Role of sarcolemmal BK(Ca) channels in stretch-induced extrasystoles in isolated chick hearts.

BACKGROUND: It remains unclear whether sarcolemmal BK(Ca) channels in post-hatch chick ventricular myocytes contribute to stretch-induced extrasystoles (SIE), and whether they are stretch-activated BK(Ca) (SAK(Ca)) channels or a non-stretch-sensitive BK(Ca) variant. METHODS AND RESULTS: To determine the role of sarcolemmal BK(Ca) channels in SIE and their stretch sensitivity, an isolated 2-week-old Langendorff-perfused chick heart and mathematical simulation were used. The ventricular wall was rapidly stretched by application of a volume change pulse. As the speed of the stretch increased, the probability of SIE also significantly increased, significantly shortening the delay between SIE and the initiation of the stretch. Application of 100 nmol/L of Grammostola spatulata mechanotoxin 4, a cation-selective stretch-activated channel (SAC) blocker, significantly decreased the probability of SIE. The application of Iberiotoxin, however, a BK(Ca) channel blocker, significantly increased the probability of SIE, suggesting that a K(+) efflux via a sarcolemmal BK(Ca) channel reduces SIE by balancing out stretch-induced cation influx via SACs. The simulation using a cardiomyocyte model combined with a new stretch sensitivity model that considers viscoelastic intracellular force transmission showed that stretch sensitivity in BK(Ca) channels is required to reproduce the present wet experimental results. CONCLUSIONS: Sarcolemmal BK(Ca) channels in post-hatch chick ventricular myocytes are SAK(Ca) channels, and they have a suppressive effect on SIE.

[Phospholipids composition of the myocardium in patients with ischemic heart disease and its connection to arrhythmias].

The purpose of this study was to establish phospholipid composition of the myocardium in patients with ischemic heart disease, and to estimate possible correlation of biochemical parameters with myocardium extrasystolic activity. The patients (n = 28) including 15 patients with ischemic heart disease and 13 patients with secondary atrium septum defect (control group) were studied. During surgical intervention the right atrium myocardium bioptates were taken. Phospholipid metabolism was studied in the myocardium samples. At the eve of surgical intervention a holter monitoring was performed. Deep changes in the myocardium lipid metabolism were found, including accumulation of free and estherified cholesterol, lysophospholipids, and sphingomyeline. An increase of free cholesterol content was accompanied by accumulation of sphingomyeline. This can be an evidence of changes in the constitution of lipid rafts. Extrasystoles, particularly ventricular ones, in patients with ischemic heart disease might depend on accumulation of lysophospholipids as they took place simultaneously with it.

Mechanism of origin of conduction disturbances in aging human atrial bundles: experimental and model study.

BACKGROUND: Aging is associated with a significant increase in atrial tachyarrhythmias, especially atrial fibrillation. A macroscopic repolarization gradient created artificially by a stimulus at one site before a premature stimulus from a second site is widely considered to be part of the experimental protocol necessary for the initiation of such arrhythmias in the laboratory. How such gradients occur naturally in aging atrial tissue is unknown. OBJECTIVE: The objective of this study was to determine if the pattern of cellular connectivity in aging human atrial bundles produces a mechanism for variable early premature responses. METHODS: Extracellular and intracellular potentials were recorded after control and premature stimuli at a single site in aging human atrial bundles. We also measured cellular geometry, the distribution of connexins, and the distribution of collagenous septa. A model of the atrial bundles was constructed based on the morphological results. Action potential propagation and the sodium current were analyzed after premature stimuli in the model. RESULTS: Similar extracellular potential waveform responses occurred after early premature stimuli in the aging bundles and in the model. Variable premature conduction patterns were accounted for by the single model of aging atrial structure. A major feature of the model results was that the conduction events and the magnitude of the sodium current at multiple sites were very sensitive to small changes in the location and the timing of premature stimuli. CONCLUSION: In aging human atrial bundles stimulated from only a single site, premature stimuli induce variable arrhythmogenic conduction responses. The generation of these responses is greatly enhanced by remodeling of cellular connectivity during aging. The results provide insight into sodium current structural interactions as a general mechanism of arrhythmogenic atrial responses to premature stimuli.

Optical mapping of ventricular arrhythmias in LQTS mice with SCN5A mutation N1325S.

