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R W Joyner

Publications and source records attributed to R W Joyner.

At least 37 records · Page 2Linked to original sources
PubMed1996

Modulating L-type calcium current affects discontinuous cardiac action potential conduction.

We have used pairs of cardiac cells (i.e., one real guinea pig ventricular cell and a real-time simulation of a numerical model of a guinea pig ventricular cell) to evaluate the effects on action potential conduction of a variable coupling conductance in combination with agents that either increase or decrease the magnitude of the L-type calcium current. For the cell pairs studied, we applied a direct repetitive stimulation to the real cell, making it the "leader" cell of the cell pair. We have demonstrated that significant delays in action potential conduction for a cell pair can occur either with a decreased value of coupling conductance or with an asymmetry in size such that the follower cell is larger than the leader cell. In both conditions we have shown that isoproterenol, applied to the real cell at very low concentrations, can reversibly decrease the critical coupling conductance (below which action potential conduction fails) for a cell pair with fixed cell sizes, or, for a fixed value of coupling conductance, increase the maximum allowable asymmetry in cell size for successful conduction. For either of these effects, we were able to show that treatment of the real cell with BayK 8644, which more specifically increases the magnitude of the L-type calcium current, was able to mimic the actions of isoproterenol. Treatment of the leader cell of the cell pair (the real cell) with nifedipine, which selectively lowers the magnitude of the L-type calcium current, had effects opposite those of isoproterenol or BayK 8644. The actions of nifedipine, isoproterenol, and BayK 8644 are all limited to conditions in which the conduction delay is on the order of 5 ms or more, whether this delay is caused by limited coupling conductance or by asymmetry in size of the cells. This limitation is consistent with the time course of the L-type calcium current and suggests that the effects of calcium channel blockers or beta-adrenergic blocking drugs, in addition to being selective for regions of the heart that depend on the L-type calcium current for the upstroke of the action potential, would also be somewhat selective for regions of the heart that have discontinuous conduction, either normally or because of some pathological condition.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1996

Action potential conduction between a ventricular cell model and an isolated ventricular cell.

We used the Luo and Rudy (LR) mathematical model of the guinea pig ventricular cell coupled to experimentally recorded guinea pig ventricular cells to investigate the effects of geometrical asymmetry on action potential propagation. The overall correspondence of the LR cell model with the recorded real cell action potentials was quite good, and the strength-duration curves for the real cells and for the LR model cell were in general correspondence. The experimental protocol allowed us to modify the effective size of either the simulation model or the real cell. 1) When we normalized real cell size to LR model cell size, required conductance for propagation between model cell and real cell was greater than that found for conduction between two LR model cells (5.4 nS), with a greater disparity when we stimulated the LR model cell (8.3 +/- 0.6 nS) than when we stimulated the real cell (7.0 +/- 0.2 nS). 2) Electrical loading of the action potential waveform was greater for real cell than for LR model cell even when real cell size was normalized to be equal to that of LR model cell. 3) When the size of the follower cell was doubled, required conductance for propagation was dramatically increased; but this increase was greatest for conduction from real cell to LR model cell, less for conduction from LR model cell to real cell, and least for conduction from LR model cell to LR model cell. The introduction of this "model clamp" technique allows testing of proposed membrane models of cardiac cells in terms of their source-sink behavior under conditions of extreme coupling by examining the symmetry of conduction of a cell pair composed of a model cell and a real cardiac cell. We have focused our experimental work with this technique on situations of extreme uncoupling that can lead to conduction block. In addition, the analysis of the geometrical factors that determine success or failure of conduction is important in the understanding of the process of discontinuous conduction, which occurs in myocardial infarction.

Action Potentials↗
PubMed1996

Discontinuous conduction at Purkinje-ventricular muscle junction.

