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(Circulation. 1997;95:2108-2114.)
© 1997 American Heart Association, Inc.
Articles |
Vesnarinone Limits Infarct Size via Adenosine-Dependent Mechanisms in the Canine Heart
From the First Department of Medicine, Osaka University School of Medicine, Suita (M.K., T.M., H.F., K.N., M.H.), and Tokai University School of Medicine, Department of Physiology, Isehara (Y.S., H.M.), Japan.
Correspondence to Masafumi Kitakaze, MD, PhD, The First Department of Medicine, Osaka University School of Medicine, 2-2 Yamadaoka, Suita 565, Japan.
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Abstract |
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Background Recently, vesnarinone, a synthetic inotropic agent, was reported to inhibit adenosine transport into cells, which may increase adenosine levels in the heart and in turn mediate cardioprotection. Thus, vesnarinone may also have protective effects in sustained ischemia-reperfusion, because adenosine limits infarct size.
Methods and Results In open-chest dogs, the left
anterior descending coronary arteries were occluded for 90
minutes followed by 6 hours of reperfusion. Vesnarinone limited infarct
size compared with controls (6.8±2.2% versus 44.7±3.9%), which was
completely reversed by a nonselective adenosine receptor
antagonist, 8-sulfophenyltheophylline (44.1±6.8%), and
partially blunted by an inhibitor of ecto-5'-nucleotidase,
,ß-methyleneadenosine 5'-diphosphate (AMP-CP,
28.9±4.7%). Dipyridamole, an inhibitor of
adenosine uptake into cells, only modestly limited infarct size
(27.4±5.5%). Furthermore, vesnarinone increased adenosine
release during coronary hypoperfusion, which was attenuated by
AMP-CP. In vitro, vesnarinone increased the activity of
ecto-5'-nucleotidase of the myocardium.
Conclusions We conclude that vesnarinone potently limits infarct size via adenosine-dependent mechanisms, mainly through activation of ecto-5'-nucleotidase.
Key Words: ischemia • reperfusion • adenosine • myocardial infarction • coronary disease
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Introduction |
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Vesnarinone, a quinolinone derivative, is an oral inotropic agent.1 2 3 Although several investigators suggest the cardioprotective effects of vesnarinone,1 2 3 4 the inotropic activity of vesnarinone seems to be unrelated to its cardioprotective effects, since several other inotropic agents, eg, phosphodiesterase inhibitors, do not mediate cardioprotection.5 6 7 Since vesnarinone inhibits phosphodiesterase,8 it is important to distinguish the differences in pharmacological and physiological effects between vesnarinone and the other phosphodiesterase inhibitors. Interestingly, phosphodiesterase inhibitors do not attenuate the severity of myocardial ischemia, whereas vesnarinone is reported to be protective in the ischemic myocardium in a canine heart model.4 Vesnarinone is also known to attenuate TNF-
production in patients with heart failure9
and in the experimental model of myocarditis.10 However,
there is no evidence that TNF- is directly linked with
ischemia-reperfusion injury,11 and thus, the
effects of vesnarinone on TNF- are unlikely to contribute to
cardioprotection for ischemic heart disease. Recently, Kumakura
et al12 reported that vesnarinone inhibits
adenosine uptake into the cells, which may lead to increases in
adenosine levels in the heart. Since adenosine is known
to be cardioprotective, especially in ischemic heart
diseases,13 14 15 the beneficial effects of vesnarinone in
such conditions may be adenosine-dependent. We have previously
reported that activation of ecto-5'-nucleotidase is potently
cardioprotective against ischemia-reperfusion
injury.16 17 18 19 Thus, it is of interest to see whether
vesnarinone may also activate myocardial ecto-5'-nucleotidase
