Biomedical subjects

P Lorente

Publications and source records attributed to P Lorente.

At least 19 recordsLinked to original sources

PubMed2004

Peripheral blood stem cell collection after intermediate-dose cytarabine in adult patients with acute myeloblastic leukemia undergoing autologous blood stem cell transplantation in first complete remission.

Different strategies for collecting peripheral blood stem cells (PBSC) for autologous blood stem cell transplantation (ABSCT) have been reported for patients with acute myeloblastic leukemia (AML). We compared the clinical results of 2 consecutive protocols in 75 adult patients with AML in first complete remission who underwent ABSCT. In the first 56 patients (group A), PBSC were collected after induction and/or consolidation chemotherapy courses. In the subsequent 19 patients (group B), PBSC collection was done after a further intensification course with intermediate-dose cytarabine and mitoxantrone. Hematopoietic engraftment was similar in the 2 groups, with the median times to reach 0.5 x 10(9) neutrophils/L and 20 x 10(9) platelets/L being 13 days each in group A, and 12 days and 24 days, respectively, in group B. There were 3 graft failures (all in group A) and 5 transplantation-related deaths (6.6%, 4 in group A and 1 in group B). Although not statistically significant, the 3-year probabilities of both relapse (31% versus 66%; P = .12) and disease-free survival (60% versus 36%; P = .1) compared favorably for group B. Our study suggests that collection of PBSC after additional intensification can result in a better outcome for AML patients who undergo ABSCT.

Adolescent↗

PubMed2003

[Headache caused by cerebral angiopathy during labor with epidural analgesia].

A 29-year-old woman presented projectile vomiting followed by frontal headache, immediately upon receiving epidural analgesia for labor. The clinical picture persisted until expulsion. Although no leaking of spinal fluid into the needle or epidural catheter had been observed, post-dural puncture headache was diagnosed. The postpartum persistence of symptoms and the patient's generally worsening condition indicated the need for more thorough physical examination, which revealed signs of neurological involvement. Those findings and imaging studies (computed tomography of the brain, transcranial Doppler and magnetic resonance angiography) established a final diagnosis of postpartum cerebral angiopathy. Although epidural analgesia is increasingly requested by women entering labor, it is not a risk-free procedure. We describe a relatively unknown clinical entity, postpartum cerebral angiopathy, that developed during epidural analgesia for labor and that was initially believed to be a complication of the analgesic technique.

Adult↗

PubMed2000

gamma-aminobutyric acid type B receptors are expressed and functional in mammalian cardiomyocytes.

gamma-Hydroxybutyrate (GHB), an anesthetic adjuvant analog of gamma-aminobutyrate (GABA), depresses cell excitability in hippocampal neurons by inducing hyperpolarization through the activation of a prominent inwardly rectifying K(+) (Kir3) conductance. These GABA type B (GABA(B))-like effects are clearly shown at high concentrations of GHB corresponding to blood levels usually reached during anesthesia and are mimicked by the GABA(B) agonist baclofen. Recent studies of native GABA(B) receptors (GABA(B)Rs) have favored the concept that GHB is also a selective agonist. Furthermore, cloning has demonstrated that GABA(B)Rs assemble heteromeric complexes from the GABA(B)R1 and GABA(B)R2 subtypes and that these assemblies are activated by GHB. The surprisingly high tissue content, together with anti-ischemic and protective effects of GHB in the heart, raises the question of a possible influence of GABA(B) agonists on excitable cardiac cells. In the present study, we provide electrophysiological evidence that GHB activates an inwardly rectifying K(+) current in rat ventricular myocytes. This effect is mimicked by baclofen, reversibly inhibited by GABA(B) antagonists, and prevented by pertussis toxin pretreatment. Both GABA(B)R1 and GABA(B)R2 are detected in cardiomyocytes by Western blotting and are shown to coimmunoprecipitate. Laser scanning confocal microscopy discloses an even distribution of the two receptors in the sarcolemma and along the transverse tubular system. Hence, we conclude that GABA(B)Rs are distributed not only in neuronal tissues but also in the heart, where they can be activated and induce electrophysiological alterations through G-protein-coupled inward rectifier potassium channels.

Adjuvants, Anesthesia↗

PubMed2000

Late post-myocardial infarction induces a tetrodotoxin-resistant Na(+)Current in rat cardiomyocytes.

