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Circulation. 1995;92:2904-2910

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(Circulation. 1995;92:2904-2910.)
© 1995 American Heart Association, Inc.

Articles

Positive and Negative Inotropic Effects of DL-Sotalol and D-Sotalol in Failing and Nonfailing Human Myocardium Under Physiological Experimental Conditions

Christian Holubarsch, MD; Ralf Schneider, MD; Burkert Pieske, MD; Thorsten Ruf, MD; Gerd Hasenfuss, MD; Gustav Fraedrich, MD; Herbert Posival, MD; Hanjörg Just, MD

From the Department of Cardiology and Angiology (C.H., R.S., B.P., T.R., G.H., H.J.), Internal Medicine, University of Freiburg; the Department of Cardiovascular Surgery (G.F.), University of Freiburg, Chirurgische Universitätsklinik; and the Center of Thoraxic- and Cardiovascular Surgery (H.P.), Cardiac Transplantation Center NRW, Germany.


*    Abstract
up arrowTop
 *Abstract
down arrowIntroduction
 down arrowMethods
down arrowResults
down arrowDiscussion
down arrowReferences
 
Background DL-Sotalol has class III antiarrhythmic activity through prolongation of the repolarization phase of the action potential as well as ß-adrenoceptor–blocking properties. Although the former effect was found to exert positive inotropic effects in animal experimental studies, the latter may be detrimental in heart failure due to negative inotropism. In contrast to DL-sotalol, D-sotalol is suggested to exert only positive inotropic effects, which were never tested in isolated human myocardium.

Methods and Results Therefore, we investigated the effects of racemic DL-sotalol and its enantiomer D-sotalol in human right atrial muscle strip preparations and in left ventricular muscle strip preparations from nonfailing and end-stage failing human hearts. DL-sotalol and D-sotalol significantly (P<.01) increased peak developed force in atrial preparations by 14.0±3.4% and 16.7±3.8%, respectively, but had no effect in ventricular myocardium. In nonfailing ventricular myocardium, both DL-sotalol and D-sotalol shifted the dose-response curve for isoproterenol to higher concentrations (P<.01); however, DL-sotalol was 100-fold more effective than D-sotalol. In nonfailing myocardium, a positive force-frequency relation was found between 30 and 120 beats per minute, but isoproterenol was much more powerful in its inotropic effects. In failing myocardium, reduction in stimulation rate from 120 to 30 beats per minute increased peak developed force more pronounced than did the application of isoproterenol.

Conclusions (1) D-Sotalol has no relevant ß-adrenoceptor–blocking activity compared with DL-sotalol. (2) Neither DL-sotalol nor D-sotalol exhibit positive inotropic effects in human left ventricular myocardium. (3) Heart rate reduction increases contractile force in end-stage failing human myocardium due to an inverse force-frequency relation and thereby counteracts the potential negative inotropic properties of ß-blockade.


Key Words: receptors • adrenergic • beta • myocardium • sotalol


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowMethods
down arrowResults
down arrowDiscussion
down arrowReferences
 
DL-Sotalol is a ß-blocker with an additional class III antiarrhythmic effect that is used widely in the treatment of cardiac arrhythmias.1 2 3 4 5 6 7 8 9 Because ventricular arrhythmias often occur in patients with reduced left ventricular ejection fractions, physicians must be aware of the potential negative inotropic effects of DL-sotalol, which may aggravate heart failure symptoms and thereby cause cardiac decompensation in those patients. However, in some clinical trials, left ventricular function has been found to be improved10 11 or unchanged12 13 with DL-sotalol. On the basis of these observations, it was hypothetized that the negative inotropic effect of ß-blockade may be compensated by a direct positive inotropic effect of DL-sotalol1 14 that has been described in some animal studies.6 8 15 16 17 18 19

Although the differences in ß-receptor–blocking characteristics of the isomers L-sotalol and D-sotalol are well explained by stereospecificity in receptor-ligand interactions, little is known about the direct positive inotropic effect of these compounds. In particular, no data are available for isolated human myocardium; studies in human myocardium are especially important in light of the divergent results depending on the species studied, the origin of myocardium, and the experimental conditions.7 9 15 17 18 19 20 21 22 We therefore investigated the positive inotropic effects of DL-sotalol and D-sotalol in atrial and ventricular human myocardium under physiological experimental conditions with DL-propranolol used as a control.

