From the Department of Medicine III (K.H., I.K., D.H., Y.Y.), University
of Tokyo School of Medicine, Tokyo, Japan; Lead Generation Research
Laboratories (T.S.), Tanabe Seiyaku Co, Ltd, Osaka, Japan; and Institute of
Applied Biochemistry (K.M.), University of Tsukuba, Ibaraki, Japan.
Correspondence to Issei Komuro, MD, Department of Medicine III, University of Tokyo School of Medicine, 7–3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan. E-mail komuro-tky{at}umin.u-tokyo.ac.jp
Methods and Results—To determine the role of
angiotensin II (Ang II) in IR injury, we examined infarct
size and arrhythmias after IR using Ang II type 1a receptor
(AT1a) knockout mice. The left coronary artery was occluded for
30 minutes followed by reperfusion for 120 minutes. There were no
significant differences in infarct size between wild-type and knockout
mice determined by dual staining with
triphenyltetrazolium chloride and Evans
blue dye. The number of ventricular premature beats after
reperfusion in knockout mice, however, was much less than in wild-type
mice. Treatment with a selective AT1 antagonist, CV-11974,
before ischemia blocked reperfusion arrhythmias in
wild-type mice but had no effects on infarct size.
Conclusions—Ang II may be critically involved in the induction of
ventricular arrhythmias but not in the
determination of infarct size after IR.
Blockade of the renin-angiotensin system with AT1
antagonists has also been reported to have beneficial
effects on MI and congestive heart failure.5
There are two major subtypes of Ang II receptors, AT1 and AT2, and AT1
receptors are further subdivided into AT1a and AT1b
receptors.6 It is generally accepted that most of
the well-known Ang II functions in the cardiovascular
system are mediated through AT1.6 However, recent
pharmacological studies3 4 have demonstrated that
an AT1 antagonist, losartan, has no effect on
infarct size after IR in vivo. In isolated heart, however, an AT1
antagonist, TCV 116, reduces release of creatine kinase
after global ischemia.7 Thus, whether Ang
II is involved in IR injury is still controversial.
We8 and others9 have
recently generated AT1a KO mice by gene targeting. The blood pressure
of AT1a KO mice was lower than that of WT mice, suggesting that
AT1a-mediated Ang II signaling is essential for the maintenance
of systemic blood pressure.8 9 Recent
studies10 have suggested that AT1b may contribute
to the regulation of blood pressure when AT1a is absent. In the
present study, to determine the role of Ang II in IR injury, we
examined infarct size and arrhythmias after IR in AT1a KO
mice.
Assessment of AAR and Infarct Size After IR Injury
Electrocardiography During IR
Injury
Statistical Analyses
Infarct Size After IR
Reperfusion Arrhythmias
It has been reported3 4 that although ACE
inhibitors reduced infarct size after IR, this beneficial
effect was abolished by a bradykinin antagonist, Hoe 140.
Direct AT1 stimulation by Ang II or AT1 blockade by losartan
also did not alter the degree of infarct size in vivo
context.4 All these results suggest that AT1 is
not involved in the determination of infarct size after IR. There has
been one report,7 however, that demonstrates that
the AT1 antagonist TCV 116 decreases the release of
creatine kinase in an isolated heart model after IR. Therefore, the
role of AT1 in determining infarct size after IR has not been
established. In the present study, there was no difference in
infarct size among the three animal groups (Fig 1
Reperfusion-induced arrhythmias are postulated to be associated
with major alterations in
[Ca2+]i
levels.12 Recent
studies13 14 have shown an association between an
increase in [Ca2+]i and
the induction of ventricular arrhythmias. In
addition, it has also been reported that the calcium channel blocker
verapamil can attenuate
electrophysiological
alterations15 and that ryanodine, an
inhibitor of calcium release from the sarcoplasmic
reticulum, can decrease the occurrence of reperfusion
arrhythmias.12 These observations suggest
that an increase in
[Ca2+]i plays an
important role in reperfusion arrhythmias. However, the
underlying mechanism of calcium overload during reperfusion remains
unknown. In the present study, we found that both genetic deletion
of the AT1a gene and treatment with the AT1 antagonist
CV-11974 significantly attenuated reperfusion arrhythmias. It
is well known that Ang II not only increases Ca2+
influx through the L-type Ca2+ channel but also
induces Ca2+ release from intracellular stores
through AT1.6 These results suggest that Ang II
may play a major role in calcium overload during reperfusion, which is
closely related to the incidence of reperfusion arrhythmias. In
addition, Ang II induces the release of catecholamines,
which also may result in an increase of
[Ca2+]i.6
ACE inhibitors have also been shown to exert beneficial
effects on inhibition of arrhythmias as well as reduction of
infarct size.1 3 Because bradykinin, which is
increased with the treatment of ACE inhibitors, may release
norepinephrine,16 blockade of AT1 may
more completely suppress the release of catecholamines.