Left ventricular remodeling after myocardial infarction is accompanied by electrical abnormalities that might predispose to rhythm disturbances. To get insight into the ionic mechanisms involved, we studied myocytes isolated from four different regions of the rat ventricles, 4-6 months after ligation of the left coronary artery. Using the whole-cell patch-clamp technique, we never observed T-type Ca(2+)current in both diseased and control hearts. In contrast, in 41 out of 78 cells isolated from 16 post-myocardial infarcted rats, analysed in the presence of 30 m m Na(+)ions, we found a tetrodotoxin (TTX)-resistant Na(+)current with quite variable amplitude in every investigated region. Albeit being resistant to 100 microM TTX, this Na(+)-dependent current was highly sensitive to lidocaine since 3 microM lidocaine induced about 65% tonic block. It was also inhibited by 5 microM nifedipine and 2 m m Co(2+), but was insensitive to 100 microM Ni(2+). The TTX-resistant Na(+)channel availability was shifted rightward by 25-30 mV with respect to TTX-sensitive Na(+)current; therefore, a large "window current" might flow in the voltage range from -70 to -20 mV. In conclusion, in late post-myocardial infarction, a Na(+)current with specific kinetics and pharmacology may provide inward charges in a critical range of membrane voltages that are able to alter action potential time course and trigger ventricular arrhythmia. These apparent new characteristics of the Na(+)channel might result in part from environmental changes during heart remodeling.

Animals↗

PubMed2000

Cellular and in vivo electrophysiological effects of dronedarone in normal and postmyocardial infarcted rats.

We studied the effects of dronedarone (SR 33589) on the action potentials, membrane ionic currents, and arrhythmic activity in control rats and in rats after myocardial infarction, a model known to develop anomalous electrical activity. Dronedarone increased action potential duration in normal hearts. It had little effect on the action potentials that were already prolonged in the postmyocardial infarcted (PMI) rats. Particularly, dronedarone reduced the late sustained K(+) current, I(K) (or Isus) by 69%. Dronedarone induced only a tonic block of I(K). Similar relative inhibitions of I(K) by dronedarone were obtained in young, sham, and PMI rats, even if I(K) was less in sham than in young and further reduced in PMI rats. The EC(50) values were 0.78 and 0.85 microM in sham and PMI rats. Dronedarone induced a weak increase in the fast transient outward current, I(to). Time-to-peak and inactivation time constant of I(to) were decreased by dronedarone that also induced a marked slowing of I(to) recovery from inactivation. Similar effects were observed on the reduced I(to) recorded in PMI rats. Holter monitoring study in control, unthetered animals showed that dronedarone had no proarrhythmic effect. On rats, which after myocardial infarction exhibited ventricular premature beats, dronedarone significantly decreased beat occurrence during the 7-day treatment; this effect was sustained for two more weeks. Thus, dronedarone exerts antiarrhythmic effects on PMI rat heart. Its effects are attributable for the most part to the inhibition of outward K(+) currents and the increase in effective refractory period.

Action Potentials↗

PubMed1999

Ionic basis of ventricular arrhythmias in remodeled rat heart during long-term myocardial infarction.