Transgenic expression of SCN5A mutation N1325S creates a mouse model for type-3 long QT syndrome (LQT3), TG-NS/LQT3. Optical mapping is a high temporal and spatial resolution fluorescence mapping system that records 256 action potentials simultaneously in a Langendorff-perfused heart. Here for the first-time, we provide a spatial view of VT in a genetic LQT3 model using optical mapping. Spontaneous VT was detected in TG-NS/LQT3 hearts, but not in littermate control hearts. VT was initiated primarily by activation of a new firing focus as well as functional conduction block of new activation waves. New firing was initiated at many different Loci in the heart, suggesting that "increased automaticity" is a key mechanism for initiation of VT. The sustained VT was maintained by a reentry mechanism. Nifedipine, an L-type calcium channel blocker, decreased the frequency of VT, indicating the involvement of abnormalities of the calcium homeostasis in the genesis of VT in TG-NS/LQT3 mice.

Impaired sarcoplasmic calcium release inhibits myocardial contraction in experimental sepsis.

PURPOSE: In septic shock, myocardial dysfunction develops over the course of illness, but the mechanism of this depression is not clear. In this study, mechanisms of myocardial dysfunction were examined in a porcine model of Escherichia coli sepsis. MATERIALS AND METHODS: Animals were subjected to 4 hours of bacteria infusion (n = 5) (septic group) or saline infusion (n = 5) (nonseptic group), after which trabeculae were removed from the right ventricle and placed into a recirculating water bath. Measurements of steady-state contraction (SSC) were obtained at 0.5, 1, and 2 Hz. Indirect indices were used to assess abnormalities in myocardial calcium metabolism in sepsis. Extrasystoles (ES) were used to assess transsarcolemmal (TSL) calcium flux and were measured at 300 milliseconds, 400 milliseconds, and 500 milliseconds after the preceding stimulus. Postrest contraction (PRC) is an indicator of SR recirculation from the uptake to the release site and was obtained after interposing intervals of rest between steady-state beats at 0.5 Hz. Rapid-cooling contracture (RCC) is an indicator of sarcoplasmic reticulum (SR) content and was obtained at 0.5, 1, and 2 Hz and after interposing intervals of rest at 0.5 Hz. RESULTS: SSC was not different between groups at 0.5 Hz, but compared with the nonseptic group, SSC decreased at 1 and 2 Hz in the septic group (P < .05). PRC and TSL were not different between groups. During rest intervals, calcium leaks out of SR through the ryanodine channel (ie, SR calcium release channel). In the septic group, as assessed by RCC, SR calcium leak was less than that found in the nonseptic group. CONCLUSION: These results indicate that myocardial dysfunction in sepsis is frequency dependent, and that the mechanism is most likely caused by inhibition of SR calcium release owing to blockade of the ryanodine channel.

The heart extrasystole: an energetic approach.

The consequences of an extrasystole (ES) on cardiac muscle's energetics and Ca2+ homeostasis were investigated in the beating heart. The fraction of heat release related to pressure development (pressure dependent) and pressure-independent heat release were measured during isovolumic contractions in arterially perfused rat ventricle. The heat release by a contraction showed two pressure-independent components (H1 and H2) of short evolution and a pressure-dependent component (H3). The additional heat released by ES was decomposed into one pressure-independent (H'2) and one pressure-dependent (H'3) component with time courses similar to those of control components H2 and H3. ES also induced the potentiation of pressure development (P) and heat release during the postextrasystolic (PES) beat. The slope of the linear relationship between pressure-dependent heat and pressure maintenance was similar in control, ES, and PES contractions (0.08 +/- 0.01, 0.10 +/- 0.02, and 0.08 +/- 0.01 mJ. g-1. mmHg-1. s-1, respectively). The potentiation of H2 (heat component related with Ca2+ removal processes) in PES was equal to H'2 at 0.3, 0.5, 1, and 2 mM Ca2+, suggesting that the extra amount of Ca2+ mobilized during ES was recycled in PES. Pretreatment with 1 mM caffeine to deplete sarcoplasmic reticulum Ca2+ content inhibited both the mechanical and energetic potentiation of PES. However, the heat released and the pressure developed during ES were not changed by sarcoplasmic reticulum depletion. The results suggest that 1) the source of Ca2+ for ES would be entirely extracellular, 2) the Ca2+ entered during ES is accumulated in the sarcoplasmic reticulum, and 3) the Ca2+ stored by the sarcoplasmic reticulum during ES induces an increased contribution of this organelle during PES compared with the normal contraction.

