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C F Starmer

Publications and source records attributed to C F Starmer.

At least 19 recordsLinked to original sources
PubMed1995

Proarrhythmic response to potassium channel blockade. Numerical studies of polymorphic tachyarrhythmias.

BACKGROUND: Prompted by the results of CAST results, attention has shifted from class I agents that primarily block sodium channels to class III agents that primarily block potassium channels for pharmacological management of certain cardiac arrhythmias. Recent studies demonstrated that sodium channel blockade, while antiarrhythmic at the cellular level, was inherently proarrhythmic in the setting of a propagating wave front as a result of prolongation of the vulnerable period during which premature stimulation can initiate reentrant activation. From a theoretical perspective, sodium (depolarizing) and potassium (repolarizing) currents are complementary so that if antiarrhythmic and proarrhythmic properties are coupled to modulation of sodium currents, then antiarrhythmic and proarrhythmic properties might similarly be coupled to modulation of potassium currents. The purpose of the present study was to explore the role of repolarization currents during reentrant excitation. METHODS AND RESULTS: To assess the generic role of repolarizing currents during reentry, we studied the responses of a two-dimensional array of identical excitable cells based on the FitzHugh-Nagumo model, consisting of a single excitation (sodium-like) current and a single recovery (potassium-like) current. Spiral wave reentry was initiated by use of S1S2 stimulation, with the delay timed to occur within the vulnerable period (VP). While holding the sodium conductance constant, the potassium conductance (gK) was reduced from 1.13 to 0.70 (arbitrary units), producing a prolongation of the action potential duration (APD). When gK was 1.13, the tip of the spiral wave rotated around a small, stationary, unexcited region and the computed ECG was monomorphic. As gK was reduced, the APD was prolonged and the unexcited region became mobile (nonstationary), such that the tip of the spiral wave inscribed an outline similar to a multipetaled flower; concomitantly, the computed ECG became progressively more polymorphic. The degree of polymorphism was related to the APD and the configuration of the nonstationary spiral core. CONCLUSIONS: Torsadelike (polymorphic) ECGs can be derived from spiral wave reentry in a medium of identical cells. Under normal conditions, the spiral core around which a reentrant wave front rotates is stationary. As the balance of repolarizing currents becomes less outward (eg, secondary to potassium channel blockade), the APD is prolonged. When the wavelength (APD.velocity) exceeds the perimeter of the stationary unexcited core, the core will become unstable, causing spiral core drift. Large repolarizing currents shorten the APD and result in a monomorphic reentrant process (stationary core), whereas smaller currents prolong the APD and amplify spiral core instability, resulting in a polymorphic process. We conclude that, similar to sodium channel blockade, the proarrhythmic potential of potassium channel blockade in the setting of propagation may be directly linked to its cellular antiarrhythmic potential, ie, arrhythmia suppression resulting from a prolonged APD may, on initiation of a reentrant wave front, destabilize the core of a rotating spiral, resulting in complex motion (precession) of the spiral tip around a nonstationary region of unexcited cells. In tissue with inhomogeneities, core instability alters the activation sequence from one reentry cycle to the next and can lead to spiral wave fractination as the wave front collides with inhomogeneous regions. Depending on the nature of the inhomogeneities, wave front fragments may annihilate one another, producing a nonsustained arrhythmia, or may spawn new spirals (multiple wavelets), producing fibrillation and sudden cardiac death.

Computer Simulation↗
PubMed1994

Late Na channels in cardiac cells: the physiological role of background Na channels.