OBJECTIVE: Deleterious electrical abnormalities evolve during myocardial infarction. The goal of this study was to analyse current changes during the late decompensated phase of heart disease induced by coronary ligation and to compare them in various heart regions. METHODS: Young rats were submitted to left coronary ligature. After 4-6 months, cells were enzymatically dissociated and isolated from the upper part basal region of the left ventricle, as well as from the septum, apex and the right ventricle before being studied under whole-cell patch-clamp. RESULTS: Basal L-type Ca2+ current, ICaL elicited at +10 mV did not exhibit regional dependence neither in control nor after post-myocardial infarction (PMI). ICaL showed both a significantly reduced peak amplitude (17.1 +/- 2.8 pA/pF versus 9.9 +/- 1.4 pA/pF in seven control and seven PMI hearts, n = 32 and 40, respectively) and a slower inactivation, such that the amount of inward charges during a 200 ms-depolarizing pulse was nearly unchanged. beta-Adrenergic stimulation was less effective in increasing ICaL in PMI cells but it slowed inactivation further. Significant differences in the K+ currents were observed. A regional distribution was seen for Ito only, with the largest amplitude in the right ventricle (in pA/pF: 23.1 +/- 2.4, 18.2 +/- 3.9, 14.8 +/- 2.4, 8.3 +/- 1.7 in the right ventricle, apex, septum and left ventricle, respectively n = 8, 7, 8 and 9). This was also true in failing heart cells despite Ito being halved in each of the four regions (in pA/pF: 12.2 +/- 2.5, 11.2 +/- 1.9, 5.1 +/- 1.0 and 4.8 +/- 1.0, respectively n = 12, 12, 11 and 13). IK1 was also significantly reduced by 20% in the PMI cells. Two-way analyses of variance demonstrated the absence of interaction between the topographical origin of the cells and the physiological state of the rats. The alpha 1-adrenergic agonist, methoxamine significantly reduced Ito and IK1 to the same extent in both sham and PMI cells, by about 35% and 20% respectively. CONCLUSIONS: Long-term left coronary occlusion induces significant alterations in both Ca2+ and K+ currents that occur with similar amplitude in both ventricles. They include a marked reduction in Ito amplitude as well as a slowing of ICaL inactivation. Both factors could contribute to the disturbances in cellular electrical behaviour and the occurrence of arrhythmias in the post-myocardial infarcted heart.

Action Potentials↗

PubMed1999

Effects of quinidine, verapamil, nifedipine and ouabain on hysteresis in atrial refractoriness in the conscious dog: an approach to ionic mechanisms.

1. This work determines the effects of quinidine, verapamil, nifedipine and ouabain on the hysteresis of the atrial effective refractory period (AERP) in the conscious dog. 2. AERP was always longer in the increasing phase than in the decreasing phase of the extrastimulus method, thus demonstrating the existence of AERP hysteresis. Calculated as the difference between the two values, hysteresis was between 8+/-0.8 and 11+/-1.0 msec. 3. Quinidine increased hysteresis from 9+/-0.7 to 13+/-0.7 msec, whereas verapamil decreased it from 10+/-0.9 to 5+/-0.5 msec and nifedipine did not affect it. Ouabain also lengthened hysteresis from 8+/-0.8 to 11+/-1.2 msec. 4. Thus, these results confirm the existence of a hysteresis phenomenon in the AERP in the conscious dog and are evidence that the fast sodium and slow calcium specific membrane currents participate in this phenomenon.

Animals↗

PubMed1999

[Descriptive study of patients diagnosed with asthma in a regional respiratory medicine practice].

OBJECTIVE: To describe the characteristics of patients diagnosed of bronchial asthma (BA) in a regional respiratory medicine practice. METHODS: Over a period of two years, 88 adult patients followed a prospective-diagnostic protocol for BA that included taking of patient history to determine the probability of initial diagnosis (PID) of asthma, assessment of atopy and a lung function test that included spirometry with a bronchodilator test, recording of forced expiratory volume, and a methacholine challenge test. BA was diagnosed when symptoms denoting high or moderate PID were present and there was a positive reversibility and/or bronchial hyperreactivity test. The severity of disease was evaluated using the consensus criteria of the Global Initiative for Asthma (GINA). A student-t test and a chi 2 test were performed to compare data. RESULTS: BA was diagnosed in 24 men (30%) and 56 women (70%) with a mean age of 43.0 +/- 17.6 years (range 16 to 68). Significant differences between men and women were detected only for function parameters and cigarette consumption (p < 0.05). Fifty-three patients (66%) were referred by general practitioners, 22 (27%) were referred by hospital, and 5 came from other sources. The first group had a shorter history of disease course (p = 0.05) upon first evaluation. Sixty-one patients (76%) had mild asthma; these patients were younger and had had symptoms for a shorter period of time than those with more serious degrees of disease (16 with moderate asthma and 3 with severe asthma) (p < 0.05). Symptoms indicated a high PID in 57 cases (71%), and this figure increased significantly to 89.5% for those with more severe asthma (p < 0.05). Asthma was intrinsic for 39 patients and extrinsic for 41, with significant differences in age and total IgE between the two groups (p < 0.01). CONCLUSIONS: 1. BA is more than twice as common among women as among men. 2. Two thirds of patients are referred by general practitioners. 3. Mild asthma clearly predominates. 4. Clinical symptoms point to asthma, the PID in most cases being high.

