blue staining technique demonstrated a patchy perfusion pattern during infusion of the antiarrhythmic drugs as compared to the homogenously stained control organ. The hemodynamic alterations and the impairment of the hepatic initial uptake function could be entirely prevented by concomitant administration of the vasodilator papaverine. Bile flow and biliary TC excretion, however, were still inhibited under these conditions. The present results indicate that antiarrhythmic drugs produce cholestasis in the isolated perfused rat liver independently of their adverse effect on hepatic hemodynamics.

[The effect of a combination of N-propylajmaline bromide and trimecaine on heart arrhythmias of different origins and on the electrophysiological parameters of the myocardium]. / Vliianie kombinatsii N-propilaimalinbromida i trimekaina na aritmii serdtsa raznogo geneza i élektrofiziologicheskie parametry miokarda.

In experiments on dogs and cats with disorders of the atrial and ventricular rhythms of various genesis the combination of N-propylaymalinebromide and trimecaine (the antiarrhythmic drugs of classes IA and IB) was found to potentiate the antiarrhythmic action. This effect was studied in electrophysiological experiments by using the microelectrode technique or on the dog and rat myocardium tissue. The combination of the antiarrhythmic drugs was shown to exert a more significant effect on some electrophysiological parameters determining the arrhythmic readiness of the myocardium.

[Combined action of anti-arrhythmia agents]. / Sochetannoe kombinirovannoe deistvie antiaritmicheskikh sredstv.

A significant potentiation of antiarrhythmic effect was observed in 121 dogs with arrhythmias 24 and 48 hours after the coronary artery ligation when the following drugs were combined: N-propylajmaline bromide (1A class) and trimecaine (1B class), quinidine (1A class) and trimecaine, N-propylajmaline bromide and anaprilin (2 class). The potentiation is attributed to the different molecular mechanisms of action of the drugs.

Dual action of prajmalium on the Ca currents in frog isolated cardiomyocytes.

The effects of N-n-propylajmaline (prajmalium) on the Na and Ca currents of single frog atrial and ventricular cells were studied by means of the whole-cell patch-clamp technique. Prajmalium (10(-9) to 10(-6) M) depressed the Na current (INa) in a dose- and use-dependent manner. In the same range of concentrations, prajmalium induced a dual effect on the high (ICaL) and low (ICaT) threshold Ca currents (the latter being only present in atrial cells). At a low concentration (10(-9) M), prajmalium increased both Ca currents while at high concentrations (10(-6) M) it depressed them. Prajmalium appeared very potent on ICaT although this current is generally reported to be barely sensitive to agonists and drugs. The action of the drug was also accompanied by a shortening in the half-time of inactivation of the Ca currents and a slight hyperpolarizing shift of their availability curves. The increase in ICaL by prajmalium was not prevented by prazosin (10(-7) M) nor by propranolol (10(-6) M), and it was also observed after ICaL had been fully stimulated by isoproterenol (10(-7)M). Nifedipine (10(-6) M), however, was able to prevent or block the prajmalium-induced increase in ICaL. Some similarities between the actions of prajmalium and dihydropyridine agonists on Ca currents are discussed.

[Effects of N-propylajmaline bromide and trimecaine combination on normal and abnormal automatism of Purkinje fibers in dogs and arrhythmias at the late stage of experimental myocardial infarct]. / Deistvie kombinatsii N-propilaimalinbromida i trimekaina na normal'nuiu i anomal'nuiu avtomatiiu volokon Purkin'e sobaki i aritmii na pozdnei stadii éksperimental'nogo infarkta miokarda.

Prajmalium bromide in combination with trimecaine was tested for effects on arrhythmias in the late period of canine experimental myocardial infarction. The combination given in subthreshold doses was found to restore sinus rhythm in 8 of 11 cases. It also decreased the maximum repolarization rate in rat papillary muscles to a greater extent than either drug given alone. The rate of spontaneous firing of Purkinje fibers from the ischemic zone was decreased by the combination of the drugs.

[Opposite control of O2 affinity for hemoglobin by donors and acceptors]. / Protivopolozhno napravlennaia donorami i aktseptorami reguliatsiia srodstva kisloroda k hemoglobinu.

The effects of electron donors and acceptors on O2 binding by hemoglobin were studied. 2,4-Dinitrophenol, levomycetin and pelargonidine-3,5-diglycoside which act as electron acceptors in free radical reactions, enhance this process. In contrast, N-propylajmalin which is known to be an electron donor in the above reactions, suppresses the O2 binding. Diphosphoglycerate and inositol hexaphosphate, the natural inhibitors of O2 binding, exhibit, similar to N-propylajamlin, the properties of electron donors, the latter being a more potent electron donor than the former.