and further potentiate the release of adenosine. The present study was undertaken to examine whether vesnarinone activates ecto-5'-nucleotidase and thus limits infarct size via adenosine-dependent mechanisms.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Instrumentation
Mongrel dogs (protocols 1 through 3) weighing 14 to 23 kg were anesthetized with pentobarbital sodium (30 mg/kg IV). The setup of the experiment was reported previously.16 17 18 19 20 In open-chest dogs, after administration of heparin (500 U/kg IV), we cannulated and perfused the LAD with blood via the left carotid artery through an extracorporeal bypass tube. CBF of the perfused area was measured with an electromagnetic flow probe attached at the bypass tube, and CPP was monitored at the tip of the coronary arterial cannula. A small, short collecting tube was cannulated into a small coronary vein near the center of the perfused area to sample coronary venous blood. The left atrium was catheterized for microsphere injection. The femoral artery was also cannulated for sampling of reference (control) blood as well as measurement of aortic blood pressure. The left atrium was catheterized for microsphere injection. The pH, Po2, and Pco2 in the systemic arterial blood before the protocols were instituted were 7.39±0.02, 107±3 mm Hg, and 38.0±2.1 mm Hg, respectively. In the dogs used in protocol 1, we measured left ventricular pressure, dP/dt, and segment length of the perfused area, as described previously.20
Experimental Protocols
Protocol 1: Effects of vesnarinone on
adenosine release from nonischemic and ischemic
myocardium. After hemodynamic
stabilization, coronary arterial and venous blood
was sampled. Hemodynamic parameters, ie,
systolic and diastolic aortic blood pressures,
heart rate, CPP, and CBF, were monitored. In the nonischemic
condition (n=5), we infused (1) DMSO (167
µg·kg-1·min-1;
infusion rate, 0.0167
mL·kg-1·min-1;
concentration of the solution, 10 mg/mL) for 7 minutes, (2) vesnarinone
(20
µg·kg-1·min-1;
0.0167
mL·kg-1·min-1;
1.2 mg/mL) dissolved with DMSO for 7 minutes, and (3) AMP-CP (80
µg·kg-1·min-1;
0.0167
mL·kg-1·min-1;
4.8 mg/mL) under administration of vesnarinone+DMSO for another 7
minutes. We measured coronary hemodynamic and
metabolic parameters at 7 minutes of each
infusion. In the other dogs, we decreased CPP so that CBF decreased to
60% of the baseline control flow. Thereafter, CBF was maintained
unchanged. Five minutes after the onset of coronary
hypoperfusion, we measured coronary hemodynamic
and metabolic parameters (control group, n=6).
Furthermore, we infused DMSO (167
µg·kg-1·min-1;
0.0167
mL·kg-1·min-1;
10 mg/mL) for 7 minutes into the LAD and vesnarinone (12
µg·kg-1·min-1;
0.0167
mL·kg-1·min-1;
0.72 mg/mL) with DMSO for another 7 minutes into the LAD. We also
measured coronary hemodynamic and
metabolic parameters at 7 minutes of each
infusion of DMSO or DMSO+vesnarinone. We also performed an identical
protocol under the administration of either 8-SPT (n=5) or AMP-CP
(n=5). Either 8-SPT (50
µg·kg-1·min-1;
0.0167
mL·kg-1·min-1;
3.0 mg/mL) or AMP-CP (80
µg·kg-1·min-1;
0.0167
mL·kg-1·min-1;
4.8 mg/mL) was administered 5 minutes before the onset of
coronary hypoperfusion and was administered continuously
throughout the experiments. The vesnarinone concentration in
coronary arterial blood in the ischemic and
nonischemic conditions became 
10 to 15 µg/mL. Regional
myocardial blood flow was determined by the microsphere
technique, as described in detail previously.21
Microspheres were administered 5 minutes after the onset of
coronary hypoperfusion.
Protocol 2: Effects of vesnarinone on 5'-nucleotidase activity. In 5 dogs, the myocardial tissue was sampled from the perfused areas of the LAD and left circumflex coronary artery and was frozen and stored under liquid nitrogen. The activity of 5'-nucleotidase was measured by enzymatic assay after incubation with vesnarinone (0.01, 0.1, 1, 10, and 100 µg/mL) with 0.1% DMSO or 0.1% DMSO alone for 30 minutes.