In addition, heart rate reduction through the use of DL-sotalol21 22 23 24 may favorably influence contractility in failing myocardium because the positive relation between heart rate and force development present in nonfailing myocardium is blunted or even reversed in ventricular myocardium from patients with end-stage heart failure.25 26 27

Therefore, we also compared the heart rate–dependent alterations of contractility with (1) the contractile reserve that can be recruited by maximum ß-adrenoceptor stimulation, (2) the negative inotropic effects due to ß-blockade by DL-sotalol, and (3) the potential direct positive inotropism of DL-sotalol.


*    Methods
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 up arrowAbstract
 up arrowIntroduction
 *Methods
down arrowResults
down arrowDiscussion
down arrowReferences
 
Sources of Myocardial Tissue
Atrial preparations were obtained from right human atria of patients without heart failure who were undergoing aortocoronary bypass surgery. Left ventricular preparations were obtained from explanted human hearts, including donor hearts that could not be used for transplantation for technical reasons and hearts from patients with end-stage heart failure who were undergoing cardiac transplantation (detailed data are given in the TableDown). In patients undergoing ACVB, previous medication included intravenous heparin, nitrates, calcium channel blockers, and ß-blockers. Patients with end-stage heart failure had been treated with digitalis (digoxin, digitoxin), diuretics (furosemide, xipamide, piretamide), angiotensin-converting enzyme inhibitors (captopril, enalapril), and, in some instances, intravenous low-dose dopamine. After surgical excision of myocardium, tissues were immediately submerged into Krebs-Ringer solution at room temperature containing 30 mmol/L butanedione monoxime.28 Transportation time during which the solution was constantly bubbled with 95% O2/5% CO2 was 30 minutes for atrial tissue and 7 hours for ventricular tissue.


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  		Table 1. Source of Cardiac Tissues, Number of Hearts and Preparations, Muscle Length, and Cross-sectional Area

Solutions and Instruments
The solution used in this study contained (in mmol/L): Na+ 152, K+ 3.6, Cl- 135, HCO3- 25, Mg2+ 0.6, H2PO4- 1.3, SO42- 0.6, Ca2+ 2.5, and glucose 11.2 and 10 IU/L insulin. This solution was continuously bubbled with a gas mixture of 5% CO2 and 95% O2. Solutions that were used for transportation and dissection purposes also contained 30 mmol/L BDM.28 29 30

The instruments used for dissection and preparation, for stimulation of preparations, and for registration of isometric force have been described previously.30

Study Protocol
The muscles were initially prestretched by a maximal load of 2.5 mN until force development was steady. Stimulation was performed with rectangular square-wave pulses of 5-millisecond duration at 25% above threshold. In all experiments, a stimulation at 60 beats per minute was used initially. In some experiments, stimulation was also performed at 30 or 120 beats per minute (see "Results"). After steady state conditions had been obtained, the muscles were carefully stretched to lmax (the optimum length at which maximum force is developed) by 0.05- and 0.10-mm stepwise stretches. The following experiments were performed at lmax.

(1) DL-Sotalol and D-sotalol were applied to muscle strips from normal left ventricles at increasing concentrations. When pharmacological concentrations were maximum (3x10-5 mol/L), isoproterenol was also applied (TableUp, Fig 1Down).