Conduction through the cardiac syncytium varies from being nearly continuous, with very well coupled cells, to being clearly discontinuous, with significant conduction delays over very short distances. The Purkinje-ventricular muscle junction (PVJ) sites on the endocardial surface have characteristic delays of conduction and the presence of discrete groups of cells that suggest significant discontinuities of the conduction process at PVJ sites, as compared with the more nearly continuous conduction within either the Purkinje or the ventricular muscle layers of the papillary muscle. The purpose of the present study was to examine the relative sensitivity of conduction at PVJ sites versus conduction within the Purkinje or the ventricular muscle layer of the canine papillary muscle to agents that modulate L-type calcium current. We have used cadmium as a relatively specific blocker of L-type calcium current and isoproterenol as an agent to increase L-type calcium current to test the hypothesis that discontinuous conduction at the PVJ sites would be more sensitive to these agents than would continuous conduction within either the Purkinje layer or the ventricular muscle layer of a canine papillary muscle. Conduction delay at the PVJ sites was significantly increased by cadmium, with some PVJ sites reversibly becoming nonjunctional at 200-400 microM cadmium. Isoproterenol significantly decreased PVJ delay, and this effect was attenuated by carbachol. All of the effects on conduction delay at the PVJ sites were much greater than the effects for the same agents on conduction velocity within either the Purkinje or the ventricular muscle layer of the papillary muscle.

Animals↗
PubMed1996

Model clamp and its application to synchronization of rabbit sinoatrial node cells.

A method for coupling an isolated cardiac cell to a simulated cardiac cell, i.e., the real-time solution of a mathematical model of such cell, has been developed. With this "model clamp" technique, the real cell and the model cell are coupled by any desired value of intercellular coupling conductance, producing the effect of mutual interaction by electrical coupling through gap junctional channels. We implemented the model clamp technique with our previously published model of an isolated rabbit sinoatrial node cell. We used this model clamp system to study synchronization of sinoatrial node cells with regard to the critical value of intercellular coupling conductance required for frequency entrainment and the common interbeat interval during frequency entrainment. This common interbeat interval lay between the intrinsic intervals of the real cell and the model cell, but was closer to that of the intrinsically faster beating cell. Critical coupling conductance increased with increasing difference in intrinsic interbeat interval of the real cell and the model cell and ranged between 50 and 300 pS in 11 hybrid cell pairs.

Action Potentials↗
PubMed1995

Developmental changes in modulation of contractility of rabbit hearts.

We recently described postnatal developmental differences of beta-adrenergic- and G-protein-mediated modulation of L-type calcium currents (ICa) in newborn and adult rabbit heart. To extend the results obtained by ICa experiments, we studied developmental changes in modulation of contractility induced by isoproterenol (ISO), forskolin (FOR) and isobutyl-methylxanthine (IBMX), all of which work through the cyclic AMP-dependent pathway. Left ventricular developed pressure (LVDP) and its first derivative (dP/dt) were measured with an intraventricular fluid-filled balloon in isolated adult and newborn (ages 1-3 days) rabbit hearts under Langendorff perfusion. ISO increased LVDP and +/- dP/dtmax dose dependently, with much greater positive inotropic effect on adult than on newborn heart. Concomitant use of a subthreshold concentration of IBMX (0.1 microM), a nonselective phosphodiesterase inhibitor (PDEI), did not significantly potentiate the dose-dependent inotropic effect of ISO in adult heart, but did markedly potentiate such effect in newborn heart. ISO 10 microM and FOR 10 microM had comparable inotropic effects on adult heart, whereas 10 microM ISO had a much weaker inotropic effect than 10 microM FOR on newborn heart. However, the increase in LVDP and +dP/dtmax and the percentage increase in these values induced by 10 microM FOR in newborn heart was still significantly lower than that in adult heart. Newborn heart has less effective signal transduction from beta-adrenergic stimulation (ISO) to increased contractility than does adult heart. Although newborn heart responds more to direct stimulation of adenylyl cyclase activity (FOR) than to beta-adrenergic stimulation, it still has less overall contractile reserve than adult heart. PDE isozymes of newborn heart are much more sensitive to IBMX than are those of adult heart, producing a significant potentiation of ISO effect by low doses of IBMX in newborn, but not adult, heart.

1-Methyl-3-isobutylxanthine↗
PubMed1995

Calcium currents of ventricular cell pairs during action potential conduction.