Differential analysis of the frequency-dependent effects of class 1 antiarrhythmic drugs according to periodical ligand binding: implications for antiarrhythmic and proarrhythmic efficacy.

The frequency-dependent block of cardiac sodium channels by class 1 antiarrhythmic drugs can be described by a periodical ligand binding process between drug molecules and channel binding sites. This predicts a linear relation between onset-rate constant of frequency-dependent block and diastolic interval as well as saturation of block with high stimulation rates. From both relationships, the binding kinetics (time constant, tau on) and saturation level of block (bdinf) can be estimated. This is exemplified for the frequency-dependent block (reduction of the maximal upstroke velocity of action potentials) induced by prajmaline (10(-6) M). In the same way, the frequency-dependent effects of 11 other class 1 drugs reported in the literature were analyzed and compared with each other. When the drugs are ranked with respect to their binding kinetics (tau on), there is a close relationship to the subclasses (1a, 1b, 1c), with 1b drugs exhibiting the fastest and 1c drugs the slowest kinetics. However, differences also exist in the saturation behavior of frequency-dependent block even within the same subclasses (1a and 1c). Thus, the class 1 drugs can also be subdivided in three other groups exhibiting clearly separated bands of block-frequency relations, with half-maximal saturation occurring at different stimulation rates. Our findings may have differential implications for the antiarrhythmic and proarrhythmic efficacy of class 1 drugs.

Comparative analysis of the action of class I antiarrhythmic drugs (lidocaine, quinidine, and prajmaline) in rabbit atrial and ventricular myocardium.

Effects of three class I antiarrhythmic drugs (quinidine, lidocaine, and prajmaline) on transmembrane resting (RMP) and action potentials (AP) of isolated rabbit atrial and ventricular myocardium were studied at different stimulation rates. The frequency-dependent depression of the maximal upstroke velocity (Vmax) of the AP (sodium channel block) was analyzed according to the "guarded receptor" hypothesis. The resting block (Vmax depression after a resting period) induced by prajmaline (10(-6) M), quinidine (2.2 x 10(-5) M), and lidocaine (4.3 x 10(-5) M) was more expressed in the atrium (44, 28, and 19%, respectively) than in the ventricle (32, 9, and 0%, respectively). There were also significant (p less than 0.05) atrioventricular differences in the frequency-dependent extra block (Vmax reduction on stimulation at 3.3 Hz) for quinidine (39 vs. 26%) and lidocaine (4 vs. 25%). From the analysis, according to the guarded receptor hypothesis, it follows that the three compounds bind preferentially to inactivated sodium channels with about the same affinity to the atrium and ventricle, except for quinidine which shows a significantly smaller dissociation constant in the atrium (5 x 10(-6) M vs. 2.7 x 10(-5) M; p less than 0.001). We conclude that the atrioventricular differences in the resting block are mainly due to atrioventricular differences in the RMP, whereas the differences in the frequency-dependent extra block are based on the shorter atrial AP duration (lidocaine) or are due to higher affinity to atrial sodium channels (quinidine).

[Effect of N-propylajmaline bromide on the normal and abnormal automatism of Purkinje fibers in the dog]. / Deistvie N-propilaimalinbromida na normal'nuiu i anomal'nuiu avtomatiiu volokon Purkin'e sobaki.

The effects of prajmalium bromide on normal and abnormal automaticity were studied in Purkinje fibers from dog hearts at late stages of experimental myocardial infarction. Prajmalium bromide (1.2 micromol/l) moderately reduced the frequency of normal and abnormal automaticity by 16 and 20% respectively. Prajmalium bromide induced early after-depolarizations, increased the frequency of spontaneous firing and decreased the maximum diastolic potential in the fibers that initially developed the automaticity of an intermediate type between normal and abnormal. It is suggested that antiarrhythmic effects of prajmalium bromide in the late stage of experimental myocardial infarction are not related to the influence of the drug on the abnormal automaticity in Purkinje fibers.