Consistent with our findings, an AT1 antagonist,
losartan, has been recently reported to attenuate
ventricular tachyarrhythmias during
reperfusion.17 Finally, there was no significant
difference in the incidence of arrhythmias between AT1
antagonist–treated WT mice and KO mice. In addition, in
spite of the highly activated renin-angiotensin
system in AT1a KO mice, fewer arrhythmias were observed in KO
mice than in control mice during reperfusion, suggesting that AT1b may
not play a major role in the induction of reperfusion
arrhythmias. Together with our findings that infarct size was
comparable in three animal groups, the present results suggest that
Ang II may be an independent endogenous inducer of
arrhythmia in the heart during IR injury and that AT1
antagonists may be useful in preventing reperfusion
arrhythmias.
Received October 27, 1997;
revision received November 24, 1997;
accepted December 1, 1997.
2.
Pfeffer JM, Braunwald E, Moye LA, Basta L, Brown EJ
Jr, Cuddy TE, Davis BR, Geltman EM, Goldman S, Flaker GC. Effect of
captopril on mortality and morbidity in patients with left
ventricular dysfunction after myocardial infarction:
results of the Survival And Ventricular Enlargement trial.
N Engl J Med. 1992;327:669–677.[Abstract]
3.
Liu YH, Yang XP, Sharov VG, Sigmon DH, Sabbah HN,
Carretero OA. Paracrine systems in the cardioprotective effect of
angiotensin-converting enzyme inhibitors on
myocardial ischemia/reperfusion injury in rats.
Hypertension.. 1996;27:7–13.
4.
Hartman JC, Hullinger TG, Wall TM, Shebuski RJ.
Reduction of myocardial infarct size by ramiprilat is
independent of angiotensin II synthesis inhibition.
Eur J Pharmacol. 1993;234:229–236.[Medline]
[Order article via Infotrieve]
5.
ELITE Study Investigators. Randomised trial of
losartan versus captopril in patients over 65 with heart
failure (Evaluation of Losartan in the Elderly Study, ELITE).
Lancet.. 1997;349:747–752.[Medline]
[Order article via Infotrieve]
6.
Timmermans PBMWM, Wong PC, Chiu AT, Herblin WF,
Benfield P, Carini DJ, Lee RJ, Wexler RR, Saye JAM, Smith RD.
Angiotensin II receptors and angiotensin II
receptor antagonists. Pharmacol Rev.. 1993;45:205–251.[Medline]
[Order article via Infotrieve]
7.
Yoshiyama M, Kim S, Yamagishi H, Omura T, Tani T,
Yanagi S, Toda I, Teragaki M, Akioka K, Takeuchi K, Takeda T.
Cardioprotective effect of the angiotensin II type 1
receptor antagonist TCV 116 on ischemia-reperfusion
injury. Am Heart J.. 1994;128:1–6.[Medline]
[Order article via Infotrieve]
8.
Sugaya T, Nishimatsu S, Tanimoto K, Takimoto E,
Yamagishi T, Imamura K, Goto S, Imaizumi K, Hisada Y, Otsuka A, Uchida
H, Sugiura M, Fukuta K, Fukamizu A, Murakami K. Angiotensin
II type 1a receptor-deficient mice with hypotension and hyperreninemia.
J Biol Chem.. 1995;270:18719–18722.
9.
Ito M, Oliverio MI, Mannon PJ, Best CF, Maeda N,
Smithies O, Coffman TM. Regulation of blood pressure by the type 1A
angiotensin II receptor gene. Proc Natl Acad Sci
U S A.. 1995;92:3521–3525.
10.
Oliverio MI, Best CF, Kim HS, Arendshorst WJ, Smithies
O, Coffman TM. Angiotensin II responses in AT1A
receptor-deficient mice: a role for AT1B receptors in blood pressure
regulation. Am J Physiol.. 1997;272:F515–F520.
11.
Hutter JJ, Mestril R, Tam EKW, Sievers RE, Dillmann WH,
Wolfe CL. Overexpression of heat shock protein 72 in transgenic mice
decreases infarct size in vivo. Circulation.. 1996;94:1408–1411.
12.
Thandroyen FT, McCarthy J, Burton KP, Opie LH.
Ryanodine and caffeine prevent ventricular
arrhythmias during acute myocardial ischemia and
reperfusion in rat heart. Circ Res.. 1988;62:306–314.
