Impact of sex and gonadal steroids on prolongation of ventricular repolarization and arrhythmias induced by I(K)-blocking drugs.

BACKGROUND: Mechanisms for longer rate-corrected QT intervals and higher incidences of drug-induced torsade de pointes in women than in men are incompletely defined, although gonadal steroids are assumed to be important determinants of these differences. METHODS AND RESULTS: We used microelectrode techniques to study isolated rabbit right ventricular endocardium from control male and female and castrated male (ORCH) and female (OVX) rabbits. Action potential duration to 30% repolarization (APD(30)) was significantly shorter in male than female and in ORCH than OVX at a cycle length of 500 ms. The I(Ks) blocker chromanol 293B had no effect on APD in males or females. The I(Kr) blocker dofetilide prolonged APD in female and ORCH more than in male and OVX. At 10(-)(6) mol/L dofetilide (cycle length=1 second), the incidence of early afterdepolarizations was: female, 67%; ORCH, 56%; male, 40%; and OVX, 28%. Serum 17beta-estradiol levels were unrelated to the effects of dofetilide, but as testosterone levels increased, the dofetilide effect to increase APD diminished, as did early afterdepolarization incidence. CONCLUSIONS: Sex-related differences in basal right ventricular endocardial AP configuration persist in castrated rabbits, suggesting that extragonadal factors contribute to the differences in ventricular repolarization. In this model, drugs that block I(Kr) but not I(Ks) prolong repolarization in a way that suggests that protection from excess prolongation in males is attributable to testosterone, whereas the risk of excess prolongation of repolarization in females is related to sex-determined factors in addition to estrogen.

Long-term electrophysiological effects of regional cardiac sympathetic denervation of the neonatal dog.

OBJECTIVE: In many cardiac arrhythmias, both a triggering factor and a favorable myocardial substrate are required. Whereas the sympathetic nervous system may trigger tachyarrhythmias, its function as a long-term modulator of the myocardial substrate is less well understood. Therefore, we tested the hypothesis that regional sympathetic denervation at birth would produce an abnormal myocardial substrate. The comparator was the substrate associated with inherited, lethal tachyarrhythmias at 5 months of age in German shepherd dogs with incomplete sympathetic innervation. METHODS: Mongrel dogs underwent right cardiac stellectomy (RSX) within the first day of life and were terminally studied with control littermates at 5 months of age. RESULTS: On days 1-21 of life, RSX animals manifested significant QT prolongation on ECG and sudden, asystolic death. Beyond this age, QT intervals normalized and deaths did not occur. At 5 months, action potentials (AP) were recorded from Purkinje fibers (PF) and midmyocardial preparations in anteroseptal (AS) and posterobasal (PB) left ventricle. Early afterdepolarizations occurred only in left ventricular PF from RSX dogs. Isoproterenol prolonged AP duration in AS and shortened it in PB of RSX but not control dogs. The incidence of isoproterenol-initiated triggered activity and the amplitude of delayed afterdepolarizations were greater in RSX than control dogs. CONCLUSION: Five months after RSX heterogeneous alterations of LV electrophysiological properties were similar to those previously observed in animals having inherited deficits in sympathetic innervation and sudden death. This implicates the sympathetic nerves as long-term modulators of an arrhythmogenic substrate. That 5-month-old RSX dogs did not experience tachyarrhythmias or sudden death indicates that further anomalies--beyond those explicable by the substrate change--must exist to induce sudden death.

Interactions between antiarrhythmic drugs and cardiac memory.

OBJECTIVE: Ventricular pacing or arrhythmias can induce cardiac memory (CM). We hypothesized that clinically administered antiarrhythmic drugs alter the expression of CM, and that the repolarization changes characteristic of CM can modulate the effects of antiarrhythmic drugs. METHODS: We studied conscious, chronically-instrumented dogs paced for two 1-h periods to study the effects of drugs on the evolution of memory (protocol 1) or for 21 days (protocol 2) to observe the effects of steady-state memory on drug actions. Dogs were treated in both settings with quinidine, lidocaine or E4031, in random order, and within therapeutic serum concentration ranges. RESULTS: Pacing, alone, for 2 h significantly prolonged ERP only near the left ventricular pacing site, whereas pacing alone for 21 days prolonged ERP at all sites (P<0.05). Quinidine and E4031, but not lidocaine, prolonged repolarization and ERP and suppressed evolution of CM in protocol 1. However, quinidine's effect in prolonging repolarization was diminished in both protocols, while its effect in prolonging ERP was diminished in the 21-day protocol only. In contrast, the effects of E4031 were additive to those of CM, prolonging repolarization and ERP in both protocols, while lidocaine showed no changes in effect at all. CONCLUSIONS: Pacing to induce CM significantly affects ventricular repolarization and refractoriness, and there are interactions between CM, quinidine and E4031. Depending on the specific drug, these interactions have the potential to be anti- or proarrhythmic, and may impact importantly on the clinical efficacy of drugs as well as on electrophysiologic testing of drug actions.