Contractile and intracellular Ca2+ decay in potentiated contractions following multiple extrasystolic beats.

Developed pressure and intracellular Ca2+ ([Ca2+i) decay in postextrasystolic beats following multiple extrasystolic contractions (ESCs) was evaluated with surface fluorometry in atrioventricular-blocked perfused rat hearts loaded with Indo-1. After priming pacing at 400 ms intervals, 1-25 ESCs were interposed with a 160 ms interval, followed by 30 postextrasystolic beats with a 400 ms interval. Both left ventricular developed pressure and the amplitude of the Indo-1 fluorescence ratio (F400/F510: an index of [Ca2+]i) increased in a monoexponential manner with an increase in the number of ESCs. Both potentiated left ventricular developed pressure and the amplitude of F400/F510 transients returned to control in a monoexponential fashion. Consistent with this exponential decay, the relationship between developed pressure or the amplitude of F400/F510 transients in a postextrasystolic beat and that in the preceding beat was linear and the slope of a fitted line (recirculation fraction; RF) was evaluated as an index of rapidity of decay. The number of ESCs did not affect RF of developed pressure and the amplitude of F400/F510 transients. Reducing extracellular Ca2+ concentration (1.25 --> 0.55 mM), and perfusion with an acidic solution (pH = 6.8) significantly decreased RF of both developed pressure (0.85 +/- 0.06 --> 0.78 +/- P < 0.05 and 0.85 +/- 0.07 --> 0.78 +/- 0.06, n=8, P < 0.05, respectively) and the amplitude of F400/F510 (0.87 +/- 0.06 --> 0.78 +/- 0.05, P < 0.05, and 0.89 +/- 0.08 --> 0.78 +/- 0.07, P < 0.05, respectively). This study confirmed that, in all conditions evaluated, contractile decay was determined by [Ca2+]i decay and RF of contractile decay was an accurate estimate of [Ca2+]i decay in physiologically paced isolated perfused rat hearts.

Mechanisms underlying the genesis of post-extrasystolic potentiation in rat cardiac muscle.

Changes of contractility resulting from changes in stimulation pattern (post-extrasystolic potentiation - PESP) were investigated in right ventricular papillary muscles from female albino rats (EPM strain, 160-200 g). The preparations were superfused with bicarbonate buffered solution at 24 +/- 0.5 degrees C, and stimulated at 0.5 Hz. Maintained paired stimulation was performed at several coupling intervals (360, 500, 660, 770 and 920 ms) with normal Krebs for 30 s. After treatment with ryanodine (1 microM), used as an inhibitor of the release of sarcoplasmic reticulum Ca2+ activity, the same protocol was repeated in the presence of normal Krebs, low Na+ (80 mM, LiCl used as substitute) and low K+ concentrations to change the level of activity of the Na+/Ca2+ exchange mechanism. With normal Krebs, paired pulse stimulation produced a maintained potentiation of the post-extrasystolic beat and an extrasystole with a reduced force generation when compared to the control steady-state contraction. As the interval between the extrasystole and the normal beat was increased the potentiation of the post-extrasystolic beat was reduced and the force of the extrasystole was increased. Ryanodine treatment reduced the force of contraction and increased its duration, and the pattern of the PESP phenomenon was altered. Both the post-extrasystolic and the extrasystolic beats were potentiated compared to the steady-state contraction obtained under ryanodine treatment. The extrasystole displayed a greater potentiation than the post-extrasystolic beat. As the interval between them increased the amplitude of the extrasystolic beat was enhanced.(ABSTRACT TRUNCATED AT 250 WORDS)

Intracellular calcium transients in potentiated contractions induced by multiple extrasystolic beats in isolated perfused rat hearts.