We have studied the L-type calcium current that occurs during action potential conduction between an isolated pair of guinea pig ventricular cells. To accomplish this, we first recorded action potentials from the leader cell (stimulated cell, cell 1) and the follower cell (nonstimulated cell, cell 2) with a fixed coupling resistance between the cells supplied by a coupling clamp circuit. We then applied these recorded action potentials as command potential waveforms for other cells studied in the voltage-clamp mode in which internal and external solutions that isolated the L-type calcium current were used. The action potential waveform of the leader cell had a rapid upstroke and then a partial repolarization during the conduction delay before activation of the follower cell. The L-type calcium current occurred with a large magnitude during the conduction delay for the leader cell but not for the follower cell. This leads to an asymmetry of calcium current for the two cells, with greater calcium current for the leader cell than for the follower cell. When we reversed the direction of conduction for cell 1 and cell 2 by stimulating cell 2, we found that application of these recorded waveforms for the action potentials for cell 1 and cell 2 to the voltage-clamped cells also reversed the asymmetry of the magnitude of the calcium current. We conclude that discontinuous conduction in cardiac tissue is associated with a directionally determined asymmetry in the magnitude of the calcium current, with the leader cell experiencing a greater peak calcium current than the follower cell.

Action Potentials↗
PubMed1994

Postnatal changes in the G-proteins, cyclic nucleotides and adenylyl cyclase activity in rabbit heart cells.

We have studied the postnatal changes in the levels of isoforms of stimulatory (Gs) and inhibitory (Gi) G-proteins, cAMP and cGMP in washed particulate membranes (WPM) from whole ventricles as well as from isolated ventricular myocytes and have also measured adenylyl cyclase (AC) activity in WPM prepared from isolated myocytes of adult (AD) and newborn (NB) rabbit heart. Immunoblot analysis for the levels of Gi alpha 1, G alpha 2, Gi alpha 3 and Gs alpha subunits showed that Gi alpha 2 and Gi alpha 3 were higher in WPM from whole ventricles of NB compared to AD. This ratio was much higher in WPM from isolated ventricular myocytes since Gi alpha 2 and Gi alpha 3 were either absent or present in extremely low immunodetectable levels in WPM from AD ventricular myocytes. Gi alpha 1 levels were not different for AD compared to NB WPM, whether prepared from whole ventricle or from isolated myocytes. Two forms of Gs alpha, a small form (Gs alpha-S) and a large form (Gs alpha-L), were immunodetected at 43 and 48 kDa, respectively. The Gs alpha-S form was higher in AD WPM and the Gs alpha-L form was higher in NB WPM while the total Gs alpha(L+S) was not different. The Gs alpha results for WPM from isolated myocytes were not different from the results for WPM from whole ventricles. Basal levels of cAMP were 80% higher in NB compared to AD whole ventricles and were 200% higher in NB compared to AD isolated myocytes. Levels of cGMP were 4-5 fold higher in NB than in AD myocytes and ventricular tissue. Basal AC activity was higher in NB than in AD WPM from isolated myocytes and was enhanced by Gpp(NH)p pretreatment in AD but not in NB WPM. The isoproterenol-induced increase in AC activity was higher in AD compared to NB WPM and was completely abolished by Gpp(NH)p pretreatment in NB but not in AD WPM. Forskolin caused a greater increase in AC activity in NB than in AD WPM. The post-natal decrease in the levels of Gi alpha 2 and Gi alpha 3, particularly in isolated ventricular myocytes, may help to explain the smaller effects of isoproterenol and greater muscarinic influence on ICa, as we previously showed, and the smaller effect of isoproterenol on AC activity in NB compared to AD WPM.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenylyl Cyclases↗
PubMed1994

Developmental changes in the actions of phosphatase inhibitors on calcium current of rabbit heart cells.