beta(1) and beta(2)-adrenergic receptor subtype effects in German shepherd dogs with inherited lethal ventricular arrhythmias.

OBJECTIVE: Delayed afterdepolarization-induced triggered activity originating in ventricular myocardium is a mechanism for some age-dependent, inherited ventricular tachycardias in a colony of German shepherd dogs. METHODS: We used standard microelectrode techniques to study beta-adrenergic receptor subtype modulation of the triggered activity in anteroseptal left ventricular myocardium from eleven of these dogs and seven unafflicted, age-matched German shepherd controls. RESULTS: During sustained stimulation at cycle lengths of 300-4000 ms, 10(-9)-10(-7) M isoproterenol concentration-dependently shortened action potential duration (APD) to 90% repolarization more in myocardium from afflicted than from unafflicted dogs. This shortening was prevented by a beta(1)-blocker CGP20712A (10(-7) M) while a beta(2)-blocker ICI118551 (10(-7) M) did not modify the effect of isoproterenol in either group. The beta(2)-agonist zinterol 10(-8)-10(-6) M had no effect on APD. Stimulation at a cycle length of 250 ms in the presence of 10(-7) M isoproterenol induced more triggered AP in myocardium from afflicted than unafflicted dogs. beta(1)-Blockade completely eliminated, while beta(2)-blockade facilitated, and the beta(2)-agonist zinterol did not induce triggered activity in the two groups. CONCLUSION: Isoproterenol effects on APD and triggered activity in the myocardium of dogs with inherited arrhythmias are due primarily to an abnormality of beta(1)-adrenoceptor mediated signaling that is subject to beta(2)-adrenergic modulation.

Two subtypes of dihydropyridine-sensitive calcium channels in rat ventricular muscle.

Two opposite inotropic effects of the dihydropyridine activators, CGP 28392 and Bay K 8644, given at the same concentration (1-2 microM) were found in rat papillary muscles: a positive effect in polarized tissue (4 mM KCl) and a negative one during partial depolarization. The depressive effect found at a low rate or after a short rest was associated with marked prolongation of the Ca2(+)-mediated action potential, indicating that the drugs behave as Ca channel stimulators. The depressive effect of the activation on the resting state contraction was antagonized by nifedipine (2 microM) and high Mg2+ (5 mM). It was suggested that at least two subtypes of the L-type, dihydropyridine-sensitive channels underlie the opposite inotropic responses of the activators. The positive effect is apparently caused by conventional stimulation of Ca2+ entry through the cell membrane, whereas the negative effect is probably due to the stimulation of Ca2+ efflux from the sarcoplasmic reticulum, leading to depletion of intracellular stores. The effect was proposed to be mediated by activation of junctional channels linked to sarcoplasmic reticulum Ca2+ release. An important role for these channels in triggering the sarcoplasmic reticulum Ca2+ release and regulation of force-frequency relation is proposed.

Positive inotropic effect of ryanodine on rabbit ventricular muscle: dependence on the intracellular calcium load.

Two types of electrical and mechanical responses to 1 mumol/l ryanodine, depending on the intracellular calcium load, were observed in rabbit papillary muscles. In a normal calcium solution, ryanodine induced a transient decline followed by a stable increase in the developed force (by 20 +/- 5% of the pretreatment level; n = 30) and prolonged the action potential (AP). The positive ryanodine response showed an increased time-to-peak force and was completely suppressed by 2 mumol/l nifedipine, partially blocked by 50 mumol/l tetracaine (Ca2+ release blocker), but greatly potentiated by 20 mmol/l CsCl or (-) Bay R 5414 which prolonged the AP. The prolonged time-to-peak force of the positive ryanodine response was shortened by procedures raising the content of Ca2+ in the sarcoplasmic reticulum (SR). It is suggested that the initial decline in the force amplitude results from Ca2+ leakage from the SR which is further compensated for by an elevation of both the transmembrane Ca2+ entry and intracellular Ca2+ release. In calcium overloaded myocardium, 1 mumol/l ryanodine caused irreversible contracture and dramatic AP shortening, explained by a massive Ca2+ release from the overloaded SR into the cytoplasm. It is concluded that the calcium content in the SR is the main modulator of the electrical and mechanical effects of ryanodine in ventricular myocardium.

