Quantitative analysis of cardiac electrical restitution.

Electrical restitution (ER) of cardiac cells is an aggregate of events that rhythmically restore the initial conditions of electric signal (action potential) generation. Its analysis represents an important insight into cardiac arrhythmogenesis. The aim of this work is to theoretically substantiate and verify a novel approach allowing for the quantification of the individual ionic current components of ER. A method of analysis of the primary, initial conditions-setting restitution processes (apart from the secondary, test pulse-affected ones) is proposed. Both processes are described as sums of their measurable constituents. It is demonstrated that the optimum parameter of ER is the electric charge that is transferred through ionic channels and carriers during the test impulse. The theory was tested by using voltage-clamped canine ventricular preparations and by computer simulations. The experimental ER curve of canine ventricular muscle was constructed using action potential (AP) plateau voltage and half-repolarization time as parameters. At 30 degrees C and 0.5 Hz stimulation, the ER curve peaked, on average, after 400 ms with a 10% overshoot. Of this plateau elevation, 50% was due to 4-aminopyridine-sensitive transient outward current and 44% was due to verapamil-sensitive current. The delayed outward current antagonized the overshoot by about 6%. It was found that the initial conditions (i.e. the primary restitution processes) tend to strongly alter the plateau voltage of the premature AP. However, the final deviation is by about one order less. It is concluded that the voltage-dependent secondary processes counteract the effect of the primary processes, thereby suggesting strong negative feedback control of natural APs.

Control of cardiac performance by Ca-turnover.

A quantitative model of Ca-turnover in cardiac cells that incorporates negative feedback modulation of sarcolemmal calcium transport (via Ca channels and Na/Ca exchange) has been designed. The Na/Ca exchange current was expressed as INaCa = INaCar + delta INaCa. The component INaCar reflects slow changes of Ca2+ and Na+ concentrations and depends on the Na/K pump. delta INaCa is the fast component related to the Ca2+ transient. The single input to the model is an arbitrary sequence of intervals between excitations; outputs are sequences of calcium amounts transferred among the compartments during individual intervals. The model operates with a combination of discrete variables (amounts of Ca transferred during contraction, relaxation and rest) and continuous variables - slow changes in ionic concentrations. Since the model is not formalistic but respects the nature of the underlying elements of the system, it enables us to stimulate the known effects of cardiotropic drugs or to predict their unknown mechanisms by visualizing the changes in individual Ca compartments. By altering the parameters, the model also stimulates the known species and tissue differences in rate-dependent phenomena.

A contraction-related component of slow inward current in dog ventricular muscle and its relation to Na(+)-Ca2+ exchange.

1. The slow inward current component related to contraction (Isic) was studied in voltage clamp experiments on canine ventricular trabeculae at 30 degrees C with the aims of (a) estimating its relation to electrogenic Na(+)-Ca2+ exchange and (b) comparing it with similar currents as reported in cardiac myocytes. 2. Isic may be recorded under conditions of augmented contractility in response to depolarizing pulses below the threshold of the classic slow inward current (presumably mediated by L-type Ca2+ channels). In responses to identical depolarizing clamp pulses the peak value of Isic is directly related to the amplitude of contraction (Fmax). Isic peaks about 60 ms after the onset of depolarization and declines with a half-time of about 110 ms. 3. The voltage threshold of Isic activation is the same as the threshold of contraction. The positive inotropic clamp preconditions shift both thresholds to more negative values of membrane voltage, i.e. below the threshold of the classic slow inward current. 4. Isic may also be recorded as a slowly decaying inwardly directed current 'tail' after depolarizing pulses. In this representation the peak value of Isic changes with duration of the depolarizing pulses, again in parallel with Fmax. In response to pulses shorter than 100 ms both variables increase with depolarization time. If initial conditions remain constant, further prolongation of the pulse does not significantly influence either one (tail currents follow a common envelope). 5. Isic differs from classic slow inward current by: (a) its direct relation to contraction, (b) the slower decay of the current tail on repolarization, (c) slower restitution corresponding to the mechanical restitution, (d) its relative insensitivity to Ca(2+)-blocking agents (the decrease of Isic is secondary to the negative inotropic of Ca(2+)-blocking agents (the decrease of Isic is secondary to the negative inotropic effect) and (e) its disappearance after Sr2+ substitution for Ca2+. 6. The manifestations of Isic in multicellular preparations do not differ significantly from those reported in isolated myocytes (in contrast to calcium current). 7. The analysis of the correlation between Isic and Fmax transients during trains of identical test depolarizing pulses at variable extra- and intracellular ionic concentrations (changes of [Ca2+]o, 50% Li+ substitution for Na+, strophanthidin) indicate that the observed effects conform to the predictions based on a quantitative model of Na(+)-Ca2+ exchange. 8. It is concluded that Isic is activated by a transient increase of [Ca2+]i, in consequence of the release from the reticular stores.(ABSTRACT TRUNCATED AT 400 WORDS)

Voltage dependence of force- and slow inward current restitution in ventricular muscle.

