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Biomedical subjects

M Delmar

Publications and source records attributed to M Delmar.

50 records · Page 3Linked to original sources
PubMed1990

Electrophysiology of single heart cells from the rabbit tricuspid valve.

1. The electrophysiology of single myocytes isolated from the rabbit tricuspid valve was studied using the patch-clamp method (whole-cell configuration). Cell dispersion was achieved by collagenase treatment, using the Langendorff retrograde perfusion procedure. 2. After isolation, and while incubating in the recovery (Kraftbrühe) solution, cells had clear striations and were mostly spindle-shaped, or rod-like (less than 10%), with length varying from 35 microns to over 150 microns, and diameter from 3 to 10 microns. 3. Upon exposure to Tyrode solution, the calcium-tolerant cells were mostly rounded with smooth surfaces and well-defined borders. The mean diameter of these cells was 15 +/- 5 microns (S.D., n = 9). A smaller percentage (about 30%) retained the original elongated shape. 4. Patch pipette recordings showed the presence of spontaneous activity in about 30% of round cells, and less frequently in elongated cells. Maximum diastolic potentials (MDPs) in the round cells averaged -82 +/- 6 mV, with a take-off potential of -56 +/- 3 mV (n = 9), and an average maximum upstroke velocity (Vmax) value of 6.3 +/- 0.6 V/s (n = 4). In quiescent cells, the mean resting potential was 69 +/- 12 mV (n = 43). 5. Voltage clamp ramps revealed a steady-state I-V relation with a negative slope region. The mean input resistance value was 25 +/- 9 M omega (n = 16) for the elongated, and 883 +/- 481 M omega (n = 8) for the round cells. 6. Hyperpolarizing 5 s pulses (holding potential = -50 mV) occasionally revealed a slow, time-dependent inward current whose peak increased progressively as a function of clamp potential. The slowly activating current was sensitive to caesium 2 mM), indicating its similarity to the so-called 'pacemaker current' (iF). In alternate voltage- and current-clamp experiments, blocking of iF did not stop pacemaker activity, but there was up to a fourfold increase in pacemaker cycle length. 7. In some cells, 5 s hyperpolarizing steps from a holding potential of -40 or -50 mV produced large, inwardly directed and voltage-dependent current surges that decayed rapidly with time, similar to the inactivation described for the inward rectifier current, iK1. The current was very prominent at voltages more negative than -100 mV, and its decay process was best fitted by two time constants, one fast and one slow. For example, at -150 mV the time constants were 61 and 634 ms. The inward current was blocked by barium (1 mM).(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed1990

Wenckebach periodicity in single atrioventricular nodal cells from the rabbit heart.

Previous studies have suggested that Wenckebach periodicity in cardiac tissues may occur because of discontinuous propagation across junctional areas in which there is high intercellular resistivity or different cell types. Under these conditions, the impulse may stop altogether at a given junction, or may renew its propagation but only after a step delay imposed by the diastolic time-dependent recovery in the excitability of cells distal to that junction. Accordingly, Wenckebach periodicity in the atrioventricular node may be explained in terms of electrotonically mediated delay in the activation of the nodal cells. To test this hypothesis, we have studied recovery of excitability, and susceptibility to rate-dependent activation failure in single myocytes isolated from the adult rabbit atrioventricular node. Recordings were obtained by using the patch technique in the whole-cell, current clamp configuration. Repetitive stimulation of single atrioventricular nodal myocytes with depolarizing current pulses of critical amplitude yielded frequency-dependent stimulus response patterns that ranged from 1:1, through various Wenckebachlike periodicities (e.g., 5:4 and 4:3) to 2:1 and 3:1. Both typical and atypical Wenckebach structures were demonstrated, as well as "complex" patterns (e.g., reverse Wenckebach or alternating Wenckebach) previously ascribed to multiple levels of block. The diastolic recovery of excitability curve, determined by application of repetitive stimuli at cycle lengths that were longer than the action potential duration, showed a monotonic function with a refractory period outlasting the action potential duration (i.e., postrepolarization refractoriness). Abbreviation of the stimulation cycle length to values below those of the action potential duration revealed the existence of a period of supernormal excitability during the repolarizing phase of the action potential. In either case, the stimulus response patterns obtained were a direct consequence of the shape of the recovery of excitability curve. The monotonic portion of the recovery curve was fitted to an empirical equation that when iterated reproduced the stimulus response patterns observed in the atrioventricular nodal cell. Our data demonstrate that recovery of excitability after an action potential is indeed a function of the diastolic interval, and that this slow process sets the conditions for the development of Wenckebach periodicity in the atrioventricular node.