Protocol 3: Effects of vesnarinone on infarct size after 90 minutes of ischemia. After hemodynamic stabilization, coronary arterial and venous blood was sampled for blood gas analysis. Hemodynamic parameters, ie, systolic and diastolic aortic blood pressures and heart rate, were monitored. In the control group (n=7), the bypass tube to the LAD was occluded for 90 minutes, followed by 6 hours of reperfusion with administration of only DMSO (167 µg·kg-1·min-1; 0.0167 mL·kg-1·min-1; 10 mg/mL) 10 minutes before 90 minutes of coronary occlusion until 1 hour of reperfusion except during coronary occlusion. Hemodynamic parameters were monitored during myocardial ischemia and after the onset of reperfusion. In the vesnarinone group (n=7), vesnarinone (20 µg·kg-1·min-1, 0.0167 mL·kg-1·min-1, 1.2 mg/mL) with DMSO was infused 10 minutes before the onset of coronary occlusion and was continued for 60 minutes after the onset of reperfusion except during the coronary occlusion period. In the vesnarinone+8-SPT group (n=6) and the vesnarinone+AMP-CP group (n=6), the effects of vesnarinone were tested under the concomitant administration of either 8-SPT (50 µg·kg-1·min-1; 0.0167 mL·kg-1·min-1; 3.0 mg/mL) or AMP-CP (80 µg·kg-1·min-1; 0.0167 mL·kg-1·min-1; 4.8 mg/mL). In the 8-SPT group (n=7) and the AMP-CP group (n=7), 90 minutes of ischemia and 6 hours of reperfusion were performed under the treatments with 8-SPT and AMP-CP. We also examined the effects of dipyridamole (10 µg·kg-1·min-1; 0.0167 mL·kg-1·min-1; 0.6 mg/mL; n=5; dipyridamole group). The dose of dipyridamole used in this protocol is the minimal dose that mediates the maximal limitation of infarct size (44±3% [n=3], 36±4% [n=3], 28±4% [n=3], and 27±4% [n=3] and 1, 5, 10, and 20 µg·min-1·kg-1 dipyridamole instead of infusion of vesnarinone in the preliminary study). Infarct size was assessed at 6 hours of reperfusion, as was previously reported.18 Microspheres were administered 45 minutes after the onset of coronary occlusion.21
Chemical Analysis
Lactate was assessed by enzymatic assay, and LER was obtained by
coronary arteriovenous difference in lactate concentration
multiplied by 100 and divided by arterial lactate
concentration.20 The method of adenosine
measurements has been reported previously20 22 23 ; we
reported the difference in adenosine levels in coronary
venous and arterial blood and calculated adenosine
release with the equation CBF times the difference in adenosine
levels in coronary venous and arterial blood.
For the measurements of ecto- and cytosolic 5'-nucleotidase of the myocardium, the preparation of the myocardium has been reported previously.16 24 Activity of 5'-nucleotidase was assessed by the enzymatic assay technique24 and was reported in units of mol·g protein-1·min-1. Protein content was assayed by the Lowry method.25
Criteria for Exclusion
To ensure that all of the animals included in the data
analysis of infarct size in protocol 3 were healthy and exposed
to similar extents of ischemia, the following standards were
used to exclude unsatisfactory dogs: (1) subendocardial collateral flow
>15 mL·100
g-1·min-1, (2)
heart rate >170 bpm, and (3) more than two consecutive attempts
required to convert ventricular fibrillation with
low-energy DC pulses applied directly to the heart.
Statistical Analysis
Statistical analyses were performed with
ANOVA26 27 when the data were compared among the groups.
When ANOVA reached a significant level, we compared pairs of data using
the Bonferroni test. Time courses in the changes in the
hemodynamic metabolic
parameters were compared by ANOVA for repeated measures.
ANCOVA with endocardial collateral blood flow in the inner half of the
LV wall as the covariate was used to account for the effect of
endocardial collateral blood flow on infarct size. Each value was
expressed as mean±SEM, with P<.05 considered
significant.