This study was aimed to assess the relationship among the voltage-dependent processes underlying the excitation-contraction coupling, viz. force restitution (FR), transmembrane Ca fluxes and Ca release. The experiments (n = 22) were performed on voltage-clamped dog trabeculae in which force and slow inward current were measured. Standard steady-state was achieved by clamp driving at 0.5 Hz, 300 ms, 70 mV depolarizing pulses from holding = resting potential at 30 degrees C. Voltage and duration of single pulses and intervals in between were varied according to five protocols. The voltage dependence of Ca release was tested by varying single pulses at equal steady-state, i.e., at equal Ca availability. Contractions could be elicited in absence of ICa (20-30 mV step) and in the presence of disproportionately small ICa (above 80 mV). The voltage dependence of Ca availability for the release was tested by constant test pulses following either a variable conditioning clamp pulse or a period of rest at a variable voltage. After a low voltage pulse and, hence, depressed or absent ICa, the test contraction is diminished in presence of normal or even augmented Isi at any test interval (i.e., FR is depressed). Diminished Ca influx thus reduces the Ca availability of the subsequent beat. During prolonged depolarization (by 60 mV and more) a tonic response appears, but a phasic response cannot be elicited (FR is inhibited). Upon subsequent repolarization FR starts from zero and is significantly enhanced. It is concluded that, during depolarization, Ca release channels are in an open state, thus allowing free recirculation of Ca, but no build-up of a sufficient Ca gradient at the release site.

Differences in the recovery of right and left ventricular function after ischaemic arrest and cardioplegia.

Differential susceptibility of right (RV) and left (LV) ventricles to plain ischaemia and the contribution of cardioplegia in reducing the ischaemic damage was evaluated in a sheep model of cardiopulmonary bypass. Sheep (n = 16) were equally divided for the two protocols of the study. Each sheep served as its own control. RV and LV functions were studied and compared by plotting ventricular function curves (Starling and Sarnoff). The mathematical centre of mass (COM) for each curve was computed by a polynomial regression program. The COM values of the contractility indices [stroke volume (SV), stroke work (SW)] represented ventricular heterometric reserve. RV and LV heterometric reserve was significantly (P less than 0.01) reduced after 1 h plain ischaemia, and quantitatively this change was more for RV than for LV (P less than 0.05). As compared to LV, a significantly greater reduction in RVSW was brought about by a significantly (P less than 0.01) greater reduction in RVSV, because there were no significant differences between the post-ischaemic recovery in the RV and LV afterloads. Cardioplegic protection nearly normalized filling pressure and contractility (SV, SW) of both ventricles, but major differences were observed in the recovery of compliance. Recovery in the RV compliance exceeded the control values, and quantitatively the recovery in RVSW was slightly more than in LVSW. The results of this study indicate that the RV suffers more damage from plain ischaemic arrest and hence benefits more from the cardioplegic protection.

Preservation of left ventricular function during coronary artery bypass graft surgery.

Effects of hypothermic potassium cardioplegia on left ventricular performance and myocardial damage were assessed in 35 patients undergoing coronary artery bypass surgery. Hemodynamic data and enzymatic evidence of left ventricular ischemic damage were examined and compared in the immediate postoperative period. Left ventricular stroke work index showed a significant depression during the first hour with gradual recovery and a significant increase after 24 h. Myocardial specific isoenzyme creatine kinase (CK-MB) showed a very good nonlinear relationship with stroke work index within the whole range, whereas lactate dehydrogenase isoenzyme (LDH-I) had no relationship with the stroke work index. There was a high incidence of transient postoperative arrhythmias and electrical activity took a long time to stabilize. Left ventricular ultrastructure was generally well preserved. The results of this study demonstrate adequate structural and functional preservation of left ventricle by hypothermic potassium cardioplegia.