We used whole-cell voltage clamp to compare the modulation of calcium current density (ICa, picoampere per picofarad) of freshly isolated, adult and newborn rabbit heart in response to intracellular application of microcystin and okadaic acid, both of which block phosphatase activity of phosphatase type 1 and 2A. Newborn cells showed a much larger response to the intracellular application of either microcystin or okadaic acid than did adult cells. In newborn cells, the application of microcystin produced an increase in ICa which appeared to maximize ICa, as shown by the rise in ICa to levels which could be reached by application of 10 microM forskolin or by the intracellular application of 200 microM 3',5'-cyclic adenosine monophosphate (cAMP). In adult cells, the maximal response to microcystin was considerably less than that obtainable with forskolin or cAMP. After achieving a maximal response with microcystin, the addition of forskolin increased ICa further in adult cells but elicited no additional response in newborn cells. The treatment of cells with 0.1 microM isoproterenol, a concentration approximately equal to that required for a half-maximal response, strongly potentiated the effect of microcystin in newborn cells, but not in adult cells. We propose that newborn rabbit heart cells compared with adult rabbit heart cells have a greater level of protein phosphatase activity (perhaps combined with a somewhat greater kinase activity), a greater proportion of the protein phosphatase activity in the form of protein phosphatase type 1 (which is inhibited by isoproterenol) and a greater dependence on the inhibition of protein phosphatase as a mechanism of action of isoproterenol, compared with the increase in kinase activity on calcium channels.

Animals↗
PubMed1994

An experimental model of the production of early after depolarizations by injury current from an ischemic region.

An ischemic myocardial region contains cells with a depolarized resting membrane potential. This depolarization leads to an intercellular current flow between the ischemic region and the surrounding normal myocardial cells which has been termed an "injury current". We have devised an experimental model system in which an isolated guinea pig ventricular cell is electrically coupled to a model depolarized cell in order to evaluate the effects of this injury current on the electrical properties of a normal ventricular cell exposed to drugs which increase calcium current or decrease potassium current. Using low doses of isoproterenol, forskolin, or Bay K 8644 (or 8-bromo-cyclic adenosine monophosphate in the pipette) we found that the action potential duration of the isolated cell was lengthened, but that early afterdepolarizations (EADs) were not produced unless the cell was also coupled to a depolarized cell model representing an adjacent ischemic region. A similar prolongation of the action potential was produced by low doses of quinidine, but EADs were not produced unless coupling to a depolarized cell model was added. EADs could not be produced in any cells in the absence of the drugs even though the coupling to the depolarized cell model was increased up to the level at which the action potential was indefinitely prolonged. At higher isoproterenol concentrations, EADs or spontaneous activity were produced without coupling to the depolarized cell model. Under these conditions, coupling of the cell to a cell model with normal resting membrane potential stopped the spontaneous activity and prevented the occurrence of EADs even with high levels of resistive coupling.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1994

Developmental changes in modulation of calcium currents of rabbit ventricular cells by phosphodiesterase inhibitors.

BACKGROUND: We have previously shown major differences in beta-adrenergic and muscarinic modulation of L-type calcium currents (ICa) in newborn and adult rabbit heart. However, little is known about developmental changes in modulation of ICa by phosphodiesterases (PDEs), which also regulate intracellular cAMP concentration by its hydrolysis. METHODS AND RESULTS: Enzymatically isolated adult and newborn (1- to 3-day-old) rabbit ventricular myocytes were used to study the effects of PDE inhibitors on ICa measured by the whole-cell patch-clamp method. 3-Isobutyl-1-methyl-xanthine (IBMX), a nonselective PDE inhibitor, increased ICa in a dose-dependent manner for both groups. The maximal effect of IBMX, expressed as percentage increase in ICa over control levels, was greater for newborn myocytes than for adult myocytes, but the effects of IBMX applied alone were observed only at concentrations > 10 mumol/L. The concomitant use of 0.1 mumol/L isoproterenol produced a significant potentiation of the IBMX effect on ICa, with a significant additive effect of IBMX in newborn myocytes even at 0.05 mumol/L IBMX. The concomitant use of a subthreshold concentration of IBMX (0.1 mumol/L) did not potentiate the dose dependence of adult ICa on isoproterenol but did markedly potentiate the dose dependence of newborn ICa on isoproterenol. The Emax and EC50 of isoproterenol in the presence of 0.1 mumol/L IBMX on newborn ICa were 235% and 8 nmol/L, respectively, whereas the Emax and EC50 of isoproterenol in the absence of IBMX on newborn ICa were 111% and 81 nmol/L, respectively. The addition of 50 mumol/L IBMX to 10 mumol/L isoproterenol markedly increased the newborn ICa density up to a level equivalent to that reached with 200 mumol/L cAMP in the pipette (14.9 +/- 1.2 versus 13.4 +/- 0.7 pA/pF). Our data suggest that the inhibition constant (Ki) of IBMX for inhibiting PDEs that participate in the regulation of ICa is much lower in newborn than in adult myocytes. Milrinone 1 mumol/L, a selective PDE III inhibitor, increased the 0.1 mumol/L isoproterenol-stimulated ICa of adult myocytes but had no significant additive effect for the 0.1 mumol/L isoproterenol-stimulated ICa of newborn myocytes. Rolipram 1 mumol/L, a selective PDE IV inhibitor, increased the 0.1 mumol/L isoproterenol-stimulated ICa for newborn myocytes but had no significant additive effect for the 0.1 mumol/L isoproterenol-stimulated ICa for adult myocytes. CONCLUSIONS: These results suggest that the most important PDE isozyme for regulation of ICa of rabbit myocytes changes from PDE IV to PDE III during the postnatal period.

