(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
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.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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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
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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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.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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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 Table
). 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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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 (Table
, Fig
1).
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(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 (Table, Fig 2).
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(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 (Table, Fig
3).
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(4) DL-Sotalol and D-sotalol were
applied to
preparations of failing left ventricles after pretreatment with
DL-propranolol (Table, Fig 4).
DL-Propanolol pretreatment was used to eliminate the
ß-adrenoceptor–blocking effects of these compounds.
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(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 (Table, Fig 5) to define
contractile
reserve.
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(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 (Table, Fig
6) to
define contractile reserve.
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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
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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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 1
;
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 
1000 (Fig
1).
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 3 and 4.
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 2, 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 10-4 mol/L, indicating that
DL-propranolol is 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
1 and 2.
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 3). 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 1 and
2, 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 4), 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
5). 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 5).
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 5).
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 6). 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 6).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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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 1). However,
DL-sotalol is 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 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 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
3).
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 4). 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
5).
In failing human left ventricles,
DL-sotalol may induce
opposite effects on contractility. First, the
ß-adrenoceptor–stimulating effect is blunted (Fig 6)
compared with control (Fig 5). 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 6). 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.
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Acknowledgments |
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This work was supported in part by the Deutsche Forschungsgemeinschaft (HO 915/4-2).
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Footnotes |
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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.
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