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.

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.

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.

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.

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.

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.

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)

[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.

[Comparative evaluation of biological availability and anti-arrhythmia effectiveness of Mexicard (mexiletine Polfa)]. / Ocena porównawcza biodostepnosci i skutecznosci antyarytmicznej Mexicordu (meksyletyny Polfa).

In 16 healthy males bioavailability of Mexicord (Polfa) was studied, in comparison with mexiletine of foreign made. Bioavailability extent (EBA) of Mexicord was over 99% in comparison with a standard drug. Comparative study of antiarrhythmic activity and side effects was performed in 32 patients with frequent ventricular premalure beats and nearly in a half of them resistant to antiarrhythmic agents. Mexicord was effective in 47% of treated patients, and side effects (most often nausea) were observed in 28% of patients, but only in 1 case therapy withdrawal was necessary. Statistical study proved a lack of significant differences in antiarrhythmic effectiveness and side effects between Mexicord (Polfa) and a drug of foreign made.

[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.

[Changes in the glycogen content of the dog myocardium at various phases of the cardiac cycle with a normal coronary blood flow]. / Izmeneniia soderzhaniia glikogena v miokarde sobaki v raznye fazy serdechnogo tsikla pri normal'nom koronarom krovotoke

Alterations in content of glycogen in myocardium of isolated heart of dog were studied at different phases of heart cycle by means of a special apparatus for myocardial biopsy and prompt freezing. Significant alterations in content of glycogen were observed during heart contraction. The maximal decrease (by 30.7%) in content of glycogen was found in preparations, obtained immediately after the R peak of electrocardiogramm. During the later steps of refractory period an increase in content of glycogen was observed and at the point, positioned 0.25 sec apart from the R peak, content of glycogen exceeded by 91.7% the initial level.

[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.

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.

[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.

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.

[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.