Adolescent↗

PubMed1998

Extracellular K+ dependence of inward rectification kinetics in human left ventricular cardiomyocytes.

BACKGROUND: In human ventricular cells, the inwardly rectifying K+ current (IK1) is very similar to that of other mammalian species, but detailed knowledge about the K+-dependent distribution of open and blocked states during rectification and about the K+-dependent modulation of inactivation on hyperpolarization is currently lacking. METHODS AND RESULTS: We used the whole-cell patch-clamp technique to record IK1 in myocytes isolated from subendocardial layers of left ventricular septum from patients with nonfailing hearts with aortic stenosis and cardiac hypertrophy who were undergoing open-heart surgery. Outward currents were very small at voltages positive to the reversal potential but increased at high external [K+]. Chord conductance measurements and kinetic analyses allowed us to estimate the proportion of channels in the open state and of those showing either slow unblock or instantaneous unblock (the so-called slow or instantaneous "activation") on hyperpolarization: the distribution in the individual states was dependent on external [K+]. The proportion of channels unblocking slowly was greater than that of channels unblocking instantaneously on hyperpolarization from the plateau voltage range. Hence, because of the previously reported link between the presence of highly protonated blocking molecules and slow unblock kinetics, it is suggested that high cellular concentrations of spermine may account for the low outward current density recorded in these cells. The current decrease observed on extended hyperpolarization was significantly relieved by an increase in external [K+]. CONCLUSIONS: The pattern of IK1 current alterations observed in the present model of human ventricular hypertrophy might favor enhanced excitability and underlie ventricular arrhythmias, possibly via increased intracellular polyamine levels.

Action Potentials↗

PubMed1997

Regional alteration of the transient outward current in human left ventricular septum during compensated hypertrophy.

BACKGROUND: A large calcium-insensitive transient outward current (I(to)) has been recorded in atria, left ventricular (LV) free wall, and right ventricular septal subendocardium of the human heart. Recent studies suggested a major contribution of this current to the electrical heterogeneity of the heart. However, no data have been reported on the distribution of I(to) density within the LV septal wall from compensated human LV hypertrophy. METHODS AND RESULTS: Microelectrode and patch-clamp techniques were used to record action potentials and I(to) in myocytes isolated from superficial (<3 mm deep) and deep (3 to 6 mm deep) layers of LV septum from patients with aortic stenosis and compensated LV hypertrophy. Subendocardial specimens were also obtained from undiseased donor hearts. In none of the superficial subendocardial cells from diseased hearts was a macroscopic I(to) recorded (n=42), whereas in cells from the same location from donor hearts, a typical I(to) was clearly present, with a peak density of 5.88+/-0.78 pA/pF at +60 mV (n=4). However, in deep layers from patients with compensated LV hypertrophy, macroscopic I(to) was present, with a peak density of 10.50+/-2.58 pA/pF at +60 mV (n=4). The absence of I(to) in superficial septal cells from hypertrophied hearts was not due to a divalent cation-related shift of the current kinetics. Instead, extracellular Ca2+ removal induced an I(to)-like current, possibly carried by K+ ions, with a peak density of 30.7+/-2.6 pA/pF at +60 mV (n=29). However, its magnitude, kinetics, and pharmacological characteristics did not allow identification of this current as the usual I(to). CONCLUSIONS: Both topography and pathology can be major modulating factors of the regional distribution of I(to) density in human LV septum. Therefore, they may play a prominent role in determining electrical gradients within this region from which the early depolarization vectors start and the left-to-right activation sequence of the interventricular septum proceeds.

Action Potentials↗

PubMed1997

Conduction block and chaotic dynamics in an asymmetrical model of coupled cardiac cells.