13.
Kihara Y, Morgan JP. Intracellular calcium and
ventricular fibrillation: studies in the aequorin-loaded
isovolumic ferret heart. Circ Res.. 1991;68:1378–1389.
14.
Brooks WW, Conrad CH, Morgan JP. Reperfusion induced
arrhythmias following ischaemia in intact rat heart: role of
intracellular calcium. Cardiovasc Res.. 1995;29:536–542.[Medline]
[Order article via Infotrieve]
15.
Hirayama Y, Saitoh H, Atarashi H, Hayakawa H.
Electrical and mechanical alternans in canine myocardium in
vivo: dependence on intracellular calcium cycling.
Circulation.. 1993;88:2894–2902.
16.
Minisi AJ, Thames MD. Distribution of left
ventricular sympathetic afferents demonstrated by reflex
responses to transmural myocardial ischemia and to
intracoronary and epicardial bradykinin.
Circulation.. 1993;87:240–246.
17.
Matsuo K, Kumagai K, Annoura M, Yamanouchi Y, Handa K,
Nakashima Y, Hiroki T, Arakawa K. Effects of an angiotensin
II antagonist on reperfusion arrhythmias in dogs.
Pacing Clin Electrophysiol.. 1997;20:938–945.[Medline]
[Order article via Infotrieve]
© 1998 American Heart Association, Inc.
Brief Rapid Communications
Angiotensin II Type 1a Receptor Is Involved in the Occurrence of Reperfusion Arrhythmias
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—A growing body of
evidence has suggested that the renin-angiotensin system
plays an important role in the development of cardiac
hypertrophy induced by hemodynamic overload
and left ventricular remodeling after myocardial
infarction. The role of the renin-angiotensin system in
ischemia-reperfusion (IR) injury, however, has not been
established.
Key Words: reperfusion • arrhythmia • angiotensin • myocardial infarction
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Occlusion of
coronary arteries induces myocardial necrosis. Although
restoration of blood flow is the only way to save the
myocardium from eventual necrosis, reperfusion often
exacerbates myocardial damage. This IR injury includes expansion of the
infarction area and the occurrence of life-threatening
arrhythmias.1 Many
studies2 3 have demonstrated that ACE
inhibitors have beneficial effects on IR injury as well as
on MI and congestive heart failure. These effects of ACE
inhibitors have been attributed to both blockade of Ang II
synthesis and a decrease in breakdown of bradykinin, which may
stimulate the production of prostaglandin and
nitric oxide.4
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
IR Injury Model in Murine Hearts In Vivo
All protocols were approved by local institutional guidelines.
Animals were assigned to three groups: AT1a KO mice 10 to 14 weeks of
age (n=5), age-matched control (no drug) WT mice (n=7), and AT1
antagonist–treated (CV-11974; 0.1 mg/kg IV) WT mice (n=5)
from the same genetic background were bred as previously
described.8 IR was produced by transiently
ligating the LCA as previously described.11 In
brief, animals were anesthetized with sodium pentobarbital (50
mg/kg IP) and artificially ventilated. After opening the left chest,
the heart was exposed and a reversible snare occluder, consisting of
8–0 nylon surgical suture and a polyethylene tube, was placed around
the proximal LCA under ECG monitoring (surface ECG lead I or II).
Animals underwent 30 minutes of LCA occlusion followed by 120 minutes
of reperfusion. Body temperature was maintained between 35°C and
37°C by heating lamps. The agents were injected into the jugular vein
5 minutes before the onset of ischemia and had no effect on
blood pressure or heart rate.
Infarct size was estimated as described
previously.11 In brief, after reperfusion for 120
minutes, the LCA was reoccluded and 100 µL of Evans blue dye was
injected into the LV cavity. The heart was excised immediately. The
atria and right ventricular free wall were removed, and the
LV was cut transversely into five sections. The AAR was the area not
stained by the Evans blue dye. Sections of the ventricle were incubated
in 1.5% TTC solution for 10 minutes. After TTC staining, viable
myocardium was stained brick red; infarct regions were not
stained by the TTC and were pale white. Each slice was then
photographed with a charge-coupled device (CCD) camera and
recording equipment (Atto Corp), weighed, and quantified by use
of image analysis software (NIH Image; NIH, Research Service
Branch). The fractions of both AAR to total slice size and infarct size
to total slice size were calculated and multiplied by the weight of the
slice to determine AAR and infarct weight per slice. Infarct size was
expressed as a percentage of LV mass and of the AAR.