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  		Figure 1. Three dose-response curves for isoproterenol obtained in normal left ventricular human myocardium contracting isometrically driven at 60 beats per minute at an experimental temperature of 37°C. Without pretreatment (control; n=3 hearts, n=8 preparations), the EC50 is somewhat less than 3x10-8 mol/L isoproterenol. With pretreatment by D-sotalol, EC50 is significantly (P<.01) increased to {approx}10-7 mol/L (n=3 hearts, n=8 preparations). After pretreatment with DL-sotalol, the EC50 is {approx}1000 times higher than without pretreatment (n=3 hearts, n=8 preparations; P<.01). I indicates initial value.

(2) DL-Sotalol, D-sotalol, and DL-propranolol were applied to myocardial preparations obtained from failing left ventricles. Again, at the highest concentrations of these compounds (3x10-5 mol/L), isoproterenol was also applied (TableUp, Fig 2Down).



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  		Figure 2. Three dose-response curves for isoproterenol obtained in failing left ventricular myocardium contracting isometrically driven at 60 beats per minute at an experimental temperature of 37°C. Preparations were pretreated with increasing concentrations of D-sotalol (n=5 hearts, n=8 preparations), DL-sotalol (n=5 hearts, n=8 preparations), and DL-propranolol (n=4 hearts, n=6 preparations) up to final concentrations of 3x10-5 mol/L. After pretreatment with DL-propranolol, the EC50 is {approx}100 times higher than after pretreatment with DL-sotalol. Note that the response to isoproterenol is markedly blunted in failing human myocardium compared with normal human myocardium in Fig 1Up. I indicates initial value.

(3) The positive inotropic effects of DL-sotalol and D-sotalol were studied in atrial cardiac muscle preparations. To eliminate the ß-adrenoceptor–blocking effects of the compounds, all preparations were pretreated with DL-propranolol before the application of DL-sotalol and D-sotalol (TableUp, Fig 3Down).



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  		Figure 3. Dose-response curves for DL-sotalol (top; n=7 hearts, n=9 preparations) and D-sotalol (bottom; n=5 hearts, n=7 preparations) in atrial human preparations contracting isometrically (stimulation rate, 60 beats per minute; experiment temperature, 37°C). All preparations were pretreated with 10-5 mol/L DL-propranolol. One set of experiments was conducted as control experiments (n=6 hearts, n=6 preparations; 10-6 mol/L DL-propranolol only). Maximum increases in developed force were 14.0±3.4% with DL-sotalol (P<.01) and 16.7±3.8% with D-sotalol (P<.01). P indicates DL-propranolol; I, initial value.

(4) DL-Sotalol and D-sotalol were applied to preparations of failing left ventricles after pretreatment with DL-propranolol (TableUp, Fig 4Down). DL-Propanolol pretreatment was used to eliminate the ß-adrenoceptor–blocking effects of these compounds.



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  		Figure 4. Dose-response curves for DL-sotalol (n=5 hearts, n=6 preparations) and D-sotalol (n=7 hearts, n=9 preparations) in human failing left ventricular myocardium contracting isometrically (stimulation rate, 60 beats per minute; experimental temperature, 37°C). Preparations were pretreated with 10-6 mol/L DL-propranolol in the D-sotalol group and with 10-5 mol/L DL-propranolol in the DL-sotalol group, respectively. One set of experiments was conducted as control experiments (n=4 hearts, n=6 preparations; 10-6 mol/L DL-propranolol). No positive inotropic effect of DL-sotalol or D-sotalol can be detected despite significant contractile reserve recruited by isoproterenol. I indicates initial value; P, DL-propranolol 10-6 or 10-5 mol/L, respectively.

(5) Left ventricular preparations from nonfailing donor hearts were subjected to different stimulation rates (30, 60, and 120 beats per minute) after pretreatment with DL-sotalol. Thereafter, DL-sotalol was increased to a maximum of 3x10-5 mol/L, and isoproterenol was applied at increasing concentrations (TableUp, Fig 5Down) to define contractile reserve.