The initiation and propagation of the cardiac impulse depends on intrinsic properties of cells, geometrical arrangements, and intercellular coupling resistances. To address the issue of the interplay between these factors in a simple way, we have used a system, based on the van Capelle and Dürrer model, including a pacemaker and a non-pacemaker cell linked by an ohmic coupling resistance. The influence of asymmetrical cell sizes and electronic load was investigated by using numerical simulations and continuation-bifurcation techniques. The loading of a small pacemaker cell by a large non-pacemaker one (pacemaker: non-pacemaker size ratio = 0.3) was expressed as a pronounced early repolarization in the pacemaker cell and a quite long latency for the impulse propagation. Using coupling resistance as the continuation parameter, three behavioral zones were detected from low to high coupling resistance values: a zone of total quiescence (0:0), a zone of effective entertainment (1:1), and a zone of total block (1:0 pattern). At the boundary between 1:1 and 1:0 patterns, for relatively high coupling resistance values, a cascade of period doubling bifurcations emerged, corresponding to discrete changes of propagation patterns leading into irregular dynamics. Another route to irregular dynamics was also observed in the parameter space. The high sensitivity of the detected irregular dynamics to initial conditions and the positive value of the maximum Lyapunov exponent allowed us to identify these dynamics as being chaotic. Since neither intermediate block patterns nor irregular dynamics were observed with larger size ratios, we suggest that the interplay between resting membrane conductance of the non-pacemaker cell and intercellular coupling may bring about these rhythmic disturbances.

Animals↗

PubMed1997

Modulation of electrical heterogeneity by compensated hypertrophy in rat left ventricle.

Modulation of the regional distribution of the action potential by left ventricular hypertrophy and the role of the L-type Ca2+ current (I(Ca)) and transient outward current (I(to)) in the action potential duration (APD) were investigated in normal and hypertrophied rat ventricular myocytes from the apex (A), septum (S) and left ventricular free wall (FW) by using whole cell current- and voltage-clamp techniques. Hypertrophy was induced by abdominal aortic constriction. In control cells, the APD measured at 20% repolarization (APD20) assumed the shortest values in the A and the longest in the S, whereas FW cells showed intermediate values. Hypertrophy significantly prolonged the APD20 and increased APD variability within the A and FW regions but did not modify the APD in S cells. Analysis of the APD, I(Ca), and I(to) at the instant of 20% repolarization in the same cell showed that in control cells the shortest APD20 was associated with a prominent I(to) in the A and FW, whereas the long APD20 was identified with a lower I(to) in S myocytes. Hypertrophy-induced prolongation ofAPD20 was associated with a reduction in the I(to) in the A and FW. Significant correlations could be established between the APD20 and the "net current," defined as the algebraic addition of I(to) and I(Ca) in the A and FW control groups but not in the control S or hypertrophied cells whatever their origin. Our results indicate that interregional APD heterogeneity is lost while intraregional APD variability is increased in the A and FW during the hypertrophic process. These effects are largely due to a change in the balance between the I(Ca) and I(to), which is a major contributing factor to the heterogeneity of the initial phase of repolarization in the normal rat ventricle.

Action Potentials↗

PubMed1997

A chloride current component induced by hypertrophy in rat ventricular myocytes.

The effect of hypertrophy on membrane currents of rat left ventricular myocytes was studied with the whole cell voltage-clamp method. We found that the slope of the total time-independent current density-voltage relationship was increased in hypertrophied cells. No change in the zero-current potential was observed. Surprisingly, the dominant time-independent current, the inward rectifier K+ current (measured as the Ba(2+)-sensitive current density) was unchanged. We therefore investigated the identity of the outwardly rectifying Ba(2+)-resistant current seen in the hypertrophied rat ventricular myocytes but not present in control cells. We found that this current 1) was not carried by monovalent cations, 2) was partially blocked by anthracene-9-carboxylic acid (9-AC), and 3) was sensitive to variations in extracellular Cl concentration. These findings are consistent with the current being carried at least partially by Cl-. The presence of an additional Cl(-)-dependent component in hypertrophied cells is supported by the actions of 9-AC on the measured action potentials (APs). 9-AC had no effect on control cells APs but prolonged hypertrophied cell APs. We conclude that a Cl- current component develops in hypertrophied rat heart cells. This component appears to shorten the AP duration and might thus provide protection from cardiac arrhythmias.

Animals↗

PubMed1996

Hysteresis in atrial refractoriness in the conscious dog: influence of stimulation parameters and control by the autonomic nervous system.