1-Methyl-3-isobutylxanthine↗
PubMed1993

Postnatal decrease in muscarinic cholinergic influence on Ca2+ currents of rabbit ventricular cells.

We have studied developmental changes in the muscarinic cholinergic modulation of L-type Ca2+ current (ICa) in enzymatically isolated adult and newborn (1-4 days old) rabbit ventricular cells using the whole-cell patch-clamp method. Carbachol (10 microM) caused a 2.8-fold increase in the half-maximal concentration (EC50) for isoproterenol to stimulate ICa for adult cells compared with the control with little effect on the maximal ICa density (Imax), whereas the stimulatory effect of isoproterenol on newborn ICa was completely eliminated by 10 microM of carbachol and was decreased by 40% at 0.1 microM carbachol. Carbachol increased the EC50 for forskolin to stimulate ICa 2.9-fold for adult cells and 7.3-fold for newborn cells with little effect on the Imax for either group. 5'-Guanylyl imidodiphosphate [Gpp(NH)p; 100 microM] reduced the stimulatory effect of 0.1 microM isoproterenol on adult ICa (percent increase over predrug level) by a factor of 1.8 compared with the control (400 microM guanosine triphosphate), whereas the isoproterenol effect on newborn ICa was completely eliminated by Gpp(NH)p. The isoproterenol effect on adult ICa persisted after the washout of isoproterenol in the presence of Gpp(NH)p. Gpp(NH)p also reduced the stimulatory effect of 1 microM of forskolin by a factor of 2.0 and 8.2 for adult and newborn cells, respectively, in comparison to the control. Carbachol caused no additional effect on forskolin-stimulated ICa for either adult or newborn ICa in the presence of Gpp(NH)p. Pretreatment with pertussis toxin completely eliminated the inhibitory effect of carbachol on forskolin-stimulated ICa for both groups. In addition, the effect of forskolin on ICa was markedly enhanced by the pertussis toxin pretreatment in newborn cells, whereas the enhancement was relatively small for adult cells. We conclude that the muscarinic cholinergic influence on L-type ICa decreases after birth in rabbit ventricular cells, presumably through a diminishing influence of an inhibitory G protein on regulating adenylyl cyclase during the postnatal period.

Adenylate Cyclase Toxin↗
PubMed1992

Action potential conduction between guinea pig ventricular cells can be modulated by calcium current.

