Mechanism of hypoxic preconditioning in guinea pig papillary muscles.

UNLABELLED: Brief ischemia or hypoxia has been found to protect the heart against subsequent long-lasting ischemia and to improve contractile dysfunction as well to reduce cell necrosis and the incidence of lethal arrhythmias. This phenomenon, termed preconditioning (PC) has been demonstrated in different species. However, little is known about PC in guinea pigs. Moreover, electrophysiological changes underlying protection have not been studied so far in conjuntion with force recovery in a setting of PC. The aim of the study was to study PC in a guinea pig papillary muscle, using recovery of contractility after long hypoxic challenge as the main end-point of protection, and to investigate concomitant electrophysiological alterations. In guinea pig papillary muscle preparations contracting isometrically (paced at 2 Hz), transmembrane action potentials (AP) and developed force (DF) were recorded by conventional microelectrode technique and a force transducer. In addition, effective refractory periods (ERP) were determined. Hypoxia was induced by superfusion with 100% N2 (pO2 < 5 kPa) and pacing at 3,3 Hz. In the control group, long hypoxia lasted for 45 min and was followed by 30 min reoxygenation. In the PC group, muscles were subjected to 5 min hypoxia followed by 10 min recovery prior to sustained hypoxia/reoxygenation. RESULTS: Long hypoxia induced a similar depression of DF in both, PC and control groups. However, a loss of contractile activity occured earlier in the PC group. AP duration and ERP decreased faster and were significantly shorter after PC. Upon reoxygenation, preconditioned muscles showed significantly better recovery of function (DF 86% of prehypoxic value vs. 36% in controls; p < 0,05). AP and ERP were completely restored in both, PC and control groups. Guinea pig papillary muscle can be preconditioned with a brief hypoxic challenge against contractile dysfunction upon long-lasting hypoxia/reoxygenation. Shortening of AP and loss of contractility occured more quickly during hypoxia and may participate in the protective effect of preconditioning. Possible mechanisms might involve facilitated opening of K(ATP)-dependent channels.

Mechanisms for hypothermia-induced increase in contractile force studied by mechanical restitution and post-rest contractions in guinea-pig papillary muscle.

Lowering myocardial temperature increases contractile force, presumably by increasing intracellular calcium content. To study the mechanisms behind this, we compared the effects of some known inotropic interventions with hypothermia on mechanical restitution and post-rest contractile force in isolated guinea-pig papillary muscles. In four groups (n = 6 per group), the effects of: (1) reducing the ability for Na/Ca exchange to extrude Ca2+ (a) by increasing [Na+]i with ouabain or (b) by increasing [Ca2+]o; and (2) activation of calcium channels with Bay-K 8644, were compared with lowering temperature from 37 to 27 degrees C. Normally (at 37 degrees C and 2 mM CaCl2), mechanical restitution could be described by a rapid recovery phase with a time constant between 180 and 220 ms, followed by a slowly decaying phase with a time constant between 5000 and 8000 ms and post-rest contractions (1-10 min rest) were markedly depressed compared to steady-state contractions. Steady-state developed force was markedly increased at 27 degrees C, after 1 microM ouabain, 6 mM CaCl2 or 0.1 microM Bay-K 8644. At 27 degrees C the rapid recovery phase of restitution was delayed while the slowly decaying phase was not affected. Ouabain and increased [Ca2+]o caused elevation of the slowly decaying phase of restitution and markedly attenuated the post-rest depression of developed force, which may be attributed to a reduced diastolic extrusion of Ca2+ via the Na/Ca exchanger. Hypothermia and Bay-K 8644 on the other hand, augmented this post-rest depression. Hence, this study suggests that increased Ca2+ influx due to delayed inactivation of calcium channels may account for the increased developed force during hypothermia rather than reduced diastolic extrusion of Ca2+ via the Na/Ca exchanger.

Effects of temperature on cycle length dependent changes and restitution of action potential duration in guinea pig ventricular muscle.