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Results |
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Effects of Vesnarinone on Adenosine Release From Nonischemic Myocardium
Infusions of DMSO, vesnarinone, and AMP-CP into the LAD did not alter systemic hemodynamic parameters (Table 1
). Infusion of DMSO increased CBF slightly but
did not affect the other parameters. During the infusion of
vesnarinone, FS increased slightly, and both CBF and the release of
adenosine were increased; these increases were not blunted by
AMP-CP. LER did not change throughout the experiments.
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Effects of Vesnarinone on Adenosine Release From
Ischemic Myocardium During Coronary
Hypoperfusion
Table 2 depicts the systemic and coronary
hemodynamic and metabolic
parameters before and during coronary
hypoperfusion. Administration of either 8-SPT or AMP-CP did not alter
systemic, coronary hemodynamic, or
metabolic parameters. Before the reduction of
CBF and CPP, there were no significant differences in the
hemodynamic and metabolic
parameters among the three groups. During the constant low
CBF in the three groups, CPP under treatment with either 8-SPT or
AMP-CP was higher than in the untreated condition, probably because of
lack of vasodilatory effects of adenosine. In the untreated
condition, administration of DMSO did not affect either CPP, LER, or
FS. However, addition of vesnarinone decreased CPP and increased both
LER and FS even under the constant low CBF condition, suggesting that
myocardial ischemia is improved by vesnarinone. These effects
of vesnarinone were blunted by administration with either AMP-CP or
8-SPT. The endocardial-to-epicardial flow ratio during administration
of vesnarinone was increased from 0.77±0.05 to 0.89±0.01
(P<.05); this increase was blunted by the administration of
either 8-SPT (0.73±0.02 and 0.72±0.03 with and without 8-SPT,
respectively) or AMP-CP (0.78±0.01 and 0.76±0.02 with and without
AMP-CP, respectively). Fig 1 shows the changes in
adenosine release during constant reduction of CBF. Vesnarinone
increased the release of adenosine during coronary
hypoperfusion, which was attenuated by AMP-CP. Fig 2
shows ecto- and cytosolic 5'-nucleotidase in the presence or absence of
vesnarinone. Vesnarinone increased ecto-5'-nucleotidase activity
dose-dependently. These results indicate that vesnarinone increases
adenosine production in the ischemic heart in
part by the activation of ecto-5'-nucleotidase.
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VA) and adenosine release during coronary
hypoperfusion. Vesnarinone increased both
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Effects of Vesnarinone on the Infarct Size–Limiting Effect: Role
of Adenosine-Dependent Mechanisms
Sixty-six dogs were randomly assigned to seven protocols for
assessment of infarct size. Nine dogs were excluded from the data
analysis because the subendocardial collateral flow was >15
mL·100
g-1·min-1.
Therefore, 57 dogs completed the protocol satisfactorily and were used
for data analysis. Among the 57 dogs, 15 developed
ventricular fibrillation at least once. Among these 15
dogs, ventricular fibrillation that fulfilled the exclusion
criteria occurred in 12 dogs, which were also excluded from the
study.
Aortic systolic and diastolic blood pressures
(140/90 mm Hg) and heart rate (140 bpm) did not vary
among the seven groups throughout the protocol. Percent risk area in
the left ventricle (40%) and endocardial collateral blood flow
during myocardial ischemia (7 to 8 mL·100
g-1·min-1) were
not significantly different among the seven groups. Fig 3 shows that vesnarinone markedly attenuates infarct
size compared with the control group; this was completely blunted by
8-SPT and partially attenuated by AMP-CP. On the other hand,
dipyridamole modestly limited infarct size
(27.4±5.5%) to the level of the vesnarinone+AMP-CP group. The infarct
size–limiting effect of vesnarinone is attributable to uptake
inhibition of adenosine into the cells and activation of
ecto-5'-nucleotidase. The regression plots of infarct size against the
collateral blood flow are depicted in Fig 4, which also
shows that the infarct size–limiting effect of vesnarinone is
attributable to adenosine-dependent mechanisms.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In the present study, we demonstrate that vesnarinone increases adenosine release in the ischemic and nonischemic hearts via ecto-5'-nucleotidase–dependent and –independent mechanisms. We further elucidated that vesnarinone limits infarct size and that the infarct size–limiting effect of vesnarinone is attributable to adenosine-dependent mechanisms.
