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(Circulation. 1999;99:305-311.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Unique Cardioprotective Action of the New Calcium Antagonist Mibefradil
From the Abteilung für Pathophysiologie, Zentrum für Innere Medizin des Universitätsklinikums Essen, Germany.
Correspondence to Prof Dr Gerd Heusch, FESC, FACC, Abteilung für Pathophysiologie, Zentrum für Innere Medizin, Universitätsklinikum Essen, Hufelandstraße 55, 45122 Essen, Federal Republic of Germany.
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Abstract |
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Background—Mibefradil is a calcium antagonist with few negative inotropic effects at therapeutic concentrations.
Methods and Results—The effect of mibefradil on infarct size (IS) was compared with those of placebo, amlodipine, and verapamil in 64 anesthetized pigs. In placebo pigs, after 90 minutes of ischemia and 120 minutes of reperfusion, IS (by triphenyl tetrazolium chloride staining) was 15.3±10.8% (SD) of the area at risk. Mibefradil (0.60 mg/kg IV) reduced heart rate and left ventricular (LV) pressure, and IS was 1.9±3.9% (P<0.05 versus placebo). Verapamil (0.15 mg/kg IV) also decreased heart rate, LV pressure, and IS (6.1±4.2%, P<0.05 versus placebo). Amlodipine (0.20 mg/kg IV) did not alter heart rate, LV pressure, or IS (9.9±5.4%, P=NS versus placebo). When heart rate was maintained constant by left atrial pacing and LV pressure was adjusted to that of the placebo group by an intra-aortic balloon, mibefradil still decreased IS (3.8±3.0%, P<0.05 versus placebo), but verapamil did not (11.6±8.3%, P=NS versus placebo). With glibenclamide infusion, mibefradil no longer reduced IS (13.1±4.3% versus 17.8±5.6% with glibenclamide alone, P=NS).
Conclusions—The IS-limiting effect of mibefradil, in contrast to that of verapamil, was not dependent on favorable hemodynamics but was abolished by glibenclamide, suggesting a direct cardioprotective action of mibefradil.
Key Words: calcium • mibefradil • myocardial infarction
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Introduction |
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TopAbstractIntroductionMethodsStep 3Data Analysis and StatisticsResultsDiscussionAddendumReferences |
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Controversy continues about the ability of calcium antagonists to reduce infarct size.1,2 Diltiazem consistently reduced infarct size in ischemia/reperfusion models3–7 as well as in a permanent occlusion model.8 Verapamil reduced infarct size in some9–13 but not all2,10 ischemia/reperfusion models; results in permanent occlusion models are also controversial (no reduction2,14,15 versus reduction of infarct size16,17). Except for one study,18 dihydropyridines did not alter infarct size in ischemia/reperfusion models12,13,19–21; once again, results in permanent occlusion models are controversial (no reduction14,22,23 versus reduction of infarct size14,22,24–26). Part of these controversial findings may be explained by the timing of treatment, ie, pre versus early versus late treatment.
Apart from these divergent effects of calcium antagonists on experimental infarct size, their clinical use in the acute phase of myocardial infarction is limited, because they reduce perfusion pressure and exert negative inotropic effects, which are of particular concern in patients with left ventricular (LV) dysfunction.27
The benzimidazolyl-substituted teraline derivative mibefradil selectively inhibits T-type calcium channels in vitro at concentrations that only partially block L-type calcium channels.28 In patients with chronic stable angina pectoris, mibefradil reduced the number of ischemic episodes by 70%29 and increased exercise duration, time to onset of angina, and time to persistent 1-mm ST-segment depression,30 with few negative inotropic effects.31 In the anesthetized dog,32 mibefradil reduced infarct size to an extent comparable to that of verapamil but to a lesser extent than ischemic preconditioning. In this study, however, both calcium antagonists also reduced heart rate and blood pressure.
Therefore, in the present study in anesthetized pigs, the effect of mibefradil on infarct size in the presence and absence of favorably altered systemic hemodynamics was compared with that of placebo and 2 other calcium antagonists, amlodipine and verapamil, at equipotent coronary dilator doses. To further elucidate the underlying mechanism of cardioprotection, mibefradil was infused in the presence of glibenclamide.
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Methods |
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The experimental protocols used in this study were approved by the Bioethical Committee of the district of Düsseldorf.