We used cell pairs electrically coupled with relatively high intercellular resistance to investigate the involvement of calcium current in the origin of the source current during the conduction process of the action potential (AP). Three interventions were used to reduce the calcium current: a specific calcium channel blocker [nifedipine (NIF)], premature stimulation, and increments in the frequency of stimulation of the cell. The ionic membrane current (Iion) after the peak of the AP of the stimulated cell was positive and small when the cell was uncoupled. However, when the stimulated cell was coupled to a cell model or to another cell, Iion during this period became negative and large to supply the coupling current. A rapid early repolarization of the AP occurred in the stimulated cell because of the removal of charge from the stimulated cell. NIF decreased the magnitude of the net negative Iion during this period and caused a more rapid early repolarization in the stimulated cell. NIF increased the delay between the activations of two coupled cells at a given coupling resistance (Rc) but decreased the longest delay that could be produced without conduction failure for a given cell pair. The highest Rc below which conduction of AP occurred was also decreased by NIF. Premature stimulation and an increase of the stimulation frequency also caused an increase in the extent of the early repolarization and increased the delay between two cell activations at a given Rc. Conduction block occurred with sufficient prematurity or at a sufficiently high frequency of stimulation even though activation of the stimulated cell occurred for each stimulus. The Iion that flows during the early plateau phase of the AP in the stimulated cell became negative and significantly large by coupling two cardiac cells together. This current flow is a major component needed to supply the coupling current through the intercellular resistance. The decrease of calcium current caused a decrease in the magnitude of this net inward ionic current, resulting in an increase of the rate of early repolarization and an increase in the conduction delay between two cells at a given Rc. These results suggest the involvement of calcium current in the conduction process when cells are coupled at relatively high Rc.

Action Potentials↗
PubMed1992

Developmental changes in the beta-adrenergic modulation of calcium currents in rabbit ventricular cells.

We studied the developmental changes in the beta-adrenergic modulation of L-type calcium current (ICa) in enzymatically isolated adult (AD) and newborn (NB, 1-4-day-old) rabbit ventricular cells using the whole-cell patch-clamp method. ICa was measured as the peak inward current at a test potential of +15 mV by applying a 180-450-msec pulse from a holding potential of -40 mV with Cs(+)-rich pipettes and a K(+)-free bath solution at room temperature. In control, ICa density (obtained by normalizing ICa to the cell capacitance) was significantly higher in AD cells (5.5 +/- 0.2 [mean +/- SEM] pA/pF, n = 65) than in NB cells (2.6 +/- 0.1 pA/pF, n = 60). Isoproterenol (ISO, 1 nM-30 microM) increased ICa in a dose-dependent manner for both groups. The maximal effect (Emax) of ISO, expressed as percent increase in ICa over control levels, and the concentration for one half of the maximal effect (EC50) were 203% and 51 nM, respectively, for AD cells and 111% and 81 nM, respectively, for NB cells. The effect of ISO (1 microM) on ICa was decreased as the test potential was increased from -10 to +40 mV. However, the ratio of the percent increase in ICa for AD versus NB cells was almost constant (2.09-2.45) at each test potential. Dose-response curves of forskolin (FOR, 0.3-50 microM) gave Emax and EC50 of 268% and 0.74 microM, respectively, for AD cells and 380% and 1.15 microM, respectively, for NB cells. After stimulating ICa by 10 microM ISO, the addition of 10 microM FOR produced a further increase in ICa of only 12 +/- 2% in AD cells (n = 4) but a further increase of 140 +/- 41% in NB cells (n = 6). FOR (10 microM) did not produce any increase in ICa for AD and NB cells after stimulating ICa by intracellular application of 200 microM cAMP. ICa density stimulated by 10 microM ISO (17.8 +/- 1.1 pA/pF, n = 7), 10 microM FOR (21.0 +/- 1.3 pA/pF, n = 8), or 200 microM cAMP (18.0 +/- 1.3 pA/pF, n = 5) was equivalent in AD cells, whereas ICa density stimulated by 10 microM ISO (5.8 +/- 0.6 pA/pF, n = 9) was significantly lower than that stimulated by either 10 microM FOR (13.8 +/- 1.5 pA/pF, n = 7) or 200 microM cAMP (13.4 +/- 0.7 pA/pF, n = 7) in NB cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed1991

Unidirectional block between isolated rabbit ventricular cells coupled by a variable resistance.