Two types of the late Na channels, burst and background, were studied in Purkinje and ventricular cells. In the whole-cell configuration, steady-state Na currents were recorded at potentials (-70 to -80 mV) close to the normal cell resting potential. The question of the contribution of late Na channels to this background Na conductance was investigated. During depolarization, burst Na channels were active for periods (up to approximately 5 s), which exceeded the action potential duration. However, they eventually closed without reopening, indicating the presence of slow and complete inactivation. When, at the moment of burst channel opening, the potential was switched to -80 mV, the channel closed quickly without reopening. We conclude that the burst Na channels cannot contribute significantly to the background Na conductance. Background Na channels undergo incomplete inactivation. After a step depolarization, their activity decreased in time, approaching a steady-state level. Background Na channel openings could be recorded at constant potentials in the range from -120 to 0 mV. After step depolarizations to potentials near -70 mV and more negative, a significant fraction of Na current was carried by the background Na channels. Analysis of the background channel behavior revealed that their gating properties are qualitatively different from those of the early Na channels. We suggest that background Na channels represent a special type of Na channel that can play an important role in the initiation of cardiac action potential and in the TTX-sensitive background Na conductance.

Action Potentials↗
PubMed1994

Open Na+ channel blockade: multiple rest states revealed by channel interactions with disopyramide and quinidine.

In voltage-clamp studies of atrial myocytes exposed to disopyramide or quinidine, pulse-train stimulation revealed use-dependent block that increased with increased pulse amplitude. Use-dependent block also became negligible at hyperpolarized holding potentials (< -150 mV), consistent with either rapid unbinding at the holding potential or trapping of the drug in a drug-complexed rest conformation followed by rapid unbinding during the next channel opening event. To explore the unbinding properties of hypothetically different rest-blocked conformations, we exposed cells to a postdepolarization "conditioning" potential after channels had become fully inactivated so as to vary the transition to different hypothetical rest-blocked channels. Pulse-train stimulation from -130 to -30 mV generated only a small amount of use-dependent block. Inserting a 120-ms subthreshold (e.g., -100 mV) postdepolarization conditioning potential before return to -130 mV increased use-dependent block. The fraction of steady-state block exhibited a bell-shaped dependence on the conditioning potential. These results are consistent with the existence of a mixture of rest-blocked channel conformations, each having direct access to the blocked-inactivated state. These intermediate rest conformations display radically different drug unbinding rates.

Animals↗
PubMed1994

Voltage-independent effects of extracellular K+ on the Na+ current and phase 0 of the action potential in isolated cardiac myocytes.

A rise in [K+]o, by depolarizing the resting membrane potential and partially inactivating the inward Na+ current (INa), is believed to play a critical role in slowing conduction during myocardial ischemia. In multicellular ventricular preparations, elevation of [K+]o has been suggested to decrease Vmax to a greater extent than expected from membrane depolarization alone. The mechanism of this voltage-independent effect of [K+]o is currently unknown, and its significance in single cardiac cells has not been determined. We have examined the voltage-independent effects of elevated [K+]o on INa and the action potential upstroke in isolated rabbit atrial and ventricular myocytes under voltage- and current-clamp conditions. Superfusate [K+] was varied from 5 mmol/L to 14 or 24 mmol/L, whereas [Na+] was maintained at 150 mmol/L. In cultured atrial cells and excised outside-out patches from freshly isolated atrial and ventricular cells, the amplitude and kinetics of INa were unchanged by elevation of [K+]o. In atrial cells, action potentials elicited from a holding potential of -70 mV had a similar Vmax (114.9 +/- 5.7 versus 112.2 +/- 4.8 V/s, mean +/- SEM, n = 6) and action potential amplitude (115.0 +/- 2.4 versus 113.4 +/- 3.9 mV) in 5 and 24 mmol/L [K+]o. In contrast, in ventricular cells at a holding potential of -70 mV, increasing [K+]o fro 5 to 14 mmol/L decreased Vmax from 161.8 +/- 18.0 to 55.3 +/- 5.0 V/s (n = 7, P < .001) and action potential amplitude from 128.1 +/- 1.3 to 86.6 +/- 5.4 mV (P < .001). This voltage-independent decrease in Vmax and action potential amplitude induced by elevated [K+]o was abolished in the presence of 1 mmol/L Ba2+, suggesting that it is attributable to an increased background K+ conductance. We conclude that elevation of [K+]o to levels expected during ischemia causes a marked voltage-independent depression of Vmax in ventricular cells, which may, in turn, contribute to the slowing of myocardial conduction characteristic of early ischemia.

Action Potentials↗
PubMed1994

Combination ethacizin and ethmozin treatment of resistant ventricular ectopy: theoretical, experimental, and clinical study.

Ethmozin (Moricizine HCl) and ethacizin are two class I antiarrhythmic drugs with different rate constants of interaction with the sodium channel. Computer simulation using the "guarded-receptor" model predicted that the combination of ethacizin and ethmozin should exert a greater decrease in excitability and conduction at short coupling intervals, but little effect at normal heart rates (HR). To test this prediction, we measured intraventricular conduction delay in canine hearts in vivo. In agreement with the model, the combination more potently prolonged the delay only at intervals < 600 ms as compared with ethacizin alone. Combination therapy was tested in 6 patients with idiopathic ventricular ectopic depolarizations (VEDs). Three patients were resistant to either ethmozin or ethacizin monotherapy, and three could not tolerate effective doses because of side effects. Quantitative continuous ECG monitoring showed that total VEDs in the resistant group decreased 0 and 17 +/- 13% for 400 and 800 mg/day ethmozin and 18 +/- 12 and 55 +/- 12% for 100 and 200 mg/day ethacizin, respectively. Combined therapy with ethmozin (400 mg/day) and ethacizin (100 mg/day) reduced the number of VEDs by 78 +/- 2% in these patients without side effects. In the "nonresistant" but intolerant group of patients, use of the combination allowed relief of symptomatic ectopy without side effects. A theoretical model correctly predicted an effective combination of class I antiarrhythmic drugs, one with "fast-off" and one with "slow-off" kinetics, which may provide a general rationale for choosing drug combinations.

Adult↗
PubMed1994

Potassium channel blockade amplifies cardiac instability numerical studies of torsades de pointes.

Suppression of responses to premature stimulation has been the guiding principle in managing many cardiac arrhythmias. Recent clinical trails revealed that sodium channel blockade increased the incidence of re-entrant cardiac arrhythmias resulting in sudden cardiac death, although the physiologic mechanism remains uncertain. Potassium channel blockade offers an alternative mechanism for suppressing responses to premature stimuli. We have developed a simple model of a 2D sheet of excitable cells. We can initiate re-entrant activation with stimuli timed to occur within a period of vulnerability (VP). Reducing the Na conductance increases the VP while reducing the K conductance increases the collective instability of the array, and arrhythmias similar to torsades de pointes seen in patients subjected to K channel blocked can be readily initiated. Thus, while K channel blockade may suppress excitability by prolonging the action potential duration, it appears to simultaneously exhibit proarrhythmic properties that result in complex re-entrant arrhythmias.

Action Potentials↗
PubMed1993

Kinetics of interaction of disopyramide with the cardiac sodium channel: fast dissociation from open channels at normal rest potentials.

Block of cardiac sodium channels is enhanced by repetitive depolarization. It is not clear whether the changes in drug binding result from a change in affinity that is dependent on voltage or on the actual state of the channel. This question was examined in rabbit ventricular myocytes by analyzing the kinetics of block of single sodium channel currents with normal gating kinetics or channels with inactivation and deactivation slowed by pyrethrin toxins. At -20 and -40 mV, disopyramide 100 microM blocked the unmodified channel. Mean open time decreased 45 and 34% at -20 and -40 mV during exposure to disopyramide. Exposure of cells to the pyrethrin toxins deltamethrin or fenvalrate caused at least a tenfold increase in mean open time, and prominent tail currents could be recorded at the normal resting potential. The association rate constant of disopyramide for the normal and modified channel at -20 mV was similar, approximately 10 x 10(6)/M/sec. During exposure to disopyramide, changes in open and closed times and in open channel noise at -80 and -100 mV are consistent with fast block and unblocking events at these potentials. This contrasts with the slow unbinding of drug from resting channels at similar potentials. We conclude that the sodium channel state is a critical determinant of drug binding and unbinding kinetics.

Animals↗
PubMed1993

Vulnerability in an excitable medium: analytical and numerical studies of initiating unidirectional propagation.

Cardiac tissue can display unusual responses to certain stimulation protocols. In the wake of a conditioning wave of excitation, spiral waves can be initiated by applying stimuli timed to occur during a period of vulnerability (VP). Although vulnerability is well known in cardiac and chemical media, the determinants of the VP and its boundaries have received little theoretical and analytical study. From numerical and analytical studies of reaction-diffusion equations, we have found that 1) vulnerability is an inherent property of Beeler-Reuter and FitzHugh-Nagumo models of excitable media; 2) the duration of the vulnerable window (VW) the one-dimensional analog of the VP, is sensitive to the medium properties and the size of the stimulus field; and 3) the amplitudes of the excitatory and recovery processes modulate the duration of the VW. The analytical results reveal macroscopic behavior (vulnerability) derived from the diffusion of excitation that is not observable at the level of isolated cells or single reaction units.

Animals↗
PubMed1993

pH dependence of kinetics and steady-state block of cardiac sodium channels by lidocaine.

The local anesthetic-class antiarrhythmic drugs produce greater depression of conduction in ischemic compared with normal myocardium. The basis for this relatively selective action is uncertain. A model of the pH-dependent interaction of tertiary amine drugs with the sodium channel suggests that the low pH occurring during ischemia slows drug dissociation from the channel by changing the drug's protonation. The importance of the proton exchange reaction and the effect of overall slowing of drug dissociation on steady-state sodium channel blockade is uncertain. We have measured whole cell sodium channel current in rabbit atrial myocytes during control and exposure to lidocaine while external pH was varied between 6.8 and 7.8 at membrane potentials of -140, -120, and -100 mV. Tonic blockade was little influenced by external pH. Decreasing the external pH from 7.8 to 6.8 slowed both the rate of development of phasic block and recovery from the block. Decreasing the membrane potential from -140 to -100 mV increased the degree of phasic block attained in the steady state. Block was further enhanced when low pH was combined with membrane depolarization. Experiments in which deuterium ions were substituted for protons suggest that the kinetics of proton exchange is not rate limiting in the dissociation of drugs from the sodium channel. We conclude that it is the combined effect of low pH and membrane depolarization that may be critical in the enhanced blocking action of local anesthetic-class drugs during ischemia.

Animals↗
PubMed1992

Na channel kinetics remain stable during perforated-patch recordings.

The results of studies on modulation of Na channel function are often difficult to interpret due to time-dependent changes in channel kinetics. Although the "tight-seal" whole cell voltage-clamp technique has proved very useful in studying the properties of the cardiac Na current, the spontaneous shift of parameters of inactivation and activation gating to more negative potential is a serious limitation to the use of the technique. The shifts are believed to result from changes in the intracellular milieu effected by dialysis; moreover, use of a variety of different anions and cations in the internal micropipette solution has not obviated the problem. The perforated-patch technique permits low-resistance intracellular access without free dialysis between the intracellular solution and the recording micropipette. We have compared steady-state inactivation and peak current-voltage relationship of whole cell Na currents measured with the conventional whole cell and perforated-patch techniques in rabbit atrial myocytes at 17 degrees C. Although gating parameters shifted to more negative potentials when recorded with the conventional technique, stable kinetics could be observed for up to 150 min with the perforated-patch technique. The potential for one-half Na channel inactivation was -73 +/- 5.1 mV and is consistent with measurements made using indirect techniques such as upstroke velocity measurements. The fact that the intracellular milieu is left relatively intact makes the approach attractive for studying modulation of the Na current by neurotransmitters and hormones.

Animals↗
PubMed1992

Cardiac instability amplified by use-dependent Na channel blockade.

Drugs that exhibit use-dependent Na channel blockade, including antiarrhythmic agents, tricyclic antidepressants, opiate-like analgesics, and cocaine, are linked with an increased susceptibility to cardiac arrhythmias and sudden death. Computer simulations indicate that Na channel blockade retards recovery of excitability, thereby increasing the spatial dispersion of refractoriness, a precursor of many cardiac arrhythmias. In isolated rabbit left atria, stimuli timed to occur at increasing intervals following conditioning stimuli reveal an unstable interval (vulnerable period) during which single stimuli initiate trains of responses. The vulnerable period is extended by use-dependent Na channel blockade and provides a model for assaying proarrhythmic potential and probing cardiac instability.

Animals↗
PubMed1992

Cellular Vmax reflects both membrane properties and the load presented by adjoining cells.

This study was designed to test the hypothesis that the electrical load seen at a microelectrode impalement site is sensitive to the direction of propagation of the approaching wavefront as a reflection of an altered spatial relationship between the impalement site and the surrounding microscopic electrical boundaries located up- and downstream. These boundaries correspond to the different sizes and shapes of the impaled and surrounding cells as well as to the distribution of the associated electrical connections between the cells. The effects of changes in these geometric relationships on maximum rate of rise of transmembrane potential (Vmax) were investigated in canine ventricular muscle by measuring Vmax in different cells while the direction of propagation was changed from along the longitudinal axis to the transverse axis of the fibers or the direction of conduction was reversed along either of these axes. Comparison of the Vmax values for longitudinal propagation (LP) and transverse propagation (TP), each in one direction, showed that TP Vmax was significantly greater than LP Vmax (P < 0.001). However, the values of Vmax were different from cell to cell during LP (93-139 V/s) and TP (110-181 V/s). The absolute values of LP Vmax and TP Vmax at the same site varied independently of each other, e.g., some of the lowest LP Vmax values occurred at the same site as the highest TP Vmax values. Furthermore, at the same site, Vmax changed considerably when propagation was maintained along the longitudinal axis but the direction of conduction was reversed. Similar prominent changes in Vmax occurred when the direction was reversed along the transverse axis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Kinetics of interaction of the lidocaine metabolite glycylxylidide with the cardiac sodium channel. Additive blockade with lidocaine.

The recovery of the sodium channel from blockade by local anesthetic antiarrhythmic drugs is voltage dependent. Recovery from lidocaine-induced blockade is accelerated by hyperpolarization, whereas that from glycylxylidide (GX) blockade has been reported to be slowed by hyperpolarization. This striking difference occurs despite similarities in chemical structure. The fast recovery from GX block at depolarized potentials may lead to a partial reversal of lidocaine blockade when the two drugs are combined. We have examined the kinetics of interaction of GX with the cardiac sodium channel over a range of membrane potentials by measuring whole-cell currents in isolated rabbit myocytes under voltage clamp at 15 degrees C. In the absence of drug, slow inactivation developed with a time constant of 10.7 +/- 5.1 seconds (n = 6). During exposure to 74 mumol/l GX, block developed with a time constant of 7.0 +/- 3 seconds (n = 6). Because of the similar time course of slow inactivation and block, we used a high concentration of GX to induce a level of block sufficient for analysis. The onset of block was slower than that induced by lidocaine and was unaffected by variation of external sodium from 20 to 75 mmol/l. Use-dependent blockade of sodium channels was greater when pulse trains were applied from a holding potential of -100 than -140 mV. This suggested that recovery from GX block might be slower at -100 than -140 mV. Direct measurements gave time constants of recovery of 10.3 +/- 4.2 seconds at -100 mV (n = 6) and 4.1 +/- 0.4 seconds at -140 mV (n = 4). The combination of GX with lidocaine produced only additive blocking effects when pulse trains were applied from both holding potentials. Computer simulations of the requirements for the competitive displacement of a sodium channel blocker with slow kinetics by one with fast kinetics suggest that the recovery time constant of the fast drug must be 10-100-fold smaller than that of the slow drug. Rapid association kinetics effected by a large binding rate constant or a higher concentration of the fast blocking drug is also important. The simulations suggest that, for the interaction of GX and lidocaine, only additive blocking action should be observed over the range of stimulus frequencies used in these experiments.

Animals↗
PubMed1992

Blockade of cardiac sodium channels. Competition between the permeant ion and antiarrhythmic drugs.

A number of basic and clinical studies suggest that elevation of external sodium concentrations, [Na]o, may reverse the cardiotoxic effect of local anesthetic-class drugs. The mechanisms of reversal are uncertain. The blocking action of lidocaine and disopyramide were studied over a range of [Na]o. Both whole-cell voltage clamp and single-channel recordings were performed on isolated rabbit myocytes at 17 and 22 degrees C, respectively. In the presence of lidocaine, an inactivated channel blocker, the level of steady-state block in response to pulse train stimulation was not affected by variations in [Na]o from 20 to 150 mM. Estimates of the rate of dissociation of drug from the channel also were unaffected. In contrast, steady-state block by disopyramide, a drug that blocks open channels, was decreased as [Na]o was increased. Single-channel measurements suggest that the influence of [Na]o on channel current amplitude was small, 12% for a 25 mM increase in [Na]o. This increase in single-channel current amplitude would affect drug-free channels only, in that our studies suggest that drug-associated channels do not conduct. The association rate constant of disopyramide with open single sodium channels was decreased from 10 x 10(6) to 5 x 10(6)/M per s by an increase in [Na]o from 120 to 180 mM. Elevation of [Na]o may reverse the blocking action of local anesthetic-class drugs by an increase in single-channel current amplitude or by a decrease in drug association rate with the sodium channel. The occurrence of the latter action depends on the mode of block of the specific agent.

Animals↗
PubMed1992

A proarrhythmic response to sodium channel blockade: modulation of the vulnerable period in guinea pig ventricular myocardium.

The vulnerable period (VP) is an interval of time during the cardiac cycle within which premature stimulation may lead to trains of responses (one: many stimulus-response coupling). Although the VP parallels the recovery of sodium channel availability, modulators of its boundaries remain unclear. Numerical studies of a uniform cable demonstrated that reduction in sodium channel availability increased the range of premature stimuli, resulting in unidirectional block, a precursor of reentrant activation. Consequently, we hypothesized that the kinetics of use-dependent sodium channel blockade could reflect one dimension of a drug's proarrhythmic potential. In strips from guinea pig right ventricle, we probed the boundaries of the VP in the presence of use-dependent sodium channel antagonists utilizing a train of stimuli followed by a premature stimulus. Under drug-free conditions when the sites of drive and premature stimulation were the same, the VP was less than 4 ms in duration. When the drive and premature sites were different, the drug-free VP was greater than 5 ms in 22 of 24 preparations and 0 in the other two, with an average VP duration of 16 +/- 10 ms (mean +/- SD). In the presence of 1 microM moricizine, VP = 17 +/- 4 ms; 12 microM moricizine, VP = 35 +/- 4 ms; 3 microM flecainide, VP = 50 +/- 17 ms; and 4 microM quinidine, VP = 2 +/- 1 ms. These results suggest that residual unsuppressed premature ventricular contractions (PVCs) in the presence of some class 1 drugs have a greater potential for initiating a proarrhythmic response than PVCs in the absence of a class 1 drug.

Action Potentials↗
PubMed1991

The quantitative investigation of the binding process of calcium blocking drugs in a sinoatrial node.

Application of existing models of sinoatrial node pacemaker activity and of channel-drug interaction allow us to reproduce action potential changes as a result of the blocking effect of drugs. Two calcium antagonistic drugs, nifedipine and mesudipine, were investigated and as a result averaged rate constants of binding and unbinding were evaluated. The procedure applied which is based on experimental results and on computer simulations, can be used as an initial step for comparison of different drugs.

Action Potentials↗