The "pacemaker" function of the transient outward current in the rabbit myocardium.

The single sucrose gap technique was employed to study the electrically induced automaticity in rabbit papillary muscles. When the potential was clamped at the level of the "maximum diastolic potential" following the first spike of automaticity an initial decline of the outward ionic current with subsequent activation of the delayed potassium current was observed. The initial decline was potential-sensitive with a maximum at approximately -2 mV; it diminished when the rate of stimulation increased and was abolished with 4-aminopyridine plus Sr2+. It is suggested that the transient outward current determines the development of the "pacemaker potential" after the first spike of electrically induced automaticity in rabbit papillary muscles.

[Genetico-demographic patterns of the prevalence of various forms of endogenous psychoses]. / Genetiko-demograficheskie zakonomernosti rasprostraneniia razlichnykh form éndogennykh psikhozov.

Prevalence rates (PRs) for EFP (schizophrenic, schizoaffective and affective psychoses), with allowance for proband sex and age-of-onset data were studied in a subdivided population from the North-East of the European Region of the USSR. The population includes three subpopulations: a small old religious semi-isolate of Russians ("Rs"), aboriginal Komi people ("Ks")--an ethnic community of Ugro-Finnish lineage, and a mixed group of migrants ("Ms") from various regions of the USSR. The latter is mainly an urban population, while the "Rs" and "Ks" are, on the whole, rural populations. The total PR for EFP was found to be 0.97% for the "Rs", 0.63% for the "Ks" and 0.35% for the "Ms", whereas PRs-0.85-1.15% in other parts of the USSR, mainly for "panmixed" populations in large towns. The lower PRs for EFP in the "Ms" is caused by a backmigration flow involving certain groups of patients; consequently, the mean liability for "Ms" offsprings (as a whole) should also be lower. On the other hand, the lower PRs for EFP in the "Ks" is caused by underpresentation of clinically mild cases of the mental disease (mainly, pseudoneurotic schizophrenia), especially among female patients, probably due to that the so affected persons are sufficiently adapted to the cultural traditions of this rural population. It was shown that in the "Rs" the total PR for "nuclear" and paranoid schizophrenia is 0.68% versus 0.25% in a "panmixed" population. The increase is most likely caused by the high inbreeding level in the "Rs" semi-isolate, and if this is correct, we may suppose that at least one or two recessive genes are involved in the liability to the most heavy forms of schizophrenia. On the other hand, in the "Ms" (as in other "panmixed" populations) positive assortative mating among hereditary-predisposed persons is a more significant factor influencing family transmission of EFP, since the correlation between probands and their spouses is rpp = 0.31 (p less than 0.001) in the "Ms", as compared to rpp = 0.19 (p less than 0.1) in the "Rs". Thus, our general conclusion is that neither the place of inhabitance nor the life mode are the causal factors for EFP, but rather some genetic factors, more accurately, certain sets of specific genes.

[Effect of preliminary stimulation on the repetitive firing of rabbit papillary muscle fibers]. / Effekt predvaritel'noi stimuliatsii na povtornye otvety volokon papilliarnykh myshts krolika.

It has been shown that the preliminary stimulation inhibits the initiation of repetitive firings (RF), increases the threshold current of RF and decreases membrane depolarization, induced by the action of constant current. It has been shown, that the higher the stimulation frequency, the higher the threshold current of RF and the lower the level of depolarization. It has been established that the time necessary for the restitution of the control firings of the tissue to the constant current after the action of the high-frequency stimulation does not exceed 2 minutes. It has been shown that the behavior of membrane potential under the constant current is characterized by two particularities: a) dissociation of the first response to switching on the constant current' b) a strong decay of the membrane potential to the resting potential.

[Effect of insulin on the myocardium of the active, hibernating and wakening ground squirrel Citellus undulatus]. / Vliianie insulina na miokard aktivnogo, giberniruiushchego i probyzhdaemogo suslika Citellus undulatus.