Role of Vesnarinone in Adenosine Release From the
Heart
In the present study, vesnarinone increased the release of
adenosine with increases in CBF in the nonischemic
heart, and this increase in adenosine release was not
attenuated by AMP-CP, suggesting that vesnarinone can increase
adenosine release via mechanisms independent of
ecto-5'-nucleotidase. Although we have shown that ecto-5'-nucleotidase
is activated by vesnarinone, the amount of substrates for
ecto-5'-nucleotidase, ie, AMP in the interstitial fluid,
may be too small to produce adenosine via ecto-5'-nucleotidase
in the nonischemic condition. Of importance, in the
nonischemic heart, basal adenosine release from the
myocardium is reported to be attributable mainly to
S-adenosylhomocysteine hydrolase.13 On the
other hand, Kumakura et al 12 reported that vesnarinone
inhibits adenosine uptake into the cells, which may increase
adenosine concentrations in the various tissues. This effect of
vesnarinone may be responsible for the increase in adenosine
release in the nonischemic heart, although we cannot exclude
the possibility of the contribution of adenosine deaminase,
adenosine kinase, and S-adenosylhomocysteine
hydrolase. We excluded the possibility of increases in cytosolic
5'-nucleotidase as a factor in the increases in adenosine
release due to vesnarinone, because vesnarinone did not alter cytosolic
5'-nucleotidase activity (Fig 2
). Another possibility is that
vesnarinone can increase AMP concentrations in the cytoplasm, because
vesnarinone increases cAMP contents via inhibition of
phosphodiesterases, which may be degraded to AMP in the cells, thereby
leading to an increase in adenosine production.
In contrast, in the ischemic heart, the release of adenosine was markedly enhanced by vesnarinone, which was largely attenuated by AMP-CP. Furthermore, we have shown that vesnarinone increases ecto-5'-nucleotidase activity dose-dependently, indicating that activation of ecto-5'-nucleotidase is responsible for adenosine release in the ischemic myocardium. In the ischemic condition, it is reported that the concentration of AMP around the cells increases because of ischemic and hypoxic stress,28 29 30 which may allow ecto-5'-nucleotidase to produce adenosine. Interestingly, the release of adenosine was not completely blunted by AMP-CP, although we used saturating amounts of AMP-CP to inhibit ecto-5'-nucleotidase. This result suggests that increases in adenosine release due to vesnarinone in the ischemic heart are in part attributable to the inhibition of adenosine uptake into the cardiomyocytes and to the activation of ecto-5'-nucleotidase.
Infarct Size–Limiting Effects of Vesnarinone: Role of
Adenosine
In the present study, we report that vesnarinone limits
infarct size via adenosine-dependent mechanisms. Vesnarinone
was originally developed as a mild inotropic agent for the effective
treatment of ischemic and nonischemic heart failure. In
addition to its inhibitory effects on phosphodiesterases,
vesnarinone decreases delayed outward rectifying K+
currents,31 which decreases cellular K+
currents, and increases intracellular Na+ concentration
caused by the prolonged opening of Na+
channels.32 However, these two actions of vesnarinone may
not explain the infarct size–limiting effect, because these two
actions instead increase infarct size because of increases in
intracellular Ca2+ concentrations in the ischemic
and reperfused myocardium. On the other hand, vesnarinone
has been reported to decrease heart rate slightly, which may be
cardioprotective.33 However, in the present study,
since we infused vesnarinone into the coronary artery directly,
neither heart rate nor aortic blood pressure was decreased, because
only a low dose of vesnarinone was necessary for intracoronary
infusion (Table 2), suggesting that reduction of the work load imposed
on the heart by vesnarinone may not contribute to the infarct size
limitation in the present study. Vesnarinone also induces
coronary vasodilation,33 which may contribute to
the infarct size limitation via increased collateral blood flow during
myocardial ischemia. However, this possibility was denied
because in the present study, collateral blood flows in the
untreated and vesnarinone groups were not different. Vesnarinone is
reported to inhibit production of cytokines in heart
failure and experimental myocarditis,9 10 suggesting that
vesnarinone may limit infarct size through attenuation of
cytokines, ie, IL-1, IL-1ß, TNF-, and
interferon-
.10 It has been shown that both IL-6 and
IL-8 are increased in acute myocardial infarction.11
However, there is no direct evidence that cytokines expand
infarct size.