OBJECTIVE: The aim was to investigate the effects of temperature on cycle length dependent changes of action potential duration and on restitution of action potential duration. METHODS: Guinea pig papillary muscle action potentials were recorded using conventional microelectrode techniques. Action potential duration was measured at cycle lengths ranging from 500 to 2000 ms at both 27 degrees C and 37 degrees C. Restitution of action potential duration was determined by introducing an extra stimulus at progressively longer diastolic intervals from 40 to 9000 ms at pacing cycle lengths of 500, 1000, and 2000 ms. RESULTS: At 37 degrees C, action potential duration measured at 90% of repolarisation (APD90) during continuous pacing and the maximum value of APD90 achieved during restitution (APD90pl) decreased by 18(SEM 6) ms (n = 7) and 24(7) ms (n = 6), respectively, when pacing cycle length was reduced from 2000 to 500 ms. At 27 degrees C, the magnitude of the shortening of APD90 and APD90pl observed when pacing cycle length was similarly reduced was greater than at 37 degrees C, ie, 143(21) ms (n = 6) and 115(11) ms (n = 6), respectively. Thus the relation for restitution of action potential duration shifted downwards with reduction in pacing cycle length, and the magnitude of this shift was greater at 27 degrees C than at 37 degrees C. The difference between APD90 at the shortest diastolic interval (40 ms) and at diastolic interval of 100 ms (range of premature action potential durations) was much greater at 27 degrees C than at 37 degrees C at all three pacing cycle lengths. CONCLUSIONS: Reduction in temperature magnifies the cycle length dependent changes in action potential duration both during abrupt changes in cycle length, as with an extra stimulus, and during changes of steady state cycle length. This may indicate a greater dispersion of premature action potential durations during hypothermia, and hence predispose to hypothermia induced arrhythmias.

Electromechanical action of dofetilide and D-sotalol during simulated metabolic acidosis in isolated guinea pig ventricular muscle.

We examined the electromechanical effects of two class III antiarrhythmic agents, dofetilide (UK-68,798) and D-sotalol, in acidic myocardium. Right ventricular papillary muscle preparations isolated from guinea pigs were divided into three groups (n = 6 per group): (a) drug-free, (b) dofetilide (10 nM), and (c) D-sotalol (30 microM). At normal extracellular pH (pH = 7.32 +/- 0.01), dofetilide and D-sotalol lengthened action potential duration (APD) to a similar extent, i.e., by 18-20%. Effective refractory period (ERP) increased in parallel, whereas membrane diastolic potential (MDP), action potential amplitude (APA), maximum velocity of depolarization (Vmax), and developed force (DF) were not significantly affected. Metabolic acidosis (pH = 6.78 +/- 0.01) was simulated by reducing the bicarbonate concentration of the Tyrode's solution from 20 to 6 mM. Superfusion with acidic solution alone for 30 min markedly decreased Vmax and DF, whereas APD and ERP were lengthened slightly. The acidosis-induced decreases in Vmax and DF were not affected by pretreatment with dofetilide or D-sotalol. In acidic superfusate, both agents still significantly increased APD and ERP to the same extent that they did at normal pH. The results indicate that metabolic acidosis, a major component of myocardial ischemia, does not attenuate the class III antiarrhythmic action of dofetilide and D-sotalol.

Class III antiarrhythmic action by potassium channel blockade: dofetilide attenuates hypoxia induced electromechanical changes.