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  		Figure 5. Frequency-modulation plot of contractility versus dose-response curves for isoproterenol in normal left ventricular human myocardium (isometric contractions, 37°C; basal frequency, 60 per minute). Preparations (n=3 hearts, n=6 preparations) were pretreated with increasing concentrations of DL-sotalol. Thereafter, stimulation frequency was decreased to 30 beats per minute and increased to 120 beats per minute. Frequency modulation was performed at 3x10-6 mol/L DL-sotalol. The force-frequency relation is demonstrated to be positive. Note that the contractile reserve available by ß-receptor stimulation is much more effective than frequency-modulated alterations of contractile force. *P<.01 compared with pretreatment values.

(6) Left ventricular preparations from failing idiopathic dilated cardiomyopathy hearts were subjected to different stimulation rates (30, 60, and 120 beats per minute) after pretreatment with DL-sotalol. At a maximum concentration of 3x10-5 mol/L DL-sotalol, isoproterenol was applied at increasing concentrations (TableUp, Fig 6Down) to define contractile reserve.



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  		Figure 6. Frequency-modulation plot of contractility versus dose-response curves for isoproterenol in failing left ventricular human myocardium (isometric contractions, 37°C, basal frequency, 60 per minute). Preparations (n=5 hearts, n=9 preparations) were pretreated with increasing concentrations of DL-sotalol. Thereafter, stimulation frequency was decreased to 30 beats per minute and increased to 120 beats per minute. Frequency modulation was performed at 3x10-6 mol/L DL-sotalol. The force-frequency relation is demonstrated to be negative. Note that the contractile reserve available by ß-receptor stimulation is less than frequency-modulated alterations of contractile force. *P<.01 compared with pretreatment values.

The time that was allowed to elapse between changes of concentrations or before applying a second compound was at least 5 minutes. In most instances, a period of 5 minutes was sufficient to allow steady state conditions to occur.

DL-Sotalol and D-sotalol were obtained from Bristol-Myers-Squibb, and DL-propranolol, isoproterenol, and 2,3-butanedione-monoxime were obtained from Sigma Chemical Co.

Statistical Analysis
Because different numbers of preparations were obtained from each available heart, statistical analysis was performed as follows: mean values were obtained for each heart, and then these mean values were used to generate a mean value for the different hearts tested. Mean±SEM values are given in text. In the figures, values were normalized for baseline conditions; mean±SEM values are given. Comparisons of repeated measurements within groups were performed by paired t test and the Bonferroni-Holm procedure.31 32 Comparisons between groups was accomplished with ANOVA and the Student-Newman-Keuls test.31 32


*    Results
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
*Results
down arrowDiscussion
down arrowReferences
 
ß-Adrenoceptor–Blocking Properties of DL-Sotalol and D-Sotalol in Normal Left Ventricular Human Myocardium
After application of isoproterenol to normal left ventricular myocardium at increasing concentrations, without pretreatment, developed peak force increased by more than 100%, and the EC50 was somewhat less than 3x10-8 mol/L isoproterenol (Fig 1Up; n=3 hearts, n=8 preparations). When preparations were pretreated with D-sotalol (3x10-5 mol/L; n=3 hearts, n=8 preparations), the dose-response curve for isoproterenol was shifted significantly (P<.01) to the right by a factor of 10. When pretreatment was performed with DL-sotalol (3x10-5 mol/L; n=3 hearts, n=8 preparations), the dose-response curve for isoproterenol was shifted significantly (P<.01) to the right by a factor of {approx}1000 (Fig 1Up).

The observed continuous decrease of peak developed force with increasing concentrations of both D-sotalol and DL-sotalol results in part from a negative inotropic effect due to ß-blockade and from a rundown of the preparations. However, the experimental rundown is relatively small, as can be seen from Figs 3Up and 4Up.