Action Potentials↗
PubMed1990

Directional differences in excitability and margin of safety for propagation in sheep ventricular epicardial muscle.

Computer simulations and isolated tissue experiments were used to characterize the relation between excitability and margin of safety for propagation in anisotropic ventricular myocardium. Longitudinal, uniform transverse, and nonuniform transverse tissue directions were modeled in a one-dimensional Beeler-Reuter based cable. Stimulation threshold was smallest in the nonuniform transverse direction. The safety factor for propagation was determined in the model as the total axial charge that was available for depolarizing downstream tissue divided by the threshold charge that was just sufficient for continued propagation and was largest in the longitudinal direction. The strength-interval plot for the junction between simulated longitudinal and nonuniform transverse directions identified a range of stimulus strengths and intervals that resulted in nonuniform transverse but not longitudinal propagation. When high values of transverse resistance were used, higher stimulus strengths during premature stimulation resulted in longitudinal but not nonuniform transverse propagation. The experimental strength interval plots from 17 L-shaped preparations of isolated sheep epicardial muscles had similar characteristics. In nine additional L-shaped tissue experiments, changing extracellular K+ concentrations from 4 to 20 mM resulted in progressive membrane depolarization and conduction impairment in both directions. However, in eight of nine experiments, complete block occurred first in the transverse direction. In one experiment, block was simultaneous in both directions. We conclude that, under normal conditions, threshold requirements for active propagation are lower for transverse than for longitudinal propagation. In addition, when active membrane properties are impaired, the safety factor for propagation is larger in the direction along the longitudinal axis of the cells.

Adult↗
PubMed1989

Modulated parasystole as a mechanism of ventricular ectopic activity leading to ventricular fibrillation.

The electrocardiograms of 2 patients with frequent premature ventricular complexes characterized by variable coupling intervals and fusions with sinus activations were analyzed according to the modulated parasystole and reflection hypotheses of Moe et al. In addition, the ectopic activity was associated with couplets, tachycardia and ventricular fibrillation. Departures from the "classic" criteria of parasystole could not be explained satisfactorily if a completely protected (insulated) pacemaker was assumed. In each instance a triphasic response curve could be constructed, suggesting that modulated parasystole was the mechanism common to both patients. Couplets and runs of ventricular tachycardia were ascribed to single and repetitive reflection, respectively, in the presence of supernormal excitability of the ectopic pacemaker, the ventricle or both. In these patients, fibrillation probably resulted from spatial nonuniformity of the ventricular response to the reflected event during a phase of vulnerability. This study suggests that modulated parasystole in the presence of supernormal excitability may lead to very severe arrhythmias and trigger ventricular fibrillation. In the clinical setting, such patients may be misdiagnosed because of atypical features.

Adult↗
PubMed1989

Electrical uncoupling and impulse propagation in isolated sheep Purkinje fibers.

Alterations in electrical coupling may have a major role in the development of cardiac rhythm and conduction disturbances. We have used microelectrodes and linear Purkinje fibers to analyze the relative importance of cell-to-cell coupling on action potential propagation and to study the changes in the relationship between conduction velocity (theta) and upstroke velocity (Vmax) induced by three agents (heptanol, hypertonic solution, and ouabain) known to alter gap junction resistance. Heptanol superfusion (1.5-3.0 mM) reversibly led to a major decrease in theta and ultimately to block at a time when Vmax had been reduced by approximately 38%. Conduction delay was closely correlated with an increase in intracellular resistance (Ri), calculated as the sum of myoplasmic and junctional resistances, assuming a one-dimensional cable model. Qualitatively similar results were obtained by superfusion with 0.1-0.5 mM ouabain or hypertonic Tyrode solution (up to 600 mM sucrose added) instead of heptanol. In contrast, when the Vmax vs. theta relationship was studied by changing the KCl from 4 to 20 mM, decreases in Vmax correlated well with changes in theta. No significant effects on Ri were observed during KCl superfusion. Finally, we developed a computer model of action potential propagation along a one-dimensional strand of 90 electrically coupled heart cells. By changing systematically the degree of electrical coupling or the maximum sodium conductance in the model and by studying the effects of these changes on propagation and Vmax, we obtained strong evidence supporting the validity of our experimental results. The overall data provide testable predictions regarding the role of electrical uncoupling on abnormal impulse propagation.