OBJECTIVE: The aim was to examine the electromechanical effects of dofetilide, a new class III antiarrhythmic agent, in isolated guinea pig ventricular muscle during hypoxia. METHODS: Hypoxia was induced by superfusing guinea pig right ventricular papillary, muscles with Tyrode's solution gassed with 95% N2 + 5% CO2 [PO2 = 5.3(SEM 1.3) kPa]. Prior to hypoxia, the preparations were either pretreated for 30 min with 0.1 microM dofetilide (n = 6) or with 100 microM glibenclamide (a blocker of ATP sensitive K+ channels, n = 6), or not pretreated (n = 6). Sixteen additional preparations were exposed to 1 mM nicorandil (an activator of ATP sensitive K+ channels) in the absence (n = 6) and presence of dofetilide (n = 6) or glibenclamide (n = 4). Transmembrane action potentials and developed force were recorded using conventional microelectrode techniques and a force transducer. RESULTS: During normoxia, dofetilide markedly increased APD90 from 236(SEM 6) ms to 298(7) ms (p < 0.05) and the effective refractory period (ERP) from 248(5) ms to 315(6) ms (p < 0.05). In the drug free group, 60 min hypoxia decreased APD90 by 47(5)% (p < 0.05), ERP by 48(4)% (p < 0.05) and developed force by 71(6)% (p < 0.05) of baseline, respectively. These hypoxia induced effects were significantly attenuated after pretreatment with dofetilide or glibenclamide. Nicorandil decreased APD90 by 45(5)% (p < 0.05), ERP by 44(6)% (p < 0.05), and developed force by 69(10)% (p < 0.05) of baseline, respectively. Pretreatment with dofetilide or glibenclamide also significantly attenuated the nicorandil induced decreases in APD90, ERP, and developed force. CONCLUSIONS: Dofetilide, like glibenclamide, effectively attenuates hypoxia and nicorandil induced action potential shortening and the associated reduction in contractile force. Thus dofetidile would be expected to retain its antiarrhythmic efficacy during myocardial hypoxia or ischaemia.

Effects of altered extracellular potassium and pacing cycle length on the class III antiarrhythmic actions of dofetilide (UK-68,798) in guinea-pig papillary muscle.

The effects of altered extracellular K+ concentrations ([K+]o) and pacing cycle lengths (CLs) on the electrophysiological actions of dofetilide (UK-68,798), a potent class III antiarrhythmic agent, were examined in isolated guinea-pig ventricular papillary muscle. At a normal [K+]o (4 mM) and at CL between 300 and 5000 msec, dofetilide (10 nM) significantly increased the action-potential duration (APD) and the effective refractory period (ERP), whereas other action-potential parameters were unaffected. Elevation of [K+]o to 10 mM reduced membrane diastolic potential (MDP), action-potential amplitude (APA), and the maximum rising velocity of the action-potential upstroke (Vmax). These changes were accompanied by a small shortening of APD90, but with an increase in ERP; i.e., the ERP/APD90 ratio was increased. Dofetilide also significantly lengthened APD90 at 10 mM [K+]o and at each CL. Even at the short cycle lengths (300 and 500 msec), dofetilide-induced increases in APD90 were not attenuated whether [K+]o was at 4 or 10 mM. These results indicate that at various pacing CLs, 10 nM dofetilide increases myocardial APD and ERP to a similar extent without significant reverse use-dependence when the cell membrane is normally polarized or partially depolarized by elevated [K+]o. Dofetilide may, therefore, be expected to be beneficial in the treatment of cardiac tachyarrhythmias related or unrelated to regional myocardial hyperkalemia during myocardial ischemia.

Hemodynamic effects of d-sotalol in acute ischemic heart failure in dogs.

This study was designed to determine the hemodynamic effects of the class III antiarrhythmic agent d-sotalol in acute ischemic heart failure at concentrations that prolong ventricular repolarization. In pentobarbital-anesthetized open-chest dogs, heart failure was induced by microembolization of the area supplied by the main left coronary artery until a stable left ventricular (LV) end-diastolic pressure of 25 +/- 2 mm Hg was achieved. Embolization shortened the QT interval by 30 +/- 11 msec, while 1 and 2 mg/kg d-sotalol intravenously after embolization lengthened the QT interval by 23 +/- 7 and 39 +/- 7 msec, respectively (n = 7). Heart rate increased after embolization by 19 +/- 7 beats/min, while it decreased by 12 +/- 6 beats/min and by 21 +/- 5 beats/min after d-sotalol. The depressed LV function after embolization assessed by LV pressures, stroke volume, cardiac output, ultrasonometrically estimated LV volume, the pressure-volume relationship, and the time for isovolumic relaxation was not changed following infusion of 1 or 2 mg/kg d-sotalol. Plasma concentrations of d-sotalol were 1.55 +/- 0.33 and 2.58 +/- 0.50 micrograms/ml, respectively. In conclusion, d-sotalol at concentrations prolonging repolarization was devoid of cardiodepressive effects in acute ischemic heart failure in dogs.