Efectos del bitartrato de N-propil ajmalina sobre la corriente de sodio en células cardíacas ventriculares / Effects if N-propyl ajmaline on sodium current in ventricular heart cells

Se estudiaron los efectos del bitartrato de N-propil ajmalina (NPAB, sintetizado en nuestro país), sobre la corriente de sodio (iNa) en células miocárdicas ventriculares. En trabéculas de pared libre de ventrículo derecho de conejo, la velocidad máxima de despolarización (dv/dt máx) se redujo significativamente con el incremento de la dosis de NPAB (de 0,125 a 20 * M) hasta llegar al 60% de inhibición a la dosis máxima. Esto se correspondió con una disminución similar en la densidad de iNa calculada a partir de los planos de fase (dv/dt vs. potencial de membrana). Los efectos sobre la dv/dt máx. mostraron dependencia directa con la frecuencia de estimulación (dependencia del uso). Con la técnica de patch-clamp en células ventriculares aisladas de corazón de rana, se demostró que el NPAB reduce la iNa en forma, no sólo dependiente de la frecuencia, sino tambièn en dependencia del potencial de membrana, pues induce un desplazamiento de 10 mV en la curva de inactivación (o de disponibilidad) hacia potenciales más negativos. La droga, además, enlenteciò el proceso de reactivaciòn de iNa. Se concluye que el NPAB sintetizado en nuestro país, tiene acciones sobre la célula cardiaca que lo pueden clasificar como un antiarrítmico de la clase 1-A

On the mechanism of drug-induced blockade of Na+ currents: interaction of antiarrhythmic compounds with DPI-modified single cardiac Na+ channels.

In patch-clamped membranes from neonatal rat cardiocytes, elementary Na+ currents were recorded at 19 degrees C for study of the inhibitory influence of several antiarrhythmic drugs including lidocaine, diprafenone, propafenone, and prajmalium on DPI-modified cardiac Na+ channels. Diprafenone (20 mumol/l) and lidocaine (300 mumol/l) induced a voltage- and time-dependent block of reconstructed macroscopic sodium current (INa). The drugs depressed the sustained, noninactivating INa component (which reflects the number and open probability of DPI-modified Na+ channels) effectively, in a voltage- and time-dependent fashion. Once opened, DPI-modified Na+ channels are highly drug-sensitive. Antiarrhythmic drugs (propafenone, diprafenone, and, to a lesser extent, lidocaine) provoke a flicker block, that is, the long-lasting openings are chopped into a large number of short and grouped openings. This indicates rapid transitions between a drug-associated, blocked state and a drug-free, conducting state. The latter has a unitary conductance of 12 pS, very similar to the control value in the absence of antiarrhythmic drugs. The decrease in open time of drug-treated DPI-modified Na+ channels is concentration-dependent. Hill coefficients for propafenone of about 1.0 and for prajmalium of about 0.7 were calculated. A blocking rate constant of 6.1 x 10(7) mol-1sec-1 for propafenone, but of 1.5 x 10(7) mol-1sec-1 for prajmalium was obtained at -30 mV. The unblocking rate constant for propafenone was, also at -30 mV, about twice as large as the unblocking rate constant for prajmalium. The open channel block kinetics are essentially voltage-dependent. The affinity of the channel-associated drug receptor increases on membrane depolarization. The blocking rate constant was inversely related to the number of Na+ ions moving through the open channel. It is concluded that the manifestation of this voltage- and Na+-dependent flicker block is intimately related to removal of fast Na+ inactivation.

[The effect of the antiarrhythmic, prajmalium bitartrate, on human thrombocyte function]. / Einfluss des Antiarrhythmikums Prajmaliumbitartrate auf die humane Thrombozytenfunktion.

Studies of the in vitro effects of the antiarrhythmic drug prajmalium bitartrate (PBT, Neo-Gilurytmal) showed inhibitory effects on platelet aggregation and thromboxane production. PBT inhibited the primary and secondary phases of aggregation induced by adrenaline (epinephrine) or adenosine diphosphate (ADP). Platelet aggregation stimulated with collagen, platelet activating factor (PAF), and the thromboxane mimetic 9,11-azo-prostaglandin H2 (U 44064) was inhibited. The secondary phase of aggregation induced by ristocetin and aggregation caused by arachidonic acid (AA) were inhibited in samples from some donors (responders) but not in others (nonresponders). Platelet aggregation by the ionophore calcimycine (A 23187) was not inhibited, but small doses of calcimycine abolished the PBT-induced inhibition of aggregation caused by ADP. Thromboxane production of platelets with collagen of ADP was inhibited by higher concentrations of PBT, whereas AA-induced thromboxane synthesis remained unchanged. The observed antiplatelet activities of PBT are thought to result from calcium and sodium channel blocking properties of the drug.