ß-Adrenoceptor–Blocking Properties of DL-Propranolol, DL-Sotalol, and D-Sotalol in Failing Human Myocardium
Three dose-response curves for isoproterenol were obtained in failing left ventricular myocardium after pretreatment with increasing concentrations of D-sotalol (n=5 hearts, n=8 preparations), DL-sotalol (n=5 hearts, n=8 preparations), and DL-propranolol (n=4 hearts, n=6 preparations). In Fig 2Up, no positive inotropic effects can be detected with increasing concentrations of D-sotalol and DL-sotalol. In contrast, DL-sotalol and, in particular, DL-propranolol exert concentration-dependent negative inotropic effects in addition to experimental rundown effects. It is likely that electrical field stimulation, as was used in the present study, releases endogenous catecholamines from intramyocardial stores, the effect of which is blocked by DL-propranolol and DL-sotalol. More important is the fact that 3x10-5 mol/L propranolol shifts the EC50 of isoproterenol to values of {approx}10-4 mol/L, indicating that DL-propranolol is {approx}100 times more potent than DL-sotalol in ß-adrenoceptor–blocking properties.

Positive Inotropic Effects of DL-Sotalol and D-Sotalol in Atrial Muscle Preparations
Because DL-sotalol has clear ß-adrenoceptor–blocking properties, its potential positive inotropic effects may be hidden in the experiments shown in Figs 1Up and 2Up.

To prevent the negative inotropic effects of DL-sotalol and D-sotalol, preparations were pretreated with DL-propranolol at a concentration of 10-6 mol/L. Both D-sotalol and DL-sotalol significantly increased peak force development in atrial preparations at concentrations of 3x10-5 and 10-4 mol/L (Fig 3Up). The maximum increases of force development were 14.0±3.4% with DL-sotalol and 16.7±3.8% with D-sotalol. Both compounds induced significant prolongation of twitch contraction: at 3x10-5 and 10-4 mol/L, DL-sotalol prolonged total contraction duration significantly (P<.01) from 381±58 to 393±66 and 395±67 milliseconds, respectively.

Positive Inotropic Effects of DL-Sotalol and D-Sotalol in Failing Left Ventricular Myocardium
In the experiments shown in Figs 1Up and 2Up, no positive inotropic effect could be observed with either DL-sotalol or D-sotalol. Because ß-adrenoceptor–blocking properties of both compounds may counterpart their positive inotropic effects, failing ventricular preparations were pretreated with either 10-6 mol/L DL-propranolol (in the case of D-sotalol) or 10-5 mol/L DL-propranolol (in the case of DL-sotalol). In none of the failing left ventricular preparations could any positive inotropic effect of D-sotalol (n=7 hearts, n=9 preparations) or DL-sotalol (n=5 hearts, n=6 preparations) be detected (Fig 4Up), although sufficient contractile reserve could be recruited by isoproterenol.

Frequency-Dependent Potentiation of Force Development Versus ß-Adrenoceptor–Mediated Contractile Reserve in Nonfailing Myocardium
In nonfailing left ventricular human myocardium (n=3 donor hearts, n=6 preparations) pretreated with DL-sotalol, a decrease in force development by 28% was observed when stimulation rate was reduced from 1 to 0.5 Hz (Fig 5Up). On the other hand, an increase in stimulation rate from 1.0 to 2.0 Hz enhanced peak developed force by more than 50% (Fig 5Up). Compared with this frequency dependence of myocardial contractility, ß-adrenoceptor stimulation is much more powerful in normal human left ventricular myocardium: optimal concentrations of isoproterenol increase peak developed force by more than 200% (Fig 5Up).

Frequency-Dependent Potentiation of Force Development Versus ß-Adrenoceptor–Mediated Contractile Reserve in Failing Myocardium
In preparations from end-stage failing left ventricles (n=5 hearts, n=9 preparations), the force-frequency relation is reversed: reduction in stimulation rate from 1.0 to 0.5 Hz increases peak developed force by more than 30%, whereas an increase in stimulation rate from 1.0 to 2.0 Hz reduces peak developed force to 70% of control (Fig 6Up). Compared with these data, isoproterenol is less effective: at optimum concentrations of isoproterenol, peak developed force increased from 80% (control) to only 120% of the initial values in failing myocardium (Fig 6Up).