Action Potentials↗
PubMed1989

Slow recovery of excitability and the Wenckebach phenomenon in the single guinea pig ventricular myocyte.

The cellular mechanisms of Wenckebach periodicity were investigated in single, enzymatically dissociated guinea pig ventricular myocytes, as well as in computer reconstructions of transmembrane potential of the ventricular cell. When depolarizing current pulses of the appropriate magnitude were delivered repetitively to a well-polarized myocyte, rate-dependent activation failure was observed. Such behavior accurately mimicked the Wenckebach phenomenon in cardiac activation and was the consequence of variations in cell excitability during the diastolic phase of the cardiac cycle. The recovery of cell excitability during diastole was studied through the application of single test pulses of fixed amplitude and duration at variable delays with respect to a basic train of normal action potentials. The results show that recovery of excitability is a slow process that can greatly outlast action potential duration (i.e., postrepolarization refractoriness). Two distinct types of subthreshold responses were recorded when activation failure occurred: one was tetrodotoxin- and cobalt-insensitive (type 1) and the other was sensitive to sodium-channel blockade (type 2). Type 1 responses, which were commonly associated with the typical structure of the Wenckebach phenomenon (Mobitz type 1 block), were found to be the result of the nonlinear conductance properties of the inward rectifier current, IK1. Type 2 sodium-channel-mediated responses were associated with the so-called "millisecond Wenckebach." These responses may be implicated in the mechanism of Mobitz type 2 rate-dependent block. Single-cell voltage-clamp experiments suggest that variations in excitability during diastole are a consequence of the slow deactivation kinetics of the delayed rectifier, IK. Computer simulations of the ventricular cell response to depolarizing current pulses reproduced very closely all the response patterns obtained in the experimental preparation. It is concluded that postrepolarization refractoriness and Wenckebach periodicity are properties of normal cardiac excitable cells and can be explained in terms of the voltage dependence and slow kinetics of potassium outward currents. The conditions for the occurrence of intermittent activation failure during diastole will depend on the frequency and magnitude of the driving stimulus.

Animals↗
PubMed1989

Ionic basis and analytical solution of the wenckebach phenomenon in guinea pig ventricular myocytes.

The ionic mechanisms of slow recovery of cardiac excitability and rate-dependent activation failure were studied in single, enzymatically dissociated guinea pig ventricular myocytes and in computer simulations using a modified version of the Beeler and Reuter model for the ventricular cell. On the basis of our results, we developed a simplified analytical model for recovery of cell excitability during diastole. This model was based on the equations for current distribution in a resistive-capacitive circuit. A critical assumption in the model is that, in the voltage domain of the subthreshold responses, the sodium and calcium inward currents do not play a significant role, and only the two potassium outward currents, the delayed rectifier (IK) and the inward rectifier, are operative. The appropriate parameters needed to numerically solve the analytical model were measured in the guinea pig ventricular myocyte, as well as in the Beeler and Reuter cell. The curves of recovery of excitability and the rate-dependent activation patterns generated by numerical iteration of the analytical model equations closely reproduced the experimental results. Our analysis demonstrates that slow deactivation of the delayed rectifier current determines the observed variations in excitability during diastole, whereas the inward rectifier current determines the amplitude and shape of the subthreshold response. Both currents combined are responsible for the development of Wenckebach periodicities in the ventricular cell. The overall study provides new insight into the ionic mechanisms of rate-dependent conduction block processes and may have important clinical implications as well.