Mechanisms underlying contractile potentiation induced by multiple extrasystolic contractions (ESC) were evaluated with surface fluorometry in isolated perfused rat hearts loaded with Indo-1/AM. After baseline pacing with a 400 ms interval, 1-25 ESC were interposed with a regular 160 ms interval followed by the postextrasystolic beat with a 400 ms interval. With an increase in the ESC number, left ventricular developed pressure and peak positive dP/dt increased in an exponential manner, reaching a plateau, that was the same for 3 extracellular Ca2+ ([Ca2+]o; 0.55 (n = 9), 1.25 (n = 11) and 2.75 mM (n = 7). Increased [Ca2+]o shifted this relationship left and upward, and with 2.75 mM [Ca2+]o developed pressure and dP/dt decreased after the maximum potentiation was obtained. The relationship between the ESC number and the amplitude of the Indo-1 fluorescence (F400/F510; an index of intracellular Ca2+ ([Ca2+]i)) was also exponential and was shifted left and upward by high [Ca2+]o; however, it lacked the declining phase. Thus, the relationship between the amplitude of F400/F510 and developed pressure or dP/dt consisted of a positively linear part until the maximum potentiation was obtained and a negatively linear part with a further increase in the amplitude of F400/F510. This observation suggests that although contractile potentiation is mediated by increased [Ca2+]i transients, the maximum response might be determined by the responsiveness of the sarcomere.

Force-interval relations of twitches and cold contractures in rat cardiac trabeculae. Effect of ryanodine.

The twitch force (Ft)-interval relation of cardiac muscle reflects recovery of calcium release from the sarcoplasmic reticulum (SR). The calcium content of the SR is thought to be reflected by force developed during a contracture (Fc), induced by rapid cooling to near 0 degrees C. In right ventricular trabeculae of rat, under control conditions, the Ft-interval relation consisted of recovery of Ft to steady state (early recovery), followed by a secondary increase of Ft up to a maximum at an interval of approximately 100 seconds (rest potentiation) and a decline of Ft at intervals greater than 100 seconds (rest depression). The mechanisms that may underlie recovery of force after the last twitch at short intervals are 1) time-dependent transport of Ca2+ from the uptake compartment of the SR to the release compartment, 2) recovery of slow inward Ca2+ current during the action potential, and 3) recovery of the Ca2+ release channels in the SR. The Fc-interval relation was similar to the Ft-interval relation in that both a rest potentiation and a rest depression phase were present. However, at short interstimulus intervals (less than 1 second), Fc was independent of time, suggesting that the mechanism underlying early recovery was bypassed. Ryanodine (0.1-10 nM) reduced rest potentiation in a dose-dependent manner and accelerated rest depression of both Ft and Fc. At high ryanodine concentration, a significant Fc could only be induced after short intervals. Significant acceleration of rest depression was observed at low ryanodine concentrations, when Ft at intervals of 5 seconds was kept constant by increasing the stimulus frequency of [Ca2+]o, suggesting that the ryanodine effect was enhanced by increased [Ca2+]i. Ryanodine also increased the rate of decay of postextrasystolic potentiation in a dose-dependent manner. A significant effect was observed in 10 nM ryanodine. The twitch was not prolonged by ryanodine at these concentrations. These results suggest that the small magnitude of the twitch at short intervals is due to the finite time required by SR Ca2+ release channels to fully recover after a twitch. Furthermore, the results offer support for the hypothesis that ryanodine (in the nanomolar range) promotes Ca2+ leak from the SR in a dose-dependent manner and thereby limits Ca2+ accumulation during the interstimulus interval. Therefore, it may be expected that the negative inotropic effect of ryanodine is due to the SR Ca2+ depletion, and it is not necessary to postulate that ryanodine "blocks" the Ca2+ release channels in the SR.

[Determination of correlations between the main pharmacokinetic parameters and physiopathological factors of flecainide in the elderly]. / Détermination de corrélations entre les principaux paramètres pharmacocinétiques et les facteurs physiopathologiques de la flécaïnide chez les sujets âgés.

The purpose of the study was to evaluate the correlation between pharmacokinetic and physiopathological parameters of flecainide in elderly population. Pharmacokinetics of flecainide was determined in seventeen patients, aged more than 60 years, with clinically documented ventricular extrasystoles. Patients received 1.5 mg/kg flecainide either by intravenous administration or by slow perfusion. In elderly population the elimination half-life, the mean residence time and the volume of distribution of flecainide are increased and the plasmatic clearance is reduced. All of these parameters show an important interindividual variability. The relationships between pharmacokinetic and physiopathological parameters were evaluated with multivariate analysis. The correlation obtained (89.86% for total clearance, 64.64% for volume of distribution, 42.59% and 31.12% for elimination and distribution half-lives) provide a relatively good determination of pharmacokinetic parameters of flecainide in aged patients.