This work (a) provides evidence for hysteresis in the atrial effective refractory period (AERP) in the conscious dog; (b) studies the main stimulation parameters that may affect this phenomenon; and (c) evaluates the influence of the autonomic nervous system. AERP was measured by the extrastimulus method in the conscious dog with chronic atrioventricular block (n = 6) during the increasing and decreasing phases of an S1S2 fixed protocol. AERP was longer during the increasing phase than during the decreasing phase, thus demonstrating hysteresis, calculated as the difference between the two values. Hysteresis was greater with an S1S1 basic cycle length of 300 ms than with a basic cycle length of 400 ms, 9 +/- 0.9, and 7 +/- 0.9 ms, respectively. It was also greater with trains of six basic cycles before each extrastimulus S2 than with trains of 12 basic cycles, 9 +/- 0.9 and 7 +/- 1.0 ms, respectively. Suppression of vagal tone with atropine reduced hysteresis from 8 +/- 0.6 to 4 +/- 0.6 ms, whereas suppression of cardioaccelerator tone with propranolol increased it from 9 +/- 0.9 to 14 +/- 1.2 ms. These data were confirmed by the neostigmine-induced increase in hysteresis from 8 +/- 0.8 to 11 +/- 0.8 ms and the isoproterenol-induced decrease in hysteresis from 9 +/- 0.6 to 4 +/- 0.4 ms. Overall, these results provide evidence for a hysteresis effect in the AERP in the conscious dog that is stimulation frequency-dependent and modulated by the autonomic nervous system with permanent increase by vagal tone and decrease by cardioaccelerator tone.

Adrenergic beta-Antagonists↗

PubMed1994

Chronotropic cardiac effects of NPY in conscious dogs: interactions with the autonomic nervous system and putative NPY receptors.

The chronotropic cardiac effects of neuropeptide Y (NPY) were studied in the conscious dog with chronic atrioventricular block. NPY (0.2-5 micrograms/kg i.v.) produced no effect on atrial cycle length (ACL), and increased ventricular cycle length (VCL) and mean arterial blood pressure (MBP). After atropine, NPY produced no effect on ACL and increased MBP. At 0.2 microgram/kg, it shortened VCL, whereas at 1 and 5 micrograms/kg, it lengthened this parameter. After pindolol, NPY produced no effect on ACL, shortened VCL and increased MBP. These results indicate that in the conscious dog, NPY (0.2-5 microgram/kg i.v.) does not exert any chronotropic effect on the sinoatrial node, most likely because of competition between opposite chronotropic effects and/or absence of specific NPY receptors in the sinoatrial node. They also suggest that the ventricular bradycardic effects produced by NPY result mainly from a reflex withdrawal of beta-adrenergic tone and that its ventricular tachycardic effects result from a direct action of NPY on specific receptors located in the His bundle.

Animals↗

PubMed1994

Electrotonic inhibition and active facilitation of excitability in ventricular muscle.

INTRODUCTION: The effects of subthreshold electrical pulses on the response to subsequent stimulation have been described previously in experimental animal studies as well as in the human heart. In addition, previous studies in cardiac Purkinje fibers have shown that diastolic excitability may decrease after activity (active inhibition) and, to a lesser extent, following subthreshold responses (electrotonic inhibition). However, such dynamic changes in excitability have not been explored in isolated ventricular muscle, and it is uncertain whether similar phenomena may play any role in the activation patterns associated with propagation abnormalities in the myocardium. METHODS AND RESULTS: Experiments were performed in isolated sheep Purkinje fibers and papillary muscles, and in enzymatically dissociated guinea pig ventricular myocytes. In all types of preparations introduction of a conditioning subthreshold pulse between two suprathreshold pulses was followed by a transient decay in excitability (electrotonic inhibition). The degree of inhibition was directly related to the amplitude and duration of the conditioning pulse and inversely related to the postconditioning interval. Yet, inhibition could be demonstrated long after (> 1 sec) the end of the conditioning pulse. Electronic inhibition was found at all diastolic intervals and did not depend on the presence of a previous action potential. In Purkinje fibers, conditioning action potentials led to active inhibition of subsequent responses. In contrast, in muscle cells, such action potentials had a facilitating effect (active facilitation). Electrotonic inhibition and active facilitation were observed in both sheep ventricular muscle and guinea pig ventricular myocytes. Accordingly, during repetitive stimulation with pulses of barely threshold intensity, we observed: (1) bistability (i.e., with the same stimulating parameters, stimulus:response patterns were either 1:1 or 1:0, depending on previous history), and (2) abrupt transitions between 1:1 and 1:0 (absence of intermediate Wenckebach-like patterns). Simulations utilizing an ionic model of cardiac myocytes support the hypothesis that electrotonic inhibition in well-polarized ventricular muscle is the result of partial activation of IK following subthreshold pulses. On the other hand, active facilitation may be the result of an activity-induced decrease in the conductance of IK1. CONCLUSION: Diastolic excitability of well-polarized ventricular myocardium may be transiently depressed following local responses and transiently enhanced following action potentials. On the other hand, diastolic excitability decreases during quiescence. Active facilitation and electrotonic inhibition may have an important role in determining the dynamics of excitation of the myocardium in the presence of propagation abnormalities.