Rate-dependent differences in dog epi- and endocardial monophasic action potential configuration in vivo.

A transient outward current (Ito), long considered to be a unique feature of Purkinje fiber tissue, has recently been demonstrated in dog ventricular tissue in vitro and most prominently in the epicardium. To investigate its possible contribution to ventricular repolarization in vivo, we recorded right ventricular endocardial and epicardial monophasic action potentials (MAP) simultaneously in pentobarbital-anesthetized open-chest dogs. Epicardial MAP had lower phase 1 than phase 2 amplitude at both spontaneous heart rate and paced cycle length of 300 and 400 ms. This "spike-and-dome" morphology of the epicardial MAP, possibly attributable to Ito, progressively disappeared at shorter extrastimulus intervals. In endocardium the phase 1 amplitude was always higher or equal to phase 2 amplitude and was not affected by shorter extrastimulus intervals. The action potential duration (APD) was shorter in epicardium than in endocardium. Both endocardial and epicardial APD shortened as the premature intervals were reduced, but the shortening was not parallel. The restitution curves converged so that, at the shortest intervals (160 ms), there were no longer any significant differences in APD between endocardium and epicardium. This study indicates that Ito contributes to ventricular repolarization in vivo, and most prominently in the epicardium. Unequal shortening of APD between endocardium and epicardium after progressively shorter diastolic intervals may thus partly result from uneven distribution of Ito across the ventricular wall.

Negative chronotropic effect of a novel class III antiarrhythmic drug, UK-68,798, devoid of beta-blocking action on isolated guinea-pig atria.

1. The chronotropic effects of a novel class III antiarrhythmic drug, UK-68,798, and the beta-adrenoceptor blocker, propranolol, for comparison, were studied on spontaneously beating right atria isolated from guinea-pigs in the absence and presence of increasing concentrations of isoprenaline (10(-10)-10(-4) M). 2. UK-68,798 (10(-9)-10(-5) M) decreased spontaneous atrial rate by 6-21%. Propranolol (10(-8) -10(-6) M) also had a negative but significantly smaller chronotropic effect. 3. UK-68,798 dose-dependently reduced the maximal positive chronotropic effect induced by isoprenaline, but without significantly shifting the concentration-response curve for isoprenaline in a parallel fashion. A pD'2 value of 5.88 was obtained. As expected, propranolol displayed a competitive inhibition with a pA2 value of 8.21. 4. The results demonstrate a negative chronotropic effect of UK-68,798, which is not associated with a beta-adrenoceptor blocking action. We suggest that the negative chronotropic effect is linked with potassium channel blockade and thereby the class III antiarrhythmic action of UK-68,798.

Class III antiarrhythmic action of d-sotalol during hypothermia.

To investigate whether changes in temperature influence the electrophysiologic effects of the class III antiarrhythmic agent d-sotalol, we studied its effects on propranolol-pretreated guinea pig papillary muscles at temperatures ranging from 37 degrees to 27 degrees C by means of conventional microelectrode techniques. We also examined the rate-dependent effect of d-sotalol at 37 degrees and 27 degrees C. Before the addition of d-sotalol, reducing the temperature from 37 degrees to 27 degrees C increased the action potential duration recorded at 50% repolarization (APD50) from 112 +/- 7 msec to 271 +/- 15 msec and action potential duration recorded at 90% repolarization (APD90) from 136 +/- 7 msec to 325 +/- 10 msec. d-Sotalol (50 mumol/L) lengthened APD50 and APD90 to a greater degree at low temperatures. Thus at 37 degrees C d-sotalol lengthened APD50 and APD90 by 12 +/- 6 msec and 19 +/- 5 msec, and at 27 degrees C by 37 +/- 5 msec and 52 +/- 7 msec, respectively. d-Sotalol produced its greatest effect on APD at long pacing cycle lengths, thus demonstrating reverse dependence. This rate-dependent effect was more marked at 27 degrees C than at 37 degrees C. The greater effect of d-sotalol on APD at long pacing cycle lengths may be explained by the modulated receptor hypothesis, assuming that the drug has a higher affinity for closed potassium channels. Such a mechanism may also explain the accentuated class III antiarrhythmic action of d-sotalol observed during hypothermia.