Regional differences of cardiovascular effects of diltiazem in the rat.

The dose-response relations of the central and peripheral effects of diltiazem were studied in 26 anaesthetized rats. Measured were the heart rate (HR), atrioventricular conduction time (PR), mean arterial blood pressure (BP), carotid and renal blood flow (Fc, Fr) and the corresponding relative regional resistance (RRc, RRr). The effects were evaluated by their maxima regularly reached 15-20 s after the i.v. bolus administration. The minimum dose which produced a significant HR decrease and PR prolongation were 0.4 and 2.0 mg/kg, respectively. In the mg/kg dose range a transient second degree AV block was regularly recorded. The lethal dose (cardiac arrest) was 20 mg/kg. BP significantly already decreased after 4 micrograms/kg. The dose-dependent decrease of Fr matched the hypotensive effect in the whole range due to unchanged RRr. In contrast Fc invariably increased at lower doses reflecting the RRc decay. Only in the mg/kg dose range Fc decreased in accord with BP since RRc dropped to a constant value (50% of control) with each administration. The peripheral reactions were significantly augmented in rats with renovascular hypertension. It is concluded that, in this model, the peripheral effects of diltiazem evidently surpass the central ones. The regional difference between the inert renal and responsive carotid vasculature might be due to a different mode of regulation of the respective vascular tone, hypothetically reflecting different density of membrane, potential-dependent Ca2+ channels.

The effect of prostaglandins E2 and F2 alpha on carotid blood flow in rats with renovascular hypertension.

The effect of i.v. bolus administration of PGE2 and PGF2 alpha on carotid blood flow (Q) and mean arterial blood pressure (MAP) was recorded in 21 anaesthetized normotensive control (N) and 12 rats with 1K1C renovascular hypertension (RH). From the measured parameters the regional vascular impedance (PVI) and the change in blood volume were calculated. In normotensive animals both PGs elicited a dose-dependent initial fast increase of Q (threshold dose 0.4 ng/kg) and a decrease of MAP and PVI (threshold dose 0.4 micrograms/kg). Subsequently, Q decreased below the initial level. MAP and PVI remained depressed after E2 but increased after F2 alpha. The time course of the Q and MAP responses was analyzed in more detail at a standard dose 4 micrograms/kg. The average time to peak of the first phase was 12 s and of the second approximately 80 s. The initial levels of Q and MAP were reestablished within 3 to 4 minutes. The total volume of carotid blood flow obtained by planimetric integration was unaltered after F2 alpha but depressed after E2. In hypertensive animals both phases of the response to E2 were significantly retarded and the Q response was nearly abolished. On the other hand, the time course of the reaction to F2 alpha was unchanged but the magnitude of the second pressoric phase was reduced. Thus, the capacity of the carotid vascular bed to dilate remains the same in RH while the ability to constrict is limited. It is concluded that the response of MAP and Q to both PGs are relatively independent.(ABSTRACT TRUNCATED AT 250 WORDS)

Recovery of the conduction system from ischemic arrest and cardioplegia in perfused rat heart.

Normothermic ischemic arrest of the perfused rat heart for 1 h was followed by severe reperfusion arrhythmias, depressed excitability, atrioventricular (AV) node and sinoatrial (SA) node conduction blocks and by marked impairment of contractility. Excitability and conduction recovered within 10 to 15 mins whereas contractility remained greatly depressed. This finding is in agreement with a theoretically based assumption of lesser sensitivity of conduction system to ischemia compared to the working myocardium. When the hearts were exposed to ischemia at 20 degrees C, the sinus rhythm recovered instantaneously upon reperfusion; excitability and SA node conduction times were not significantly different from control; and contractility was much less depressed than after 34 degrees C ischemia. However, AV node conduction times did not normalize even after 15 mins of reperfusion. Potassium cardioplegia (34 degrees C) did not prevent post ischemic arrhythmias but evidently protected both SA node and AV node conduction. Optimum recovery of the conduction system and contractility was achieved by hypothermic (20 degrees C) potassium cardioplegia. Other cardioplegic additives did not further improve the hypothermic potassium protection of the conduction system.

Inotropic effects of ionic and nonionic contrast materials in isolated heart preparations.