Experimental Model
The experimental model has been described
elsewhere33; in brief, 64 Göttinger
miniswine (20 to 40 kg) of either sex were initially sedated with
ketamine hydrochloride and anesthetized with
sodium thiopental; anesthesia was then maintained
with enflurane with an oxygen/nitrous oxide mixture. Rectal temperature
was monitored, and body temperature was kept between 37°C and 38°C
with heating pads. Both common carotid arteries were cannulated, one
for the measurement of arterial pressure and the insertion
of an intra-aortic balloon (5F Fogarty, Baxter Deutschland GmbH) and
the other to supply blood to the extracorporeal circuit. A left lateral
thoracotomy was performed, and a micromanometer was
placed in the left ventricle through the apex.
The proximal left anterior descending coronary artery (LAD) was cannulated and perfused from an extracorporeal circuit. Before coronary cannulation, the pigs were anticoagulated with sodium heparin. The system included a roller pump, Windkessel, and 2 side ports for the injection of radiolabeled microspheres and the infusion of drugs. Coronary arterial pressure was measured from the sidearm of a polyethylene T connector. Heart rate was controlled by left atrial pacing.
Regional Myocardial Blood Flow
Radiolabeled microspheres (15-µm diameter;
141Ce, 114In,
51Cr, 113Sn,
103Ru, 95Nb, or
46Sc; NEN–Du Pont Co) were injected into the
coronary perfusion circuit (1x105 to
2x105 suspended in 1 mL saline) to determine the
regional myocardial blood flow in the LAD perfusion bed (model 5912,
Gammaszint BF 5300, Packard). The averaged subendocardial blood flow to
the entire LAD-perfused territory was measured and related to
myocardial infarct size.
Morphology
The heart was sectioned from base to apex into 5 transverse
slices in a plane parallel to the atrioventricular
groove. The tissue slices were immersed in a 0.09 mol/L sodium
phosphate buffer (pH 7.4) containing 1.0% triphenyl tetrazolium
chloride (TTC, Sigma) and 8% dextran (molecular weight,
77 800) for 20 minutes at 37°C to identify infarcted tissue.
Reductions of blood flow during ischemia by >85% were taken
to indicate myocardium at risk.34
Infarct size is expressed as a percentage of the LV area at
risk.
Experimental Protocols
In a first step, the effect of mibefradil on infarct size was
compared with that of amlodipine and verapamil. Because
only mibefradil and verapamil significantly reduced infarct
size, the importance of decreases in heart rate and LV pressure for
such cardioprotection was investigated in a second step. Because
mibefradil in the presence of matched heart rate and LV pressure still
reduced infarct size, an effect similar to that of ischemic
preconditioning, the importance of activation of ATP-dependent
potassium channels (KATP) for the effect of
mibefradil was assessed in the third step. Activation of
KATP is the most likely end effector of
ischemic preconditioning.35
A total of 8 groups of pigs were studied (Figure 1
). In each group, systemic
hemodynamics and regional myocardial blood flow were
measured under control conditions and at 5 and 90 minutes after the
reduction in coronary blood flow, which was set to decrease
mean coronary arterial pressure to 
30
mm Hg. After 90 minutes of ischemia, the
myocardium was reperfused for 120 minutes to facilitate the
identification of necrotic tissue.
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Step 1
Placebo (Group 1, n=9).
After control measurements, 1 mL/min saline solution was infused
intravenously over 30 minutes.
Mibefradil (Group 2, n=9) or Amlodipine (Group 3, n=9), or
Ve-rapamil (Group 4, n=8).
After control measurements, either mibefradil (0.60 mg/kg)
[(1S,2S)-2-(2-[(3-2(benzimidazolyl)propyl)methylamino]ethyl)-6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthyl-methoxy-acetate
dihydrochloride], or amlodipine (0.20 mg/kg), or verapamil
(0.15 mg/kg) was infused intravenously. The peak free
plasma concentration with 0.6 mg/kg mibefradil averaged 348±44 (SD)
ng/mL in 4 additional pigs. At constant coronary
arterial pressure, each of the calcium
antagonists doubled coronary blood flow within 20
to 25 minutes after its administration. Measurements were performed no
earlier than 30 minutes after administration of the calcium
antagonist before coronary blood flow was
reduced.
Step 2
Mibefradil (Group 5, n=9) or Verapamil
(Group 6, n=6) Plus Matched Heart Rate and LV Pressure.
After control measurements, either mibefradil or verapamil
was infused intravenously. Measurements were repeated 30
minutes after administration of either drug and once again in the
presence of matched heart rate and LV pressure before coronary
blood flow was reduced.
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Step 3 |
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Glibenclamide (Group 7, n=7).
After control measurements, glibenclamide was infused intravenously (0.5 mg/kg bolus followed by 0.5 mg/min). This dose regimen has previously been demonstrated to abolish ischemic preconditioning in the same porcine preparation.33 Thirty minutes after the bolus injection of glibenclamide, measurements were repeated before coronary blood flow was reduced.