We have used pairs of electrically coupled cardiac cells to investigate the dependence of successful conduction of an action potential on three components of the conduction process: (a) the amount of depolarization required to be produced in the nonstimulated cell (the "sink" for current flow) to initiate an action potential in the nonstimulated cell, (b) the intercellular resistance as the path for intercellular current flow, and (c) the ability of the stimulated cell to maintain a high membrane potential to serve as the "source" of current during the conduction process. We present data from eight pairs of simultaneously recorded rabbit ventricular cells, with the two cells of each pair physically separated from each other. We used an electronic circuit to pass currents into and out of each cell such that these currents produced the effects of any desired level of intercellular resistance. The cells of equal size (as assessed by their current threshold and their input resistance for small depolarizations) show bidirectional failure of conduction at very high values of intercellular resistance which then converts to successful bidirectional conduction at lower values of intercellular resistance. For cell pairs with asymmetrical cell sizes, there is a large range of values of intercellular resistance over which unidirectional block occurs with conduction successful from the larger cell to the smaller cell but with conduction block from the smaller cell to the larger cell. We then further show that one important component which limits the conduction process is the large early repolarization which occurs in the stimulated cell during the process of conduction, a process that we term "source loading."

Action Potentials↗
PubMed1991

Cellular mechanisms of delayed recovery of excitability in ventricular tissue.

It is well established that ventricular tissue, under some conditions, exhibits the phenomenon of postrepolarization refractoriness (PRR) in which the tissue excitability is depressed after an action potential. We have done parallel experiments on rabbit papillary muscles and on isolated rabbit ventricular cells to explain the cellular basis of this phenomenon, using elevated extracellular K+ concentration ([K+]o) (8 mM) to depolarize the tissue and the isolated cells. For isolated cells, we could separately measure cellular excitability (the inverse of the cellular current threshold) and the cellular responsiveness (the ability of the cell to generate inward current after excitation has occurred). We present two hypotheses that could explain the magnitude and time course of tissue PRR in terms of either changes in cellular excitability or changes in cellular responsiveness. We show that, although small changes in cellular excitability do occur, the predominant cellular mechanism for tissue PRR is the time course of recovery of the cellular responsiveness.

Action Potentials↗
PubMed1991

Developmental changes in calcium currents of rabbit ventricular cells.

We investigated the postnatal development of L-type Ca2+ current (ICa) in enzymatically isolated adult (AD) and newborn (NB) (1-3-day-old) rabbit ventricular cells using the whole-cell, patch-clamp method. ICa was recorded with Cs(+)-rich pipettes and a Na(+)- and K(+)-free bath solution at 36 degrees C to eliminate other currents. ICa density (obtained by normalizing ICa to the cell capacitance) was significantly higher in AD cells than in NB cells at potential levels between 0 and +50 mV with 1.8 mM Ca2+ as the charge carrier. There was no shift in the current-voltage relation between AD and NB cells. The maximum ICa density was 9.9 +/- 2.0 pA/pF at 14 +/- 5 mV in AD cells (n = 11) compared with 5.6 +/- 2.0 pA/pF at 13 +/- 5 mV in NB cells (n = 7) (mean +/- SD). Time to half inactivation (T 1/2) showed a nearly U-shaped relation to membrane potentials from -10 to +30 mV with the shortest T 1/2 at the potential giving the maximum ICa density in both groups. T 1/2 at 0 and +10 mV was slightly but significantly longer in NB cells (16.8 +/- 4.6 and 13.5 +/- 2.4 msec, respectively) than in AD cells (12.6 +/- 3.0 and 10.6 +/0 1.5 msec).(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium Channels↗
PubMed1991

Experimental model of effects on normal tissue of injury current from ischemic region.

An ischemic myocardial region contains cells with a depolarized resting membrane potential. This depolarization leads to an intercellular current flow between the ischemic region and the surrounding normal myocardial cells, which has been termed an "injury current." We have devised an experimental model system in which an isolated rabbit ventricular cell is electrically coupled to a model depolarized cell to evaluate the effects of this injury current on the electrical properties of a normal ventricular cell. We found that the action potential duration of the isolated cell could be reversibly altered by varying the coupling resistance such that the action potential duration was shortened by high values of coupling resistance but could be considerably prolonged by lower resistance coupling. We did not observe automaticity in the isolated cell as a consequence of coupling to the depolarized model. The changes in action potential duration were accompanied by alterations in the frequency at which the isolated cell could respond to repetitive stimuli. In addition, the depolarization of the isolated cell produced by the electrical coupling led to a significant increase in the cellular excitability. This last effect may be of particular importance in understanding the mechanisms for origination of arrhythmias in the border zone of myocardial ischemia.

Action Potentials↗