Interestingly, the present study reveals another aspect of vesnarinone that contributes to cardioprotection in ischemic heart disease: Vesnarinone limits infarct size via adenosine-dependent mechanisms. 8-SPT abolished the infarct size–limiting effect of vesnarinone, and AMP-CP attenuated the vesnarinone-induced increases in adenosine release and the infarct size–limiting effect by 70%. Since this dose of AMP-CP almost completely inhibits ecto-5'-nucleotidase,17 34 the remaining 30% of the vesnarinone-induced enhanced release of adenosine and cardioprotection may be attributable to the inhibition of adenosine uptake into the cells.12 The presence of both activation of ecto-5'-nucleotidase and inhibition of adenosine uptake may be most effective in adenosine concentration in the heart. We have reported that activation of ecto-5'-nucleotidase contributes to the cardioprotection afforded by ischemic preconditioning.16 17 18
Activation of ecto-5'-nucleotidase may occur by phosphorylation, as seen in the case of ischemic preconditioning in which activation of protein kinase C possibly leads to activation and phosphorylation of ecto-5'-nucleotidase.19 However, activation of ecto-5'-nucleotidase due to transient exposures to vesnarinone disappeared when vesnarinone was washed out (data not shown), whereas methoxamine, which phosphorylates ecto-5'-nucleotidase, activated ecto-5'-nucleotidase for 1 hour.18 This suggests that vesnarinone does not activate ecto-5'-nucleotidase via phosphorylation. Rather, direct interaction of vesnarinone on the active site of ecto-5'-nucleotidase, such as Mg2+, may be responsible for vesnarinone-induced activation of this enzyme.
Adenosine-Dependent Mechanisms by Which Vesnarinone Reduces
Infarct Size
Several lines of evidence support the idea that adenosine
administration markedly attenuates ischemia-reperfusion
injury.35 36 37 38 Thus, administration of adenosine or
potentiation of adenosine release is effective in improving the
contractile function and limiting infarct size during reperfusion after
sustained myocardial ischemia. We have previously shown that
adenosine A1 as well as A2 receptor
activation improves contractile dysfunction39 by (1)
inhibition of norepinephrine release from the presynaptic
vesicles and attenuation of Ca2+ influx into myocytes via
A1 receptors through the inhibitory G
protein40 41 42 and (2) increases in CBF, inhibition of
platelet aggregation, and leukocyte activation via A2
receptors through the stimulatory G protein.42 43 44 45
Clinical Relevance and Limitations
Here, we demonstrated that vesnarinone limits infarct size via
adenosine-dependent mechanisms. It is intriguing to relate the
infarct size–limiting effect of vesnarinone to the clinical settings
of acute myocardial infarction with coronary
revascularization, because adenosine
administered during reperfusion limits infarct size.13 14
Furthermore, since adenosine can precondition
myocardium to obtain myocardial tolerance before sustained
ischemia,15 administration of vesnarinone may be
useful for pretreatment of patients with coronary
arterial diseases to make the myocardium
resistant to acute myocardial infarction in the clinical
settings. Further validation is necessary to develop vesnarinone as a
drug to treat acute ischemic heart diseases.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by a Grant-in-Aid for Scientific Research (No. 05454272 and 05670617) from the Ministry of Education, Science, and Culture, Japan. We thank Drs Taku Kambayashi, Jim Cone, and Masuhiro Yoshitake for helpful discussions. We also thank Makoto Hasegawa, Kayoko Yoshida, and Yukiyo Nomura for technical assistance in performing the animal experiments and measuring 5'-nucleotidase activity.
Received October 2, 1996; revision received November 13, 1996; accepted November 25, 1996.
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