Glibenclamide Plus Mibefradil Plus Matched Heart Rate and LV
Pressure (Group 8, n=7).
After control measurements, glibenclamide was infused
intravenously. Thirty minutes after the bolus injection of
glibenclamide, mibefradil was infused intravenously.
Measurements were repeated in the presence of matched heart rate and LV
pressure before coronary blood flow was reduced.
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Data Analysis and Statistics |
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Hemodynamic parameters were continuously digitized and recorded. A 20-second period during each microsphere injection (
33 consecutive beats over 
2
complete respiratory cycles) was analyzed with CORDAT II
software.33 Hemodynamic
parameters were calculated on a beat-to-beat basis, and
data were then averaged. The incidence of ventricular
extrasystoles was determined from a surface ECG lead and counted in
5-minute intervals, starting 10 minutes before ischemia in
group 1 and 10 minutes before drug infusion in groups 2 through 8. Statistical analysis was performed with SYSTAT software. Hemodynamic data were compared by 2-way ANOVA for repeated measures. Area at risk and infarct size were compared by 1-way ANOVA. When significant differences were detected, individual mean values were compared by use of least significant difference post hoc tests. Data are reported as mean±SD; a value of P<0.05 was accepted as indicating a significant difference. Linear regression analyses between subendocardial blood flow at 5 minutes of ischemia in the area at risk and infarct size were performed in all groups and compared by ANCOVA.
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Results |
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There were no significant differences in any measured parameter between groups under control conditions (Table
).
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Thirty minutes after administration of either mibefradil (group 2) or amlodipine (group 3) or verapamil (group 4), coronary blood flow was almost doubled. LV pressure decreased in all groups, but heart rate was reduced only with mibefradil and verapamil. Glibenclamide (groups 7 and 8) slightly increased LV pressure. In the presence of glibenclamide, at matched heart rate and LV pressure, mibefradil had no effect on systemic hemodynamics during control conditions.
In all groups, by a decrease in the pump speed, coronary blood flow was reduced. In groups 1 through 6, LV pressure was significantly decreased at 5 minutes of ischemia. During the remainder of the 90-minute ischemic period, systemic hemodynamics did not change further.
Arrhythmias
In all groups, the incidence of arrhythmias was <2 within
a 5-minute interval before ischemia. During ischemia,
the incidence of extrasystoles increased, with a peak between 40 and 60
minutes of ischemia. The peak rate of extrasystoles averaged
14±25, 10±25, 10±21, 5±9, 5±7, 4±5, 12±15, and 4±4
(P=NS) per 5-minute interval in groups 1 through 8,
respectively.
Infarct Size
The area at risk was comparable among all groups (Figures 2, 4, and 6). Infarct size tended to be
decreased with amlodipine but was reduced significantly only with
mibefradil (P<0.05 versus placebo and amlodipine) and
verapamil (P<0.05 versus placebo) (Figure 2).
Subendocardial blood flow in the area at risk at 5 minutes of
ischemia correlated inversely with infarct size (Figure 3). The relationships between infarct
size and subendocardial blood flow were shifted downward significantly
with mibefradil (P<0.05 versus placebo and amlodipine) and
verapamil (P<0.05 versus placebo) (Figure 3).
At matched heart rate and LV pressure, the decrease in infarct size
with verapamil was no longer significant (Figure 4). The relationships between
subendocardial blood flow and infarct size in the placebo and
verapamil groups were now superimposable, whereas the
relationship was still shifted downward significantly with mibefradil
(P<0.05 versus placebo and verapamil, Figure 5). Glibenclamide prevented the
significant decrease in infarct size achieved by mibefradil (Figure 6), and the relationships between
subendocardial blood flow and infarct size in the glibenclamide and
glibenclamide+mibefradil groups were superimposable (Figure 7).
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Discussion |
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In the present study, both mibefradil and verapamil, in contrast to amlodipine, reduced infarct size. The infarct size–limiting effect of mibefradil, in contrast to that of verapamil, was not dependent on decreases in heart rate and LV pressure. Infarct size reduction by mibefradil was abolished by glibenclamide, suggesting that mibefradil and ischemic preconditioning may converge to the same effector, the activation of KATP.