The effect of insulin (0.1-100 nM) on isometric force of contraction in isolated ground squirrel papillary muscle was investigated. In summer, autumn and winter active animals, insulin had a negative inotropic effect on papillary muscles, decreasing the amplitude of contraction by about 30% of the control value. In some cases, predominantly in the summer group of animals, insulin produced different effects on contractility: low doses (0.1-0.5 nM) caused a transient activation of isometric contraction by about 10-15% of control, whereas high doses produced a negative inotropic effect by about 30% of the control level. During deep hibernation (at 5-6 degrees C of heart temperature) and during arousal from hibernation (from 3 to 20 degrees C), insulin had no significant effect on contractility. Opposite inotropic effects of insulin at concentrations of 0.1-50 nM were found during arousal: from 26 to 31 degrees C of heart temperature--a positive inotropic effect by about 20-25% of control, and from 32 to 36 degrees C--a negative one by about 30-40% of the control value.

[Characteristics of force-frequency relations in the myocardium of the squirrel Citellus undulatus]. / Osobennosti ritmoinotropnykh otnoshenii v miokarde suslika Citellus undulatus.

The force-frequency relationship (FFR) in papillary muscles of the heart of active ground squirrel in different seasons was studied. For comparison, similar preparations from rat and rabbit were used. It was shown that the FFR of papillary muscles of active ground squirrel undergo significant seasonal changes. In summer and a part of autumn squirrels, a negative staircase (a decrease in the isometric force with increasing stimulation frequency) similar to that in adult rat was revealed. The FFR of the majority of autumn, winter and spring squirrels were polyphasic and contained both positive and negative components. Changes in the force in response to the introduction of pauses at a constant stimulation frequency were recorded. Two types of the post-rest recovery pattern were revealed in the myocardium of ground squirrels. For frequencies range with the negative direction of FFR, a typical pattern of rest-potentiation similar to that in rat papillary muscles was observed. The amplitude of the first post-rest contraction (F1) was usually higher than that of the preceding steady-state contraction. In papillary muscles of autumn animals the F1 value was greater that in summer, which suggests an enhanced release of Ca2+ from the sarcoplasmic reticulum. There was no post-rest potentiation in the range of frequencies with positive direction of FFR, and the post-rest recovery pattern in these cases was principally different from those of rat and rabbit preparations. It was proposed that seasonal differences of the FFR of active ground squirrel heart are associated with changes in the ratio of activities of the calcium-transporting system in the hibernation period.

[The action of insulin on cardiac contractility in active, hibernating and arousing susliks Citellus undulatus]. / Vliianie insulina na izmenenie napravleniia inotropii sokrashcheniia miokarda giberniruiushchego suslika Citellus undulatus na razlichnykh stadiiakh protsessa probuzhdeniia.

During the deep hibernation (at 5-6 degrees C of the heart temperature) and during arousal from hibernation (at 15-16 degrees C) insulin have no effect on contractility. Two opposite inotropic effects of insulin at concentrations 0.1-50 nM were found at higher temperature of arousing: a transient positive inotropic effect between 21-28 degrees C, and a negative one (about 20-30% from the control value) above 28 degrees C. In active summer and winter animals insulin produced mainly the negative inotropic effect.

[Clinico-demographic characteristics and features of the social and occupational adaptation of schizophrenics in 3 population groups living in the northeastern region of the European portion of the USSR (clinico-epidemiologic study)]. / Kliniko-demograficheskaia kharakteristika i osobennosti sotsial'no-trudovoi adaptatsii bol'nykh shizofreniei trekh grupp naseleniia, prozhivaiushchikh v severo-vostochnom regione Evropeiskoi chasti SSSR (kliniko-épidemiologicheskoe issledovanie).

The authors conducted a clinico-epidemiological study of schizophrenics among the indigenous population, including that living in isolated areas and newcomers, taking into consideration forms of the disease course and employing a uniform syndromal assessment of the mental state. The authors have established general pathogenetic regularities of the course and their relationship with the age and sex. Patients from the indigenous population, particularly of geographically isolated areas, showed a higher incidence of schizophrenia, a more severe clinical picture of the disease and a lower level of social and occupational adaptation as compared to the migrated population.

[Value of polarography in the control of viability of free compound flaps]. / Znachenie poliarografii v kontrole za zhiznesposobnos'tiu svobodnykh sostavnykh loskutov.