Action Potentials↗
PubMed1987

Low Ba-induced pacemaker current in well-polarized cat papillary muscle.

It has previously been reported that superfusion of normally quiescent mammalian ventricular muscle with low concentrations of Ba (less than 0.3 mM) can induce spontaneous activity with maximum diastolic potentials (MDP) that are similar to the normal resting potential (-80 mV or larger). The mechanism for this activity was studied in cat papillary muscle sucrose-gap preparations under current clamp and voltage-clamp conditions. Hyperpolarizing current pulses decreased or abolished the amplitude of the pacemaker potential in a voltage-dependent manner. When Ba concentration was increased to 2 mM the MDP depolarized by approximately 20 mV. Hyperpolarizing steps under these conditions abolished the diastolic depolarization, also in a voltage-dependent manner. Voltage clamping the preparation at the MDP during superfusion of 0.2 mM Ba revealed a time-dependent, inwardly directed current. Hyperpolarizing voltage-clamp steps from a holding potential of -50 mV showed that this current was maximal at approximately -70 mV and frequently reversed at membrane potentials of approximately -95 to -115 mV. The time course of this current was biexponential, and the time constant of the faster component decreased with larger hyperpolarization. When the same voltage-clamp protocol was repeated in the presence of 2 mM Ba, no time-dependent current change was detected. In four out of five experiments, Cs (2.5 mM) reduced (but never abolished) the amplitude of the low Ba-induced current. Our results do not support the hypothesis that a hyperpolarization-induced current (iF-like current) is responsible for the automaticity in well-polarized ventricular muscle at low Ba concentrations. Instead, our data suggest that this pacemaker activity is the result of a Ba-induced, time-dependent blockade of the inward rectifier potassium current (iK1).

Animals↗
PubMed1987

Effects of increasing intercellular resistance on transverse and longitudinal propagation in sheep epicardial muscle.

Propagation in cardiac muscle is faster in the longitudinal than in the transverse axis of the cells. Yet, as a result of the larger upstroke velocity of action potentials propagating transversely, it has been suggested that longitudinal propagation is more vulnerable to block. To study the relation between conduction velocity and maximal upstroke velocity (Vmax), as well as the time course of conduction delay and block in the transverse vs. longitudinal direction, thin square pieces of sheep epicardial muscle were superfused with the cellular uncoupler heptanol (1.5 mM). Action potentials were recorded with microelectrodes at opposite corners of the preparation while stimulating alternately in the longitudinal or transverse direction with bipolar electrodes located at contralateral corners. In all cases, block occurred more promptly for transverse than for longitudinal propagation. The decrease in conduction velocity was greater than expected for Vmax decay and, in some cases, Vmax increased while conduction velocity decreased. In the presence of high grade conduction impairment, foot potentials appeared and the upstrokes became "notched." We conclude that when intercellular coupling is impaired, transverse propagation is more vulnerable to block, and need not be dependent on changes in Vmax.

Action Potentials↗
PubMed1986

Effects of changes in excitability and intercellular coupling on synchronization in the rabbit sino-atrial node.

The mechanisms of synchronization between sino-atrial pace-maker cells were studied in biological preparations from rabbit hearts, and in computer simulations of the Hodgkin & Huxley type. For biological experiments, thin strips of sino-atrial node were placed in a three-compartment bath. The electrical properties of the tissue in the middle segment (the 'gap') were manipulated pharmacologically to alter electrical coupling and/or excitability of cells in that segment, and to study the patterns of interaction between two pace-maker centres in the external segments. Superfusion of the gap segment with either verapamil (2 microM) or acetylcholine (10 microM) produced a loss of 1:1 synchrony (entrainment) of spontaneous discharges generated by the external pace-makers but subharmonic (i.e. 3:2; 5:4; 9:8; etc.) entrainment was always maintained. When the gap segment was superfused with heptanol (3.5 mM), which is known to increase intercellular resistance, the pace-maker centres in the external chambers beat independently of one another. Progressive loss of synchrony paralleled reductions in amplitude of electrotonic responses to current pulses applied across the gap. Gap superfusion with hypertonic Tyrode solution (600 mosM) produced a major reduction in the degree of synchronization between the external pace-makers, even though the cells in the central compartment maintained their excitability. Under these conditions, as many as three independent pace-maker centres, one in each chamber, coexisted in a given preparation. Using computerized simulations based on equations of time- and voltage-dependent membrane currents, three 'cells', each capable of maintaining spontaneous activity, were connected in a linear array through ohmic resistances. When selective parameters (e.g. membrane conductances, coupling resistance) were modified appropriately, the mathematical simulations reproduced very closely the interaction patterns observed in the experimental preparations. Our results show that synchronization in the sinus node results from mutual interactions and entrainment between all the cells in this region. These interactions are of the kind expected for a population of coupled, self-sustained oscillators, and are mediated through electrotonic propagation of current across low-resistance junctions.