Critique of Methods
Infarct size as determined by TTC staining after 90 minutes of
ischemia and 2 hours of reperfusion was one major end point of
the present study. Studies from different laboratories have used
TTC staining to delineate myocardial necroses within such a time frame
of ischemia/reperfusion.36–38
In pigs, complete occlusion of the LAD results in a high incidence of ventricular fibrillation and extensive infarction of the left ventricle, with subsequent pump failure. Therefore, the LAD perfusion territory was hypoperfused at low but maintained flow, resulting in a large area at risk (45% of the LV mass) but a small infarct size when expressed as a percentage of the area at risk (15.3±10.8% in group 1). However, infarct size expressed as a percentage of total LV mass in the present study averaged 8% in the placebo group and was thus comparable to that in a previous study using pigs with total occlusion of only one distal LAD branch (7%).39 Many patients suffering from coronary artery disease over prolonged periods of time develop an extensive collateral circulation.40 In this scenario, an acute total occlusion of one coronary artery will result in low-flow rather than no-flow ischemia in the dependent myocardium. Technically, perfusion at low flow permits the delivery of drugs throughout the ischemic period. Also, low-flow hypoperfusion in our study allowed us to relate infarct size to ischemic subendocardial blood flow. Apart from the size of the area at risk, ischemic blood flow is the major determinant of infarct development,41 and therefore the relation of infarct size to subendocardial blood flow is a more sensitive end point than infarct size per se.
In the present study, a dose dependency of the effect of mibefradil was not established. The peak free plasma concentration of mibefradil averaged 348±44 (SD) ng/mL and thus was close to the peak free plasma concentration of 200 to 700 ng/mL with oral application of 50 to 100 mg mibefradil in patients, respectively.42 Although the mibefradil dose in the present study thus appears to be clinically relevant, the doses of amlodipine and verapamil were chosen with reference to their equipotent coronary dilation.
Mibefradil and Infarct Size
The extent of infarct size reduction with mibefradil was similar
to that achieved by ischemic preconditioning in the same animal
model.33 Activation of KATP
is the most likely end effector of ischemic
preconditioning.35 In the present study,
blockade of KATP by glibenclamide prevented the
infarct size reduction achieved by mibefradil. Activation of
KATP results in shortening of action potential
duration,33 and indeed,
mibefradil,43 like ischemic
preconditioning,33 also reduces action potential
duration. However, glibenclamide also blocks chloride channels at
higher concentrations,44 and blockade of chloride
channels has been demonstrated to contribute to protection from
ischemia/reperfusion injury.45 Classic
KATP openers, such as cromakalim, increase the
incidence of ventricular arrhythmias and
fibrillation in the scenario of
ischemia/reperfusion.46 Although
mibefradil may interact with KATP, the incidence
of arrhythmias with mibefradil was not different from that with
placebo. In the anesthetized dog,32
mibefradil reduced infarct size to a lesser extent than
ischemic preconditioning. One potential explanation for the
observed difference in the extent of cardioprotection between this and
the present study is the mibefradil concentration used. In the
anesthetized dog, mibefradil was infused at a high
concentration of up to 40 µmol/L, whereas in the present
study, the concentration was <10 µmol/L. In cultured cardiac
fibroblasts, mibefradil at concentrations <10 µmol/L reduces
the intracellular calcium content, whereas at higher concentrations (10
to 100 µmol/L), the intracellular calcium content is
significantly elevated,47 possibly as a result of
calcium release from intracellular stores. Such intracellular calcium
release at high mibefradil concentrations might partially offset its
otherwise infarct-size-reducing effect. In anesthetized
rats,48 the infarct size reduction after
mibefradil infusion was also independent of changes in the
rate-pressure product. However, the extent of infarct-size
reduction was less than that observed in the present study.
Clinical Implications
The experimental model used in the present study can be
extrapolated only to the situation of patients pretreated with
mibefradil who suffer an acute myocardial infarction and are reperfused
within 90 minutes after the onset of ischemic symptoms. Whether
the results of the present study can also be extrapolated to a
broader spectrum of coronary artery disease, ie, whether
patients will also have less irreversible tissue damage and better
prognosis if reperfusion is lacking or treatment is started after the
onset of ischemic symptoms, remains to be determined.
In 1992, Opie49 introduced, entirely on experimental grounds, the concept of ischemia selectivity of calcium antagonists, which was later expanded by Heusch.50 Mibefradil—interestingly, as initially hypothesized by Opie49—might indeed be classified as an ischemia-selective agent with few negative inotropic effects but a marked cardioprotective effect on ischemic myocardium.
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Addendum |
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Since this article was written, the manufacturer has withdrawn mibefradil from the market because of serious drug interactions but not because of its lack of cardioprotection.
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Acknowledgments |
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The present study was supported by Hoffman–La Roche AG, Grenzach, Germany. We thank Claus Martin, PhD, and Ursula Prägler for the chemical analyses and Petra Gres for her technical support.
Received June 9, 1998; revision received August 13, 1998; accepted August 20, 1998.
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