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
up arrowResults
*Discussion
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Study Rationale
The use of DL-sotalol and D-sotalol has never been studied in isolated left ventricular human myocardium. The differences in the ß-adrenoceptor–blocking properties between DL-sotalol and D-sotalol, which have been extensively investigated in animal experiments, are accepted to be representative for human myocardium. However, regarding the direct inotropic effects of both compounds, results from previous animal studies should not be accepted as representative for human myocardium because inotropic effects have been shown to be species, temperature, and rate dependent.7 9 15 17 18 19 20 21 22 30 Furthermore, because in failing human myocardium ß-adrenoceptor density and therefore contractile reserve to catecholamines are decreased33 34 35 and rate-dependent modulation of contractility is altered,25 26 27 it is important to investigate the use of DL-sotalol and D-sotalol in human failing myocardium.

We studied the inotropic effects of DL-sotalol and D-sotalol in comparison with DL-propranolol in human failing and nonfailing isolated myocardia. In addition, because of the pronounced negative chronotropic effects of DL-sotalol,36 37 38 we varied stimulation rates in both types of preparations to compare force-frequency relations with catecholamine effects.

ß-Adrenoceptor–Blocking Potency of D-Sotalol, DL-Sotalol, and DL-Propranolol
The ß-adrenoceptor–blocking properties of both DL-sotalol and D-sotalol are clearly demonstrated; the dose-response curve for isoproterenol is significantly shifted to higher isoproterenol concentrations with DL-sotalol and D-sotalol (Fig 1Up). However, DL-sotalol is {approx}100 times more effective than D-sotalol in ß-blockade. These findings are in good agreement with previous animal studies.6 7 8 9 The purity of D-sotalol was {approx}99%, and consequently L-sotalol may be present in experiments with D-sotalol at concentrations of 1/100th of D-sotalol. Therefore, we cannot exclude the possibility that our results obtained with D-sotalol regarding ß-blockade are due to contamination by L-sotalol.

To evaluate the ß-blocking potency of DL-sotalol, a direct comparison with DL-propranolol was performed: DL-propranolol shifted the dose-response curve to higher isoproterenol concentrations, indicating that the ß-blocking potency of DL-propranolol is {approx}100 times more pronounced than that of DL-sotalol. This finding is in good agreement with the reported pA2 values of 6.4 for DL-sotalol and 8.7 for DL-propranolol in animal studies1 9 and may partially explain some clinical observations that DL-sotalol is less cardiodepressive.10 11 12 13

Positive Inotropic Effects of D-Sotalol and DL-Sotalol
It has been postulated that DL-sotalol and D-sotalol may have positive inotropic properties because of their effects on the duration of the action potential.1 14 DL-Sotalol and D-sotalol exhibit significant positive inotropic effects in atrial human preparations (Fig 3Up).

These effects of DL-sotalol and D-sotalol may be related to the prolongation of action potential duration; however, at these high concentrations of the two compounds, other unspecific effects may also come into play. We consider these positive inotropic effects of DL-sotalol and D-sotalol to be without clinical relevance for the following reasons. First, the inotropic effect is small compared with ß-adrenoceptor–mediated changes in contractile force; second, the inotropic effect is observed at extremely high concentrations that are far above the concentrations necessary for maximum ß-blockade.