Action Potentials↗

PubMed1993

Effects of propafenone on calcium current in guinea-pig ventricular myocytes.

1. The modulation of L-type voltage-sensitive calcium channels in guinea-pig isolated ventricular myocytes by propafenone was examined by the whole cell voltage-clamp technique. 2. Propafenone, 10(-7) -5 x 10(-5) M, produced a concentration-dependent inhibition of Ca current (ICa) without any significant change in the current-voltage relation. Half-blocking concentration (IC50) of propafenone for the peak ICa at +10 mV was 5 x 10(-6) M. 3. The voltage-dependence of ICa inactivation was shifted in the hyperpolarizing direction in the presence of 5 x 10(-6) M propafenone. 4. A frequency-dependent relative block by propafenone was observed after repetitive depolarizing test pulses at a frequency of 0.5 and 1 Hz. The recovery of ICa from inactivation was prolonged by propafenone and the reactivation exhibited an additional exponential component attributed to the slow release from drug block of Ca channels. 5. These results suggest that propafenone, at therapeutic concentrations exhibits Ca channel blocking properties that may be involved in its antiarrhythmic mechanism.

Animals↗

PubMed1993

Heterogeneity of the early outward current in ventricular cells isolated from normal and hypertrophied rat hearts.

1. The nature, magnitude and kinetics of the 4-aminopyridine-sensitive early outward current (Ito) were analysed in isolated ventricular myocytes from the septum, the apex and the left ventricular free wall of rat ventricles using the whole-cell voltage clamp method. The modulatory effect of pressure overload-induced cardiac hypertrophy on the regional variations of Ito was assessed in each topographical class of cells. 2. Voltage clamp experiments were performed at room temperature (20-25 degrees C) in the absence of Na+ on both sides of the membrane and in the presence of 3 mM CoCl2. Ito was studied from a holding potential of -80 mV and determined by subtraction of total outward currents elicited by the same protocols in the presence of 3 mM 4-aminopyridine (4-AP) from those obtained in its absence. 3. In normal hearts, membrane passive properties were very similar in each topographical class of cells. Our results confirmed that the predominant early outward current in rat ventricular cells was 4-AP-sensitive, time and voltage dependent, and demonstrated that the magnitude of the current varied on a regional basis: current density of Ito in left ventricular free wall cells (30.1 +/- 9.2 pA/pF at +60 mV) was larger than in apex cells (20.2 +/- 1.7 pA/pF) or in septum cells (11.9 +/- 3.3 pA/pF). We noticed a larger variability in data from left ventricular free wall compared with other regions. 4. No shift in steady-state voltage dependence of Ito activation and inactivation was found. However, the maximal computed chord conductances were (in microS/pF): 0.18 +/- 0.07 for left ventricular free wall cells, 0.13 +/- 0.02 for apex cells, and 0.08 +/- 0.02 for septum cells. These findings might reflect a differential distribution in functional channel densities. 5. No difference in voltage-dependent Ito activation kinetics was present with respect to topography. However, inactivation time constants in septum were longer than those of both other groups. 6. Left ventricular hypertrophy was induced by abdominal aortic constriction and its effects compared to the findings from normal rats. Hypertrophied cells had similar resting potentials but higher capacitance values than normal cells. Although Ito magnitude appeared not to be modified, the current density-voltage curves were slightly shifted to more positive potentials and significantly decreased as compared to normal cells (in pA/pF, at +60 mV): 8.4 +/- 5.0 in the left free wall group, 11.6 +/- 2.0 in the apex group, and 3.8 +/- 1.5 in the septum group.(ABSTRACT TRUNCATED AT 400 WORDS)

4-Aminopyridine↗