The inotropic effects of ionic (amidotriazoate) and nonionic (iohexol) contrast material were compared in isolated rat heart preparations. Left atria exposed to amidotriazoate for 10 mins exhibited a dose dependent depression of contractile force approximately twice as large as that brought about by equiosmolar sucrose. When the driving rate was reduced from 60 to 20 beats/min, this specific effect was abolished. The spontaneously beating hearts perfused with amidotriazoate-containing medium had increased resting tension and depressed force of contractions. These effects tended to spontaneously normalize. Upon bolus administration of amidotriazoate the contractile force of perfused hearts was briefly depressed and heart rate, action potential duration and time to peak force decreased. Iohexol did not produce any significant changes in the contractile force. The experiments illustrated direct action of ionic contrast dye on cardiac inotropy probably resulting from an immediate, slowly compensated ionic imbalance, and demonstrated a definite superiority of the nonionic contrast material.

Significance of the site of premature excitation for the left and right ventricular performance in open chest dogs.

The haemodynamic response to premature excitation was studied in open-chest dog hearts. Intraventricular pressure, dP/dt and outflow rate of the left and right heart (5 experiments each) were compared at variable preextrasystolic intervals and with the stimulation at three different sites (left ventricle--LV apex and base, right ventricle--RV free wall). In both ventricles and at any driving interval the reduction of all extrasystolic parameters is significantly more pronounced on ipsilateral stimulation. This reduction is apparent even at the fusion interval, demonstrating the importance of normal spread of excitation. The differences between apex and base stimulation are, however, only insignificant. The outflow valves opening interval greatly differs in aorta and pulmonary artery, namely if LV is stimulated, which results in a considerable disproportion between LV and RV extrasystolic stroke volumes. The extrasystolic augmentation is revealed by all parameters in the right heart but is surprisingly absent in the peak pressure and relaxation rate (dP/dt) in the LV.

Influence of temperature and rate on the effectiveness of nifedipine in isolated rat heart preparations.

The negative inotropic effect of nifedipine (0.1-2.5 mg/l) was studied on isolated atria at different temperatures (36 degrees, 29 degrees, 22 degrees C) and frequencies of stimulation (20, 60, 180/min). The effect on peak force and dF/dt increased with dose, frequency and cooling from 36 degrees to 29 degrees. Rate of contraction was affected slightly more than rate of relaxation. The effect on time to peak was small, dose and frequency independent but potentiated by lowering the temperature. An analysis of mechanical transients showed that at 22 degrees C and 180/min stimulation the effect of nifedipine gradually diminished and only slowly reappeared upon transition to 20/min stimulation. In spontaneously beating perfused hearts the effects of nifedipine (0.5 mg/l) in general did not differ significantly at 36 degrees and 23 degrees C. The heart rate was reduced and atrioventricular conduction prolonged. At constant heart rate, nifedipine considerably depressed contractions, shortened the action potential duration and reduced the height of plateau. These effects of nifedipine are similar to those of verapamil in other animal species and the results support the idea that calcium antagonists might have secondary intracellular effects apart from direct consequences of slow current inhibition.

Differences in electrical and mechanical recovery from ischemic heart arrest and cardioplegia.

The course of recovery of heart activity [assessed by heart rate, atrioventricular (AV) conduction time, monophasic action potentials, contractile force, and perfusion rate] from hypothermic ischemic arrest was studied on isolated perfused rat hearts. The effect of control ischemic arrest was compared with various cardioplegic protective formulations based on high K+ content. During control hypothermic ischemia (20 degrees C), the heart activity extinguished only gradually, action potentials were biphasic, AV conduction was extremely prolonged, and contractions were slow and relatively strong. On reperfusion (37 degrees C), the recovery of electrical activity was almost instantaneous and normalized within 2 min, whereas the contractile force remained substantially depressed. In contrast, K+-containing cardioplegic solutions stopped the heart within several cycles. Postarrest recovery was delayed and transitorily associated with severe arrhythmias (AV block, repetitive afterdepolarizations and oscillations during elevated plateau, and ventricular fibrillation). Nevertheless, the action potentials as well as the contractile force virtually normalized in 10-15 min. Procaine-containing cardioplegic solutions were ineffective in preventing the onset of postarrest reperfusion arrhythmias, whereas addition of nifedipine to the K+-containing cardioplegic solutions largely prevented these arrhythmias, and contractile force was further improved by high concentrations of glucose. The data indicate that postarrest electrical and mechanical recovery do not recover in parallel. Furthermore, high concentrations of calcium antagonist and glucose preserve the electrical and mechanical properties of the cardiac muscle during periods of cardiac arrest.