Cardiac electrophysiology during hypothermia. Implications for medical treatment.

Reduction in body temperature induces characteristic electrophysiological and mechanical alterations of the heart. The heart rate is markedly reduced. Myocardial conduction is slowed, partly due to reduced rate of depolarization of the action potential, and is reflected by widening of the QRS-complex in the ECG. There is also a fall in resting membrane potential. Action potential duration and refractory period are markedly lengthened during hypothermia, attributed to delayed repolarization. This is reflected by increased QT-time in the ECG. Since action potential duration changes significantly even after as small temperature changes as 1 to 2 degrees C, nonuniform cooling or rewarming of the heart may cause significant dispersion of conduction, action potential duration and refractoriness in the myocardium. This dispersion may cause unidirectional block, hence creating a substrate for reentry atrial and ventricular arrhythmias, and may be an important mechanism for explaining the hypothermia-associated arrhythmias. Class III antiarrhythmic drugs such as d-sotalol lengthen long action potentials at low temperatures to a greater extent than the shorter action potentials at higher temperatures. This may further increase dispersion and thereby the tendency towards arrhythmias. Sotalol as an example, shows that some antiarrhythmic drugs may have increased arrhythmogenic effect and should probably be contraindicated during hypothermia.

Positive inotropy linked with class III antiarrhythmic action: electrophysiological effects of the cardiotonic agent DPI 201-106 in the dog heart in vivo.

STUDY OBJECTIVE: The aim was to investigate whether the positive inotrope DPI 201-106 prolongs ventricular monophasic action potential duration and refractoriness in vivo without affecting conduction, thus possessing class III antiarrhythmic characteristics in vivo. DESIGN: Electrophysiological and haemodynamic effects of DPI 201-106 (0.5, 1.0, and 2.0 mg.kg-1 intravenously) were studied at spontaneous heart rate and at three different paced cycle lengths (353, 300, and 261 ms). The following were recorded: monophasic action potentials from right ventricular endocardium; intracardiac conduction times by His bundle electrocardiography; refractoriness by programmed electrical stimulation; and left ventricular (LV) pressures. SUBJECTS: Seven mongrel dogs of either sex, weighing 14-24 kg, were studied under sodium pentobarbitone anaesthesia. MEASUREMENTS AND MAIN RESULTS: DPI 201-106 prolonged ventricular monophasic action potential duration and refractoriness dose dependently and most effectively at long cycle lengths, with no effect on intracardiac conduction times. DPI 201-106 increased LV dP/dtmax, while LV systolic and end diastolic pressures were unchanged both during spontaneous and paced heart rate. DPI 201-106 decreased spontaneous heart rate. CONCLUSIONS: Prolonged monophasic action potential duration and increased refractoriness, with no effect on conduction, indicate class III antiarrhythmic action of DPI 201-106 in vivo.

Plasma concentrations and haemodynamic effects of d-sotalol after beta-blockade in dogs.