[Evaluation of biological availability and anti-arrhythmic effect of a new drug Phenytoinum "Polfa"]. / Ocena dostepnosci biologicznej i dzialania przeciwarytmicznego nowego preparatu Phenytoinum "Polfa".

Studies were performed in 15 patients with ventricular arrhythmia. During the first day, the patients received 1000 mg of a new micronised form of Phenytoinum "Polfa" or adequate dose of a foreign drug in 3 doses every 3 hours and subsequently during 10 days alternatively native or foreign drug in a daily dose 300 mg. Twenty-four EKG Holter monitoring and determination of serum drug level were carried out after a 10-day treatment; area under the curve (AUC) in one 8 h dose interval was determined. Studies have shown usefulness of a new form of Phenytoinum (Polfa). Blood serum drug levels near to the therapeutic ones were observed. Steady-state Phenytoinum concentration was 11.1 +/- 5.9 micrograms/ml and after foreign drug it was 11.7 +/- 6.1 micrograms/ml, AUC0-8 was 90.4 and 105.3 micrograms/ml/h respectively. In 9/15 patients (60%) Phenytoinum (Polfa) produced substantial improvement in the cardiac arrhythmia.

The effects of an extra-stimulation on post-extra-systolic potentiation in papillary muscle of rats.

The mechanism of post-extrasystolic potentiation (PESP) is unclear. It has previously been suggested that changes in both the calcium release from the sarcoplasmic reticulum (SR) and the transsarcolemmal calcium influx are factors in the development of PESP in guinea-pigs. This experiment investigated the effects of a resting interval and a coupling interval on PESP in rat papillary muscles, which have a well-developed SR. An extra-stimulation was induced at various coupling intervals and a variety of post-extrasystolic intervals were set. The PESP was not dependent on the coupling interval. The post-extrasystolic interval at which the maximal % PESP was obtained was about 90 sec, and post-extrasystolic interval-% potentiation of the PESP relationship curve consisted of an ascending limb and a descending limb. Caffeine eliminated the PESP in a concentration-dependent manner. These findings suggest that SR calcium release plays an important role in the mechanism of PESP in rats. This is consistent with results from guinea-pigs, and implies that the calcium capacity and/or retention of the SR may characterize the post-extrasystolic interval-% PESP relationship in muscle from different species.

[A comparative study of the pharmacokinetics and pharmacodynamics of bonnecor]. / Sravnitel'noe izuchenie farmakokinetiki i farmakodinamiki bonnekora.

The pharmacokinetics and pharmacodynamics of bonnecor were studied simultaneously in animals with experimental arrhythmia. It was shown that irrespective of the animal species and individual features of the drug elimination kinetics the level of bonnecor concentration correlated with the antiarrhythmic effect. The data on the excretion of bonnecor and its metabolites in the urine in the dog and man were obtained. The decrease of bioavailability at oral administration of bonnecor was demonstrated to be related to its intensive conversion in metabolite M-I.

Suppressing effects of caffeine on postextrasystolic potentiation in papillary muscles of guinea pigs.

It is well known that the strength of postextrasystolic potentiation (PESP) is dependent on the prematurity of the ectopic beat, though the fundamental mechanism of the potentiation is still obscure. In this study, the effect of a resting interval on the strength of PESP was investigated in isolated papillary muscles of guinea pigs in the presence or absence of caffeine, which inhibits the functions of sarcoplasmic reticulum (SR). PESP of a fixed coupling interval increased and then decreased as the resting interval was prolonged. The maximum of PESP was obtained at a resting interval of 3 to 4 sec. The dependency of PESP on a coupling interval was decreased considerably by 5 x 10(-4) M caffeine and removed completely by 10(-2) M caffeine. Although 5 x 10(-4) M caffeine decreased the degree of contraction of postextrasystole, the maximum contraction of postextrasystole was still obtained at a resting interval of 3 to 4 sec. After the application of 10(-2) M caffeine, the postextrasystolic contraction gradually declined as the resting interval was prolonged. We conclude that SR Ca release contributes largely to a mechanism of PESP and increases in contribution as the coupling interval of an extrastimulation shortens, and that the optimal resting interval is determined by a balance between the activity of SR function and the activity of the sarcolemmal Ca extrusion mechanism.