ECGs (lead I or II) were obtained by subcutaneously inserting
needle electrodes into the limbs and were recorded for 1 minute
during the control period before occlusion, for 1 minute at 15 and 30
minutes after occlusion, and for 120 minutes from the start of
reperfusion. The duration of VT and the number of VPBs were
analyzed.
All results are expressed as mean±SEM. Multiple comparisons
among three groups were carried out by two-way ANOVA and Fisher's
exact test for post hoc analyses.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
This study summarizes results from 17 mice (AT1a KO, n=5; control
WT, n=7; and AT1 antagonist–treated WT, n=5). Two control
WT mice were dead immediately after reperfusion owing to
ventricular fibrillation. Fifteen of 17 mice survived the
experiments, and 5 mice in each group were used for the following
assessment.
Because we ligated the LCA at the most proximal portion, the
coronary artery occlusion consistently created a large
AAR. The size of MI in KO mice was almost identical to that in the
other two groups. There were no significant differences in infarct
size/LV, AAR/LV, or infarct size/AAR ratios among the three animal
groups (Fig 1
).
View larger version (22K):
[in a new window]
Figure 1. Infarct size after IR. The LCA was occluded for 30
minutes followed by reperfusion for 120 minutes. There were no
significant differences in infarct and ischemic risk areas
among the three animal groups. Control indicates control WT mice;
CV-11974, CV-11974–treated WT mice.
VT was defined as a run of three or more consecutive, rapid VPBs
that were morphologically similar to each other (Fig 2A). No VPBs were detected during
ischemia, and almost all VPBs were observed within 10 minutes
after reperfusion in the three animal groups. The number of VPBs was
27±8 in controls, 5±3 in drug-treated WT mice, and 4±2 in KO mice
(Fig 2B). Nonsustained VT occurred in all five WT mice, with an average
duration of 13±5 seconds, whereas there was no VT or
ventricular fibrillation in either the five KO mice or the
five AT1 antagonist–treated WT mice (Fig 2C).
View larger version (20K):
[in a new window]
Figure 2. A, Examples of ventricular
arrhythmias in WT mice. Paper speed: 25 mm/s during sinus
rhythm and episodes of VT and VPBs (arrowheads). B, The incidence of
VPBs during 10 minutes of reperfusion. *P<.01 versus
controls. C, Duration of VT (in seconds). **P<.01
versus AT1a KO mice and CV-11974. VF indicates ventricular
fibrillation; Control, control WT mice; and CV-11974, CV-11974–treated
WT mice.
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
The cardioprotective efficacy of AT1 antagonists
during IR injury has been controversial.3 7 In
the present study, we tried to clarify the role of AT1 in IR injury
using AT1a KO mice. Although there was no difference in infarct size
between control WT mice and KO mice, KO mice showed less
postreperfusion ventricular arrhythmias than WT
mice. In addition, treatment with an AT1 antagonist,
CV-11974, also elicited preventive effects on reperfusion
arrhythmias in WT mice. These results suggest that during IR,
Ang II is involved in the induction of arrhythmias through
AT1. 
), strongly suggesting
that AT1 is not involved in determining infarct size after IR.
Selected Abbreviations and Acronyms
AAR
=
area at risk
Ang II
=
angiotensin II
AT1
=
angiotensin II type 1 receptor
AT1a
=
angiotensin II type 1a receptor
AT1b
=
angiotensin II type 1b receptor
[Ca2+]i
=
intracellular calcium
IR
=
ischemia-reperfusion
KO
=
knockout
LCA
=
left coronary artery
LV
=
left ventricle, left ventricular
MI
=
myocardial infarction
TTC
=
triphenyltetrazolium chloride
VPB
=
ventricular premature beat
VT
=
ventricular tachycardia
WT
=
wild-type
Acknowledgments
This work was supported by a grant-in-aid for scientific
research and developmental scientific research from the Ministry of
Education, Science, and Culture and a grant from the Study Group of
Molecular Cardiology, Japan (Dr Komuro). We are very
grateful to Hiroshi Chiyonobu for animal care and acknowledge Takeda
Chemical Industries, Ltd (Osaka, Japan) for providing
CV-11974.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
1.
Parrot JR. Cardioprotection by
angiotensin converting enzyme inhibitors: the
experimental evidence. Cardiovasc Res.. 1994;28:183–189.
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|
|
|
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D. Li, B. Yang, M. I. Philips, and J. L. Mehta Proapoptotic effects of ANG II in human coronary artery endothelial cells: role of AT1 receptor and PKC activation Am J Physiol Heart Circ Physiol, March 1, 1999; 276(3): H786 - H792. [Abstract] [Full Text] [PDF]
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S. N. Harrison, