On the neural connection.

Discoveries concerning cardiac neural-electrical modulation and local neural remodeling provide powerful new approaches for the development of novel antiarrhythmic strategies. This "view" of developments in this emerging field highlights recent advances and suggests that additional neurally targeted investigations have considerable potential for prevention of arrhythmic diseases.

Pharmacological block of the slow component of the outward delayed rectifier current (I(Ks)) fails to lengthen rabbit ventricular muscle QT(c) and action potential duration.

1. The effects of I(Ks) block by chromanol 293B and L-735,821 on rabbit QT-interval, action potential duration (APD), and membrane current were compared to those of E-4031, a recognized I(Kr) blocker. Measurements were made in rabbit Langendorff-perfused whole hearts, isolated papillary muscle, and single isolated ventricular myocytes. 2. Neither chromanol 293B (10 microM) nor L-735,821 (100 nM) had a significant effect on QTc interval in Langendorff-perfused hearts. E-4031 (100 nM), on the other hand, significantly increased QTc interval (35.6+/-3.9%, n=8, P<0.05). 3. Similarly both chromanol 293B (10 microM) and L-735,821 (100 nM) produced little increase in papillary muscle APD (less than 7%) while pacing at cycle lengths between 300 and 5000 ms. In contrast, E-4031 (100 nM) markedly increased (30 - 60%) APD in a reverse frequency-dependent manner. 4. In ventricular myocytes, the same concentrations of chromanol 293B (10 microM), L-735,821 (100 nM) and E-4031 (1 microM) markedly or totally blocked I(Ks) and I(Kr), respectively. 5. I(Ks) tail currents activated slowly (at +30 mV, tau=888.1+/-48.2 ms, n=21) and deactivated rapidly (at -40 mV, tau=157.1+/-4.7 ms, n=22), while I(Kr) tail currents activated rapidly (at +30 mV, tau=35.5+/-3.1 ms, n=26) and deactivated slowly (at -40 mV, tau(1)=641.5+/-29.0 ms, tau(2)=6531+/-343, n=35). I(Kr) was estimated to contribute substantially more to total current density during normal ventricular muscle action potentials (i.e., after a 150 ms square pulse to +30 mV) than does I(Ks). 6. These findings indicate that block of I(Ks) is not likely to provide antiarrhythmic benefit by lengthening normal ventricular muscle QTc, APD, and refractoriness over a wide range of frequencies.

Multiple agents potentiate alpha1-adrenoceptor-induced conduction depression in canine cardiac purkinje fibers.

BACKGROUND: Halothane more so than isoflurane potentiates an alpha1-adrenoceptor (alpha1-AR)-mediated action of epinephrine that abnormally slows conduction in Purkinje fibers and may facilitate reentrant arrhythmias. This adverse drug interaction was further evaluated by examining conduction responses to epinephrine in combination with thiopental and propofol, which "sensitize" or reduce the dose of epinephrine required to induce arrhythmias in the heart, and with etomidate, which does not, and responses to epinephrine with verapamil, lidocaine, and l-palmitoyl carnitine, a potential ischemic metabolite. METHODS: Action potentials and conduction times were measured in vitro using two microelectrodes in groups of canine Purkinje fibers stimulated at 150 pulses/min. Conduction was evaluated each minute after exposure to 5 microm epinephrine (or phenylephrine) alone or with the test drugs. Changes in the rate of phase 0 depolarization (Vmax) and the electrotonic spread of intracellular current were measured during exposure to epinephrine with octanol to evaluate the role of inhibition of active and passive (intercellular coupling) membrane properties in the transient depression of conduction velocity. RESULTS: Lidocaine (20 microm) and octanol (0.2 mm) potentiated alpha1-AR-induced conduction depression like halothane (0.4 mm), with maximum depression at 3-5 min of agonist exposure, no decrease of Vmax, and little accentuation at a rapid (250 vs. 150 pulses/min) stimulation rate. Thiopental (95 microm), propofol (50 microm), and verapamil (2 microm) similarly potentiated epinephrine responses, whereas etomidate (10 microm) did not. Between groups, the decrease of velocity induced by epinephrine in the presence of (10 microm) l-palmitoyl carnitine (-18%) was significantly greater than that resulting from epinephrine alone (-6%; 0.05

The role of the delayed rectifier component IKs in dog ventricular muscle and Purkinje fibre repolarization.

1. The relative contributions of the rapid and slow components of the delayed rectifier potassium current (IKr and IKs, respectively) to dog cardiac action potential configuration were compared in ventricular myocytes and in multicellular right ventricular papillary muscle and Purkinje fibre preparations. Whole-cell patch-clamp techniques, conventional microelectrode and in vivo ECG measurements were made at 37C. 2. Action potential duration (APD) was minimally increased (less than 7%) by chromanol 293B (10 microM) and L-735,821 (100 nM), selective blockers of IKs, over a range of pacing cycle lengths (300-5000 ms) in both dog right ventricular papillary muscles and Purkinje fibre strands. D-Sotalol (30 microM) and E-4031 (1 microM), selective blockers of IKr, in the same preparations markedly (20-80%) lengthened APD in a reverse frequency-dependent manner. 3. In vivo ECG recordings in intact anaesthetized dogs indicated no significant chromanol 293B (1 mg kg-1 i.v.) effect on the QTc interval (332.9 +/- 16.1 ms before versus 330.5 +/- 11.2 ms, n = 6, after chromanol 293B), while D-sotalol (1 mg kg-1 i.v.) significantly increased the QTc interval (323.9 +/- 7.3 ms before versus 346.5 +/- 6.4 ms, n = 5, after D-sotalol, P < 0.05). 4. The current density estimated during the normal ventricular muscle action potential (i.e. after a 200 ms square pulse to +30 mV or during a 250 ms long 'action potential-like' test pulse) indicates that substantially more current is conducted through IKr channels than through IKs channels. However, if the duration of the square test pulse or the 'action potential-like' test pulse was lengthened to 500 ms the relative contribution of IKs significantly increased. 5. When APD was pharmacologically prolonged in papillary muscle (1 microM E-4031 and 1 microg ml-1 veratrine), 100 nM L-735,821 and 10 microM chromanol 293B lengthened repolarization substantially by 14.4 +/- 3.4 and 18. 0 +/- 3.4% (n = 8), respectively. 6. We conclude that in this study IKs plays little role in normal dog ventricular muscle and Purkinje fibre action potential repolarization and that IKr is the major source of outward current responsible for initiation of final action potential repolarization. Thus, when APD is abnormally increased, the role of IKs in final repolarization increases to provide an important safety mechanism that reduces arrhythmia risk.

Cardiac effects of non-depolarizing neuromuscular blocking agents pancuronium,vecuronium, and rocuronium in isolated rat atria.

Pancuronium, vecuronium, and rocuronium produce different cardiac effects. Using spontaneously beating right and electrically stimulated left rat atria, while measuring developed force, effective refractory period, and heart rate, we determined and compared the concentration-dependent cardiac effects of the compounds. The preparations were exposed to five progressively increasing concentrations of these compounds (10(-9), 10(-8), 10(-7), 10(-6), and 10(-5) mol/L). Pancuronium increased heart rate; vecuronium and rocuronium produced positive inotropic effects; and vecuronium shortened refractoriness. These effects may be the result of a blockade of the M2 muscarinic receptors. However, the concentrations required to produce changes were higher than those observed in patients under neuromuscular blockade.

Effects of the optical isomers of verapamil on electrophysiological properties of the heart in conscious dogs.

We compared the cumulative dose-response relations of verapamil (0.1, 0.2 and 0.4 mg kg(-1)) in different R/S enantiomer ratios (100/0, 90/10, 80/20, 50/50 and 20/80) on the electrophysiological and hemodynamic characteristics of the heart using the conscious dogs. A reduction of mean arterial pressure occurred with 20R/80S producing a 3-times greater decrease than 100R/0S, but an increase in heart rate occurred with 20R/80S producing a 9-times greater increase than 100R/0S. Increased heart rate was concurrent with decreased mean arterial pressure most prevalent with a higher ratio of S-isomer that produced a greater reduction in mean arterial pressure and increase in heart rate at lower overall verapamil doses. Atrio-ventricular conduction time increased 3-5 min after each infusion, with 20R/80S producing a 4-times greater effect than 100R/0S. These results indicate that the peripheral and cardiac electrophysiologic properties of various nonracemic verapamil mixtures are mainly attributable to the concentration of S-isomer.

The role of glycolysis in myocardial calcium control.

Because glycolysis is thought to be important for maintenance of cellular ion homeostasis, the aim of the present study was to examine the role of glycolysis in the control of cytosolic calcium ([Ca2+]i) and cell shortening during conditions of increased calcium influx. Thus, [Ca2+]i and unloaded cell shortening were measured in fura-2/AM loaded rat ventricular myocytes. All cells were superfused with Tyrode's solution containing glucose and pyruvate (to preserve oxidative metabolism), and glycolysis was inhibited by iodoacetate (IAA, 100 microM). Calcium influx was increased, secondary to an increase in intracellular sodium, by addition of veratrine (1 microgram/ml), or directly by either elevating [Ca2+]o from 2 to 5 mM or by exposing the cells to isoproterenol (1 to 100 nm). Veratrine exposure caused a time-dependent increase in both diastolic and systolic [Ca2+]i that resulted in cellular calcium overload and hypercontraction. The rate of increase in [Ca2+]i was more rapid in IAA-treated than in untreated myocytes, leading to a 13+/-3 v 5+/-2% increase (P<0.05) in diastolic [Ca2+]i after 5 min of exposure. The corresponding increases in systolic [Ca2+]i were 43+/-6 and 24+/-5% (P<0.05). Elevated [Ca2+]o resulted in increased [Ca2+]i transient amplitudes and cell shortening. These responses were each attenuated by inhibiting glycolysis, so that the increase was 38+/-5 v 68+/-9% ([Ca2+]i transient amplitude, P<0.05) and 41+/-11 v 91+/-18% (cell shortening, P<0.05). Inhibition of glycolysis did not, however, affect the increase in calcium transient or cell shortening during addition of isoproterenol. We conclude that glycolysis plays an essential role in the maintenance of intracellular calcium homeostasis during severe calcium overload. Glycolysis was also essential for signalling the inotropic effect that accompanied elevation in extracellular calcium, while the changes in intracellular calcium following administration of isoproterenol were not influenced by glycolysis in the present model.

Action-potential duration and contractility in canine cardiac tissues: action of inotropic drugs.

1. Inotropic and electrophysiologic effects of veratrine, vesnarinone, d-sotalol and tetraethylammonium (TEA) were compared. Action-potential duration (APD) and contractility were measured in isolated canine Purkinje fiber and ventricular trabecular muscle preparations by using standard microelectrode techniques. Each drug significantly increased APD and force development in either tissue. 2. Drug-induced increases in force development were normalized to increases in APD. The order of efficacy was found to be vesnarinone>veratrine>TEA in ventricular myocardium, whereas it was veratrine>>vesnarinone=d-sotalol=TEA in Purkinje fibers. 3. The force-APD relation was linear for all drugs in the concentrations used. 4. Simultaneous measurements of APD, force development and intracellular sodium ion activity (a(i)Na) in the presence of either veratrine or lidocaine indicated a linear relation between force development and changes in a(i)Na. 5. The relation between APD and force development was different in ventricular and Purkinje fiber preparations. Differences in the veratrine sensitivity of the force-APD relation observed between Purkinje and ventricular preparations suggest that a(i)Na-dependent changes in Na+/Ca2+ exchange may play a more important role in regulation of force generation in Purkinje fibers than in ventricular myocardium.

Reversal of hypothermia-induced action potential lengthening by the KATP channel agonist bimakalim in isolated guinea pig ventricular muscle.

1. ATP-sensitive potassium (KATP) channel openers shorten cardiac ventricular muscle action potential duration (APD), reduce resting and developed contractile force, and have been shown to provide cardioprotection when given before, during, and after either short-term ischemia or long-term hypothermia. The authors' aim was to determine the concentration-dependent effect of the potent KATP channel opener bimakalim on transmembrane action potential changes induced by mild (27 degrees C) and moderate (20 degrees C) hypothermia in isolated guinea pig ventricular muscle. 2. Conventional microelectrode techniques were used to record action potentials (APs) in single myocytes during normothermia (37 degrees C) and hypothermia in the presence and absence of 0.1 to 30 mumol.l-1 bimakalim. 3. Hypothermia alone increased APD and depolarized the diastolic membrane potential (DMP): APD90 = 141.7 +/- 7.0 msec and DMP -86.2 +/- 1.4 mV (n = 6) at 37 degrees C versus 235.7 +/- 7.8 msec and -75.6 +/- 1.0 mV at 20 degrees C (n = 7). At 37 degrees C, bimakalim (0.1-10 mumol.l-1) shortened APD in a concentration-dependent fashion. 4. APD90 was markedly reduced from 141.7 +/- 7.0 msec without bimakalim to 9.5 +/- 2.6 msec with 10 mumol.l-1 bimakalim (n = 6); this effect was blocked by glibenclamide. DMP was hyperpolarized by bimakalim. More bimakalim was required to shorten APs during mild and moderate hypothermia. The 50% effective concentration (EC50) of bimakalim required to maximally shorten APD90 was 0.96 +/- 0.10 mumol.l-1 at 37 degrees C; this increased to 3.96 +/- 0.24 mumol.l-1 at 27 degrees C, and to 12.34 +/- 0.72 mumol.l-1 at 20 degrees C. Relative to hypothermia-induced depolarization, bimakalim hyperpolarized DMP toward drug-free values obtained at 37 degrees C. 5. These results indicate that hypothermia shifts the bimakalim concentration APD90 response curve to the right such that 13 times more bimakalim is required at 20 degrees C shorten APD by the same amount as at 37 degrees C. Bimakalim also reverses hypothermia-induced AP lengthening and tends to reverse the hypothermia-induced decrease in DMP. 6. These findings aid in our understanding of the cardioprotective effects of KATP channel openers during hypothermia.

Diazepam-induced Ca(2+)-channel blockade reduces hypothermia-induced electromechanical changes in isolated guinea pig ventricular muscle.

Calcium-channel blockers reduce the in vitro effects of hypothermia and benzodiazepines have been reported to reduce inward calcium flow through L-type cardiac-calcium channels. Thus, this study was designed to determine if diazepam could reduce hypothermia-induced changes in ventricular papillary muscle electromechanical activity. Conventional microelectrode techniques were used while force was recorded using a miniature force transducer. Six experimental groups of electrically paced papillary muscles were formed (n = 6 per group). One was exposed to one microM nisoldipine and four were exposed to one of four diazepam concentrations (0.1, 1.0, 10 or 100 microM). A final group had no drug and provided a time-matched control. The effects were determined at 37 degrees C and then at 27 degrees C. At 37 degrees C, diazepam initially increased and then reduced inotropy and APD90. Nisoldipine reduced both APD90 and inotropy. At 27 degrees C, 100 microM diazepam and nisoldipine (1.0 microM) reduced the hypothermia-induced lengthening of APD and the increase in force. Although diazepam reduced the hypothermia-induced alterations, the concentration required to do so (100 microM) suggests that this effect has little role in clinical use.

Influence of hypothermia on the cardiac effects of propranolol observed in isolated rat atria.

UNLABELLED: 1. The purpose was to determine if hypothermia influences cardiac responses to propranolol. 2. Rat atria were used and 11 test groups were created; 3 control groups were maintained at 35, 28 or 20 degrees C. Two additional groups, at each temperature, were exposed to 1.2 or 40 mumol/l propranolol. Developed force and effective refractory period (ERP) were measured. 3. At 35 degrees C, propranolol decreased developed force and lengthened ERP. At 28 degrees C, propranolol did not affect developed force, but ERP was lengthened. At 20 degrees C, 1.2 microM propranolol neither affected developed force or ERP, but 40 microM reduced developed force and lengthened ERP. CONCLUSION: hypothermia reduced propranolol's usual negative inotropic effect.

Electrical restitution in diseased human ventricular myocardium.

Action potential configuration and electrical restitution were studied in diseased human ventricular muscle by comparing the characteristics of hypertrophic (HYP) and dilated (DIL) human ventricular preparations. Conventional microelectrode techniques were used to evaluate action potentials evoked at increasingly longer diastolic intervals. The steady-state action potential duration (APD90) was significantly longer in DIL than in HYP preparations (393 +/- 5 ms, n = 4 and 296 +/- 11 ms, n = 4, respectively; P < 0.001, mean +/- SEM). In the dilated preparations studied at long diastolic intervals, the initial period of rapid repolarization (phase 1) was absent, and the rate of final repolarization (phase 3) was reduced. Electrical restitution relations in these preparations were fitted as the sum of two exponentials. The time constant of the fast component was significantly longer in DIL than in HYP preparations (242 +/- 9 ms and 121 +/- 4 ms, respectively; P < 0.001). No difference was observed in the time constants for the slow component of restitution in the two groups. Electrical restitution was also studied in single human ventricular myocytes by using patch clamp techniques. The initial 600 ms period of restitution was fitted in these cells to a monoexponential function. The time constant for this period of the restitution relation was significantly longer, while the estimated amplitude of this early rising phase was significantly lower in human cells obtained from DIL hearts than the respective parameters obtained in the healthy canine and guinea pig cells also examined. The observed changes in the restitution kinetics of the dilated human heart are, likely, the consequence of alterations in the ionic currents that underlie the cardiac action potential.

Alteration of the cardiac effects of isoproterenol and propranolol by hypothermia in isolated rat atrium.

1. Hypothermia alters the myocardial response to some inotropic maneuvers. By measuring developed force and effective refractory period in isolated left atrial preparations, we determined whether hypothermia affected the cardiac response to isoproterenol and propranolol. 2. Twelve experimental groups were formed, each consisting of 6 atrial preparations. Three groups maintained at either 35, 28 or 20 degrees C served to determine the effects of hypothermia alone. 3. At each temperature, 3 additional groups were exposed to 1.0 microM isoproterenol alone or in combination with either 0.3 or 10.0 microM propranolol. At 35 degrees C, isoproterenol produced an increase in developed force and decreased effective refractory period. Propranolol reversed these isoproterenol-induced effects in a concentration-dependent manner. 4. Decreasing temperature to either 28 or 20 degrees C significantly increased developed force and effective refractory period. At 28 degrees C, isoproterenol no longer produced a significant increase in developed force, although effective refractory period was still decreased. At 20 degrees C, isoproterenol significantly reduced both developed force and effective refractory period. These effects of isoproterenol were reversed by the addition of propranolol, so that the effective refractory period was increased and developed force was not different from that observed at 20 degrees C in the absence of isoproterenol. 5. These effects of isoproterenol might be explained by effects on Na+/Ca(2+)-exchange.

Alteration of the cardiac effects of midazolam by hypothermia in rat isolated atria.

Hypothermia produces marked changes in cardiac activity and response to different anesthetic interventions. Isolated spontaneously beating right, or electrically stimulated left rat atria were examined while heart rate, sinus node recovery time, developed force, and effective refractory period were measured at 35 and 20 degrees C. Thus, we wanted to investigate the influence of low temperature on the cardiac effects of midazolam. The preparations were exposed to seven progressively increasing concentrations of midazolam. At 35 degrees C, midazolam produced a concentration-dependent positive inotropic effect and had a biphasic effect (shortening followed by lengthening) on the effective refractory period. These effects are best explained as due to a release of endogenous catecholamines, since the positive inotropy was completely blocked by propranolol. In reserpinized animals, there was no effect of midazolam. Midazolam, however, significantly decreased heart rate and increased the sinus node recovery time; these responses are believed to be direct effects. At 20 degrees C, midazolam had no effect on the developed force but, when a high concentration was administered, it significantly reduced the effective refractory period. Heart rate values were first increased and the reduced to control values. No effect on the sinus node recovery time was observed. Thus, hypothermia may reduce the catecholamine release and mask the effect of midazolam on cardiac tissue by mechanisms not yet fully understood.

Effects of veratridine on Na and Ca currents in frog skeletal muscle.

1. Voltage-clamp experiments were performed to determine the effects of veratridine on Na and Ca currents in frog skeletal muscle fibres. 2. Veratridine (1 microM) did not affect the kinetics of the fast Na current but it did induce a slowly inactivating tetrodotoxin-sensitive inward current that was apparent after Na current inactivation. This slow current had a peak amplitude of 6.7 +/- 0.7 microA/cm2 at -20 mV and decayed monoexponentially with a time constant of 606 +/- 77 ms. 3. The slow current had a voltage-dependence for activation that was similar to that of the fast Na current. Single depolarizing prepulses that induced complete inactivation of the fast Na channels, prevented development of the slow current. Trains of brief depolarizations at increasing frequencies increased the amplitude of the slow current. These results suggest that the slow current may be mediated by veratridine modified Na channels that must be in the open position. 4. The low concentration of veratridine (1 microM) did not affect the Ca current, while 100 microM veratridine reversibly suppressed the Ca current and shifted its peak current-voltage relation towards more negative potentials. Thus, veratridine appears not to be a selective fast Na channel modifier as it may also alter Ca channel gating properties in skeletal muscle fibres.

Effects of veratrine on ion currents in single rabbit cardiomyocytes.

1. Voltage-clamp experiments were performed to determine the effects of veratrine (1 microgram/ml) on Na and K currents in isolated rabbit ventricular cardiomyocytes. 2. Veratrine did not affect the inward rectifier K current, increased the inactivation time constant of the transient outward current (I(to)) and induced a slowly decaying inward current component (Iv), which was sensitive to tetrodotoxin. 3. Inactivation of fast Na channels by application of short depolarizing prepulses to potentials between -90 and -50 mV prevented the development of Iv.Iv decayed biexponentially with time constants equal to 139 +/- 9.0 ms and 776 +/- 47 ms. The net amplitude of Iv and the time constants for its rapidly and slowly inactivating components were little affected by trains of conditioning prepulses to 0 mV. The contributions, however, of the fast and slow components to the net current were significantly altered by repetitive depolarizations. 4. These components of Iv are likely due to modification of open cardiac Na channels by veratrum alkaloids.

Prevention of some hypothermia induced electromechanical changes by calcium channel blockade.

OBJECTIVE: Cooling induces electromechanical changes in the heart. The aim of the study was to examine how the calcium channel blocker, nisoldipine (NIS), altered these changes compared to those induced by other drugs that shorten action potential duration such as tetrodotoxin and nicorandil. METHODS: Guinea pig papillary muscle action potentials and developed force were recorded using the conventional microelectrode technique and a force transducer. Restitution of action potential duration was determined by introducing extrastimuli at progressively longer diastolic intervals from 40 to 9000 ms. Preparations were divided into four groups: (1) no drug (control); (2) 1 microM tetrodotoxin, a sodium channel blocker; (3) 1 mM nicorandil, an ATP sensitive potassium channel activator; and (4) 1 microM nisoldipine (n = 6 in each group). Action potential duration and developed force were recorded after addition of drug at 37 degrees C, and at each 1 degree C change in temperature during cooling to 27 degrees C. The restitution protocol was performed at 37 degrees C and 27 degrees C. RESULTS: Tetrodotoxin had no effect on action potential duration at 90% of repolarisation (APD90) while nisoldipine and nicorandil greatly shortened APD90. Cooling from 37 degrees to 27 degrees C with nisoldipine produced less hypothermia induced lengthening in APD90 than in the other group. Developed force did not increase with reduction in temperature in the presence of nisoldipine. The range of premature action potential durations was defined as the difference in APD90 at diastolic interval of 40 and 100 ms. This range decreased with nisoldipine in contrast to the marked increases that occurred in the other groups during cooling. CONCLUSIONS: Increased intracellular Ca2+ might be responsible for the hypothermia induced increase in APD90, developed force, and range of premature action potential durations, since calcium channel blockade, which prevents an increase in intracellular Ca2+, greatly reduced these changes. The reduced range of premature action potential durations may reduce dispersion of ventricular refractoriness, and hence be expected to decrease hypothermia induced arrhythmias.

Effect of stimulation and veratrine on total cellular calcium in rat and guinea-pig ventricular myocytes.

In rat cardiac myocytes, calcium efflux by Na+/Ca(2+)-exchange is expected only during ventricular systole following initial action potential repolarization. In contrast, in guinea-pigs, calcium influx via Na+/Ca(2+)-exchange is expected only during the initial portion of the action potential. Thus electrical stimulation is expected to result in reduced intracellular calcium ([Ca2+]i) in rat and an increase in guinea pig. We tested this hypothesis by measuring total cellular calcium ([Ca]tot) using 45Ca following stimulation of isolated rat and guinea-pig ventricular myocytes. Many studies have also emphasized that the rate and the direction of Na+/Ca(2+)-exchange across the sarcolemma are in part dependent on the magnitude of the transsarcolemmal sodium gradient. Thus, increasing intracellular sodium ([Na+]i) is expected to result in an increased [Ca2+]i. This hypothesis was also tested by measuring [Ca]tot following veratrine administration. Enzymatically isolated rat and guinea-pig ventricular myocytes were divided into two groups; non-stimulated and stimulated (1 Hz). The concentration-dependent effects of veratrine (1,10,100 micrograms/ml) on [Ca]tot were determined in both these groups. In the absence of veratrine, non-stimulated rat myocytes had a significantly higher [Ca]tot than did stimulated ones. Non-stimulated guinea-pig myocytes had a significantly lower [Ca]tot when compared with stimulated ones. Veratrine increased [Ca]tot in both species in a concentration-dependent fashion. In addition, following veratrine the difference between [Ca]tot in non-stimulated and stimulated rat myocytes was no longer significant. These results support those of others who have demonstrated that stimulation is associated with a gain of cellular calcium in both rabbit and guinea-pig ventricle and a calcium loss in rat ventricle.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in ventricular fibrillation threshold during acute hypothermia. A model for future studies.

Hypothermia and rewarming are associated with an increased incidence of lethal arrhythmias in man. The relationship between reduction in body temperature and ventricular fibrillation threshold was studied in 7 pentobarbital anaesthetized dogs using programmable electrical stimulation while cooling and rewarming between 37 degrees C and 25 degrees C in steps of 3 degrees C. Fibrillation threshold was defined as the number of extrastimuli required to evoke ventricular fibrillation. QRS-durations and corrected QT-intervals (QTc) were measured from surface electrocardiograms. Monophasic action potential durations were recorded from the base and apex of the heart. Fibrillation threshold decreased with decreasing temperatures; e.g., at 37 degrees C ventricular fibrillation was not inducible after 5 extrastimuli, while at 25 degrees C only 2 extrastimuli were required. From 37 degrees C to 25 degrees C QRS-width, monophasic action potential durations and QTc increased while conduction velocity decreased. The differential effects on conduction and monophasic action potential duration provide a basis for induction of ventricular fibrillation during acute hypothermia. This model of hypothermia-induced ventricular fibrillation should prove useful for future studies aimed at understanding the mechanisms responsible for hypothermia-related deaths.