Clinical pharmacokinetics of levorotatory and racemic disopyramide, at steady state, following oral administration in patients with ventricular arrhythmias.

Electrophysiological effects, antiarrhythmic activity and kinetics of levorotatory disopyramide (R(-) DP) and racemic disopyramide (equimolar mixture of R(-) DP and S(+) DP) were compared in patients with ventricular arrhythmias. This double blind cross-over randomized trial was achieved, at steady-state, following oral administration of 200 mg three times a day. In comparison with baseline values, electrophysiological data indicated that R(-) DP and racemic DP prolonged, significantly and similarly, PR interval (+11.7% and +10%, respectively, P less than .01), and QTc interval (+9.2% and +7%, respectively, P less than .001), while QRS interval was not significantly affected. The antiarrhythmic activity, assessed by percent reduction in ventricular extrasystoles frequency, showed a similar efficiency of levorotatory and racemic DP: 80% and 74%, respectively (P = .24). Ventricular tachycardias disappeared with both treatments in the three patients concerned. During the racemic period, the mean total plasma clearance, expressed as CL/F, of S(+) DP (114.6 ml/min), was significantly lower than that of R(-) DP (157 ml/min), (P less than .001). The mean total plasma clearance of R(-) DP, during the levorotatory period (163 ml/min), did not differ from the respective value determined during the racemic period (P = .32). During the racemic period, the stereoselective difference in total plasma clearances, which is not observed when DP enantiomers are administered separately, may result from an increase in unbound fraction of R(-) DP, due to the presence of S(+) DP, which is known to be a potent displacer of R(-) DP.

[Pharmacokinetics and pharmacodynamics of the new Russian anti-arrhythmia drug allapinin]. / Farmakokinetika i farmakodinamika novogo otechestvennogo antiaritmicheskogo preparata allapinina.

Pharmacokinetics of allapinin tablets, used as a single dose, alone or in combination with other antiarrhythmic drugs (cordarone, mexitil, ritmilen) were assessed in 11 patients with frequent extrasystoles. Allapinin pharmacokinetic pattern was basically similar in patients in whom it was very effective and those in whom it had no effect. Combined use of the above-mentioned antiarrhythmic drugs and allapinin did not affect the latter's pharmacokinetic parameters. Allapinin pharmacokinetics can be described using a one-part model.

[Interrelation of changes in the levels of calcium, calmodulin and cyclic nucleotides in children with ectopic types of arrhythmia]. / Vzaimosviaz' izmenenii soderzhaniia kal'tsiia, kal'modulina i tsiklicheskikh nukleotidov pri ektopicheskikh vidakh aritmii u detei.

In 61 children with different patterns of ectopic arrhythmias (premature heart beat, paroxysmal and non-paroxysmal tachycardia), the peripheral blood leukocytes and myocardial tissues were examined for the content of calmodulin (CM), ionized calcium (Ca2+) and cyclic nucleotides (CN). The data obtained indicate that the CM-Ca2+ and CN system are involved in the genesis of arrhythmias in children and may be used as additional criteria in the diagnosis of cardiac rhythm abnormalities.

[Effectiveness of intravenous infusion of ethmozin in patients with chronic ventricular arrhythmias]. / Effektivnost' etmozina pri vnutrivennoi infuzii bol'nym s khronicheskimi zheludochkovymi aritmiiami.

Intravenous ethmozin in a dose of 270-730 mg for 4 h had pronounced antiarrhythmic effect in 80% of patients with frequent ventricular extrasystoles. In 10-14% of patients it may have arrhythmogenic effect. Positive correlation between duration and degree of the antiarrhythmic effect and dose and plasma ethmozin concentration was found. The character of the effect (antiarrhythmic or arrhythmogenic) did not depend on the dose and concentration of the drug. The indicated doses of intravenous ethmozin produce no serious side effect and may be recommended for treatment of chronic ventricular arrhythmias.