Time course of oxygen tension in 30 free compound flaps was studied by the polarographic method. The use of two types of polarographic electrodes--open needle and closed membrane epicutaneous--in control over the viability of free compound flaps revealed essential differences in the obtained results. Zero pO2 value in measurement with an epicutaneous electrode is not always evidence of flap non-viability. A negative "oxygen test" in measurement with an open needle electrode was an indication for a repeated operation. Repeated operations were undertaken for circulatory disorders after transplantation of 13 flaps and were successful in 8 cases. In 10 of these 13 cases the circulatory disorder was detected in the stage of subcompensation.

Transient outward current and rate dependence of action potential duration in rabbit cardiac ventricular muscle.

A conventional (single sucrose gap) voltage clamp technique was employed to investigate the rate dependence of ionic currents activated in the plateau range of potential in the rabbit ventricular muscle. A transient outward current of increasing amplitude was observed when the period of rest preceding the test voltage clamp pulse was increased from 0.7-60 s. The action potential duration was short when the transient outward current peak (100-150 ms after the voltage clamp pulse beginning) was high under the studied conditions of stimulation (interbeat intervals 0.7-60 s). The rate dependent transient outward current was small at low levels of depolarization above the resting potential (40 mV), had a maximum at some 90-100 mV and decreased at more positive potentials. This current was sensitive to the simultaneous application of 4-aminopyridine and calcium substitution with strontium in the Tyrode solution. It is suggested that the transient outward current is probably responsible for the changes of the action potential duration in rabbit papillary muscles when the interbeat interval varies from some 0.7-60 s.

The prolongation of the action potential in mammalian ventricular muscle at rest. Is it due to intracellular calcium content changes.

The conventional microelectrode technique was used to investigate the effect of long periods of rest (greater than 10s) on the action potential duration of mammalian ventricular muscle. The action potential duration increased as the rest period increased. This prolongation of the action potential was the greatest and the slowest in rabbit ventricle, was smaller and more rapid in guinea-pig ventricle, and was practically absent in rat ventricle. The prolongation of the action potential at rest was suppressed with aminazine and strophanthin. Low sodium concentration, lanthanum ions, ruthenium red and acidosis failed to suppress the slow prolongation. It is concluded that the slow prolongation of the action potential at rest is related to changes in the intracellular calcium content induced by a mechanism different from Na/Ca exchange.

Contribution of a Ca-dependent component to the transient outward current in rabbit ventricular fibres.

To evaluate a Ca-sensitive component of the transient outward current, we studied action potentials, isometric tension, and membrane currents (single sucrose gap voltage clamp) of rabbit ventricular heart muscle in the presence of Ryanodine that selectively blocks the intracellular Ca release. Ryanodine (1 microM) prolonged the post rest (10 s) action potential, abolished the "notch" preceding the plateau phase, and depressed the isometric tension. With the same protocol a diminished transient outward current was measured. Application of 1 mM 4-aminopyridine in the presence of Ryanodine further prolonged the duration of the action potential, decreased the transient outward current but increased the maximal tension. It is concluded that in rabbit ventricular myocardium both a Ca-dependent component and a 4-aminopyridine sensitive component compose the transient outward current; however, the 4-aminopyridine sensitive component is dominating.

[An electrophysiological study of the anti-arrhythmia effect of antioxidant ionol]. / Elektrofiziologicheskoe issledovanie antiaritmicheskogo deistviia antioksidanta ionola.

The paper describes the study of anti-arrhythmia effects of ionol. In isolated rabbit papillary muscle, ionol (a) had no effect on the depolarization-induced automaticity; (b) did not influence early afterdepolarizations: (c) delayed the onset of post-depolarizations initiated by Ca-overload and therefore inhibited the ectopic focal activity in myocardium. In isolated left auricles of rabbit, ionol suppressed the shortening of the excitation wavelength induced with adrenaline and thus protected the heart of reentry and consequent rhythm disturbances.

The controversial M cell.

A recent publication by us has been interpreted by some as arguing against the existence and importance of M cells. We suppose this is the reason we have been asked to write this "controversy." Regrettably for the controversy, neither our work nor we deny the existence of M cells. Rather, we have confirmed, conceivably ad nauseum, that M cells do exist and contribute importantly to the expression of electrical activity in the intact myocardium. What controversy there is relates to (1) whether there is an inhomogeneous transmural gradient for ventricular repolarization in normal hearts, and (2) why the electrophysiologic properties of different myocardial sites differ so markedly at the level of the isolated tissue and single cell and yet become so much more homogenous in the intact ventricle. These issues are addressed on the following pages.