This study was designed to investigate the haemodynamic effects of d-sotalol at plasma concentrations producing class III antiarrhythmic effects. d-Sotalol 1, 4 and 10 mg/kg intravenously was given after beta-blockade (propranolol 0.25 mg/kg intravenously) to seven pentobarbital anaesthetized dogs. Left ventricular (LV) systolic and end-diastolic pressures, LV dP/dtmax, mean aortic pressure, stroke volume, cardiac output and total peripheral resistance were not significantly changed by d-sotalol. There was a linear correlation between the dose of d-sotalol infused and the plasma concentration of d-sotalol obtained. Heart rate decreased and QT-time increased with increasing plasma concentrations of d-sotalol, whereas the QRS-width did not change. There was a linear correlation between the decrease in heart rate and the increase in QT-time, and between the plasma concentration of d-sotalol and increase in QT-time. In conclusion, the study indicates that after beta-blockade, d-sotalol has no cardiodepressive effects at concentrations that prolong repolarization.

Rate-dependent class III antiarrhythmic action, negative chronotropy, and positive inotropy of a novel Ik blocking drug, UK-68,798: potent in guinea pig but no effect in rat myocardium.

The electromechanical effects of UK-68,798 (UK), a novel class III antiarrhythmic drug, were studied in guinea pig and rat papillary muscles (PMs) and atria in vitro using conventional microelectrode technique. UK (10(-8)-10(-6) M) prolonged the action potential duration (APD) by 21-58% and effective refractory period in parallel, without affecting the resting potential or maximum rate of depolarization in guinea pig PM stimulated at 1 Hz. UK increased the contractile force without prolonging the time to peak force or relaxation. In comparison, 5 x 10(-5) M d-sotalol was needed to induce the same electrophysiological effects as 10(-8) M UK. UK prolonged the APD significantly less at 2 Hz than at 1 and 0.5 Hz. Early afterdepolarizations (EADs) developed in 2 of 11 preparations after 10(-6) M at 0.5 Hz. No reversal of drug effect was seen after up to 2 h washout. UK (10(-9)-10(-5) M) reduced the spontaneous heart rate and prolonged the sinus node recovery time of guinea pig right atria. No effects on rat PM or atria, even after 10(-5) M, indicate a selective action of UK on the delayed rectifying outward potassium current, Ik. These results indicate a potent and selective, rate-dependent class III antiarrhythmic action of UK-68,798 linked with positive inotropy. Increased APD, bradycardia, and induction of EADs, however, represent a potential arrhythmogenic combination.

Electromechanical effects of two low osmolality contrast media, ioxaglate and iohexol, on isolated rat atria.

This study aimed at investigating the direct effects of two low osmolality radiographic contrast media, iohexol (non-ionic) and ioxaglate (ionic), on transmembrane action potentials, contractile force and refractoriness of isolated rat atrial preparations. Superfused with 10% solution, ioxaglate induced a biphasic mechanical response, initially decreasing and thereafter increasing contractile force. The same concentration of iohexol only increased contractile force. The two contrast media increased the resting membrane potential, action potential amplitude and rate of depolarization to the same extent. Iohexol prolonged repolarization. Both contrast media decreased the effective refractory period. The direct effects of contrast media on myocardial contractility in this study can explain the different haemodynamic effects of iohexol and ioxaglate in vivo. The observed effects on the action potentials in vitro can explain commonly observed ECG changes during coronary arteriography. The changes in depolarization, repolarization and refractoriness are probably related to the arrhythmogenic properties of these contrast media.

Mechanism of ECG changes and arrhythmogenic properties of low osmolality contrast media during coronary arteriography in dog.

STUDY OBJECTIVE: The aim of the study was to investigate the mechanisms behind ECG changes and ventricular arrhythmias during coronary arteriography. DESIGN: Transmembrane action potentials were recorded from isolated heart muscle preparations superfused with contrast media. Conductivity of plasma diluted with contrast media was determined in vitro. Epicardial ECG recordings were made during coronary arteriography. SUBJECTS: Epicardial ECG recordings were made in eight mongrel dogs of either sex, weight 14-22 kg. Atrial appendages were excised from the same dogs and used for heart muscle preparation studies. MEASUREMENTS AND MAIN RESULTS: Iohexol and ioxaglate affected the action potentials similarly: resting potential, amplitude, rate of depolarisation, and action potential duration increased; effective refractory period decreased. Both contrast media reduced plasma conductivity. During coronary arteriography both media increased R wave amplitude, depressed ST segment, and prolonged QT time on epicardial ECG. CONCLUSIONS: ST segment deviation on ECG reflects hyperpolarization and increased amplitude of action potential rather than depolarisation consistent with ischaemia. Increased rate of depolarisation and amplitude of action potential together with reduced conductivity after contrast media may explain increased amplitude of QRS voltage on ECG. Observed regional changes in depolarisation, repolarisation, and refractoriness may be important in the genesis of ventricular arrhythmias.