Acetylcholine↗
PubMed1986

Electrophysiological actions of dantrolene sodium in isolated sinoatrial and atrioventricular nodes and in a model of ischemia.

Recent experiments have suggested that the electrophysiological actions of dantrolene sodium in cardiac tissues may be mediated in part by slow inward current blockade. The authors report here the effects of this agent in tissues the electrical activity of which depends mainly on the slow inward current. In isolated rabbit sinoatrial node tissue, dantrolene (35.1 microM) significantly diminished maximal diastolic potential, action potential amplitude and upstroke velocity, and it prolonged action potential duration and spontaneous cycle length. Most effects were reversible upon washout. In isolated rabbit atrioventricular nodal tissue, dantrolene diminished action potential amplitude, delayed activation time, prolonged refractoriness and led to frequency-dependent block, also in a reversible manner. Through these actions, dantrolene showed an antiarrhythmic effect by preventing atrioventricular nodal reentry in the form of atrial "echoes." These results support the hypothesis that dantrolene inhibits slow inward current and suggest that, at adequate doses, it might effectively suppress supraventricular arrhythmias in patients. In a third group of experiments, addition of dantrolene (35.1 microM) to the central segment of a canine Purkinje fiber in an "ischemic gap" preparation led to conduction impairment. Consequently, reflections were obtained at relatively slow frequencies, whereas, at faster frequencies, the incidence of reflection was reduced. These effects were similar to those previously reported for other agents such as lidocaine and verapamil. The authors conclude that dantrolene behaves as a calcium channel blocking agent and has potential value as an antiarrhythmic drug.

Action Potentials↗
PubMedDate not supplied

[Effect of inhibition of converting enzyme by captopril on arterial pressure, renin and aldosterone in essential hypertension].

The response of arterial blood pressure, plasma renin activity (PRA) and plasma (PA) or urinary aldosterone (UA) concentrations to the administration of captopril, was studied in patients with established essential hypertension. Captopril was effective in lowering significantly the blood pressure (189.4/111.2 +/- 23.9/9.7 to 163.4/98.1 +/- 20.7/8.6 mmHg. mean +/- SD, p less than 0.01/0.001). Normal arterial blood pressure values (140.4/86.5 +/- 20.7/10.8 mmHg, were achieved by the addition of hydrochlorothiazide. Captopril administration was followed by a decrease in PA and in UA and an increase in PRA, suggesting the inhibition of angiotensin II formation. Captopril attenuated hypokalemia and hyperaldosteronism produced by the simultaneous administration of hydrochlorothiazide.

Aldosterone↗
PubMedDate not supplied

[Primary aldosteronism. Diagnostic aspects and treatment].

Despite the relatively low frequency of primary aldosteronism, its diagnosis is of great importance because surgical treatment results, in the majority of cases, in the disappearance of arterial hypertension. We present in this paper six cases with this type of secondary hypertension. The disease was suspected by the coexistence of hypertension and hypokalemia. The decrease in serum potassium after an oral load of salt proved to be of great value for the diagnoses. In the five patients treated surgically, the removal of the tumor produced the normalization of the arterial pressure and corrected the biochemical alterations. In four of the patients the tumor was located in the left adrenal gland and in one in the right adrenal gland. The patient not treated surgically has remained normotensive with spironolactone. This data confirm what has been described in the medical literature and emphasizes the importance of a correct diagnosis and treatment in patients with this form of hypertension.

Adenoma↗