More important, no positive inotropic effects of DL-sotalol or D-sotalol were seen in human left ventricular myocardium (Fig 4Up). Although in the present study no measurements of action potentials were performed, it can be assumed that pharmacological concentrations of DL-sotalol profoundly prolong action potential durations. Echt et al40 and Schmitt et al22 report in vivo measurements that indicate significant prolongation of right ventricular monophasic action potentials at pharmacological concentrations of DL-sotalol. This prolongation of action potentials correlated directly with DL-sotalol plasma concentration.40 Average therapeutic plasma levels of 2.4 µg/mL DL-sotalol prolonged the action potential duration by 20%.22 42 Furthermore, this prolongation of action potentials was found to be heart rate dependent; the more pronounced the prolongation, the lower was the heart rate. We therefore conclude that action potential duration at pharmacological concentrations of DL-sotalol is present and contributes to heart rate reduction. This effect may be potentiated if a weak ß-blockade also lowers heart rate.

Effects of Frequency Modulation on Contractile Force
In two additional experiments, we compared the potential negative inotropic effects of DL-sotalol induced via ß-blockade with alterations of contractility that are heart rate dependent. These experiments were carried out in both nonfailing and failing left ventricular human myocardia. In accordance with previous studies, in nonfailing human myocardium, the force-frequency relation is positive,41 whereas in failing human myocardium, the force-frequency relation is reversed.23 24 25 Therefore, reduction of heart rate through application of ß-blockade may exert a positive inotropic effect and thereby counteract the potential negative inotropic action of myocardial adrenoceptor blockade in failing human myocardium.

In nonfailing human left ventricles, DL-sotalol may have a negative inotropic effect through two mechanisms: (1) It blocks adrenoceptors and thereby eliminates the positive inotropic effects of endogenous catecholamines, (2) it reduces heart rate and thereby exerts an indirect negative inotropic effect due to the positive force-frequency relation. However, ß-blockade is the more powerful effect when maximum alterations are compared (Fig 5Up).

In failing human left ventricles, DL-sotalol may induce opposite effects on contractility. First, the ß-adrenoceptor–stimulating effect is blunted (Fig 6Up) compared with control (Fig 5Up). This effect is clearly explained by ß-receptor downregulation in the failing myocardium.33 34 35 Second, the heart rate–dependent modulation of contractile force is inversed compared with normal human myocardium, ie, a decrease in heart rate improves contractile performance, whereas an increase in heart rate decreases peak developed force. More important, the contractile reserve available by ß-adrenoceptor stimulation was shown to be less pronounced than the frequency-modulated alteration of contractility (Fig 6Up). Therefore, ß1-blockade in nonfailing human left ventricles may decrease contractility directly through myocardial ß1-blockade and indirectly through reduction in heart rate. In failing human left ventricles, the negative inotropic effect of ß-blockade may be compensated or even overcompensated by the indirect positive inotropic effect induced by reduction of heart rate.

Clinical Relevance of the Data
The data of the present study are of clinical importance because they add new information to the understanding of the myocardial effects of DL-sotalol in the failing heart. (1) The hypothesis of a direct positive inotropic effect of DL-sotalol on left ventricular myocardium that may counteract the cardiodepressive action due to ß-blockade is rejected. (2) Compared with DL-propranolol, ß-adrenoceptor–blocking potency of DL-sotalol is less pronounced despite similar effects on heart rate. (3) In failing left ventricular human myocardium, alterations in contractile force induced by frequency modulation are of the same order of magnitude as those induced by ß-adrenoceptor stimulation or blockade. Therefore, weak cardiodepressive effects of DL-sotalol may easily be compensated or even overcompensated for by an indirect positive inotropic effect induced by heart rate reduction in the failing human myocardium. Because the effect on heart rate is brought about by the combination of a prolongation of the repolarization phase of the action potential and a weak ß-blockade, DL-sotalol is unique and may be superior to other ß-blockers43 44 45 in the long-term treatment of chronic congestive heart failure.


*    Acknowledgments
 
This work was supported in part by the Deutsche Forschungsgemeinschaft (HO 915/4-2).


*    Footnotes
 
Reprint requests to Prof Dr Christian Holubarsch, Department of Cardiology and Angiology, University of Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany.

Received November 9, 1993; revision received May 17, 1995; accepted June 23, 1995.


*    References
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
up arrowResults
up arrowDiscussion
*References
 

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