Class III antiarrhythmic action linked with positive inotropy: acute electrophysiological and inotropic effects of amiodarone in vitro.

Negative inotropy is an adverse feature of most antiarrhythmic drugs. Positive inotropy, however, has been demonstrated for some drugs with class III antiarrhythmic action. Although amiodarone exerts its antiarrhythmic effect by an interplay of different actions on cardiac cells, it has been regarded to be the prototype class III drug due to its prolongation of action potential duration. The present study was designed to test the hypothesis that class III antiarrhythmic action and positive inotropy may be linked. We compared the effects of amiodarone in Cordarone and its solvent Tween 80 on automaticity, refractoriness and inotropy. Two series of experiments were done; one with spontaneously beating rat atria to study the effects on sinus node function, and one with electrically stimulated left atria to study the effects on excitability, refractoriness and inotropy. Amiodarone 1 x 10(-4) M decreased spontaneous heart rate by 13% and prolonged sinus node recovery time by 105%. Without affecting the excitability amiodarone prolonged the effective refractory period by 12%. At the same time contractile force increased by 12%. Lower concentration of amiodarone (5 x 10(-6) M) or Tween 80 had no significant effects. In conclusion, amiodarone exerts acute electrophysiological and inotropic effects in vitro. The class III antiarrhythmic action of amiodarone is linked with positive inotropy.

Selenium deficiency and cardiac electrophysiological and mechanical function in the rat.

Earlier studies have shown that selenium and vitamin E are important in maintaining normal cardiac function. The present study was designed to test the effect of sole selenium deficiency on electrophysiological and mechanical characteristics of the rat heart. Male weanling rats were fed a standardized vitamin E adequate but selenium deficient diet, or a control diet. Deficiency of selenium was verified by direct (tissue selenium analyses) and indirect (glutathione-peroxidase tissue analyses) methods. In vivo electrocardiographic recordings as well as in vitro electrophysiological and mechanical recordings did not reveal abnormalities in any of the two groups. In conclusion, earlier studies have shown that the combined deficiency of selenium and vitamin E leads to abnormal cardiac function. Selenium deficiency alone, however, does not appear to significantly affect cardiac function in the rat.

Class III antiarrhythmic action linked with positive inotropy: effects of the d- and l-isomer of sotalol on isolated rat atria at threshold and suprathreshold stimulation.

The beta-adrenoceptor blocker sotalol has been shown to possess class III antiarrhythmic action. The present study was designed to test the hypothesis that class III antiarrhythmic action and positive inotropy may be linked. Since d,l-sotalol has previously been reported to have variable inotropic effect, we studied direct effects of the d- and l-stereoisomer of sotalol on refractoriness and inotropy of isolated rat atria at different strengths of electrical stimulation. Both the d- and l-stereoisomer of sotalol (7.5 x 10(-5) M) increased the effective refractory period, and to the same extent. However, d-sotalol increased isometric contractile force by 10%, while l-sotalol had no significant effect, when the atria were stimulated at close to threshold values (10 +/- 1 mA). Probably due to release of noradrenaline within the myocardium, contractile force increased when the atria were stimulated at suprathreshold values (40 mA). At suprathreshold stimulation, however, d-sotalol induced a 10% decrease and l-sotalol a 20% decrease, in contractile force. In conclusion, the class III antiarrhythmic action of sotalol is linked with positive inotropy. In the presence of neurotransmitter release, negative inotropic effect of d- and in particular l-sotalol, may occur due to beta-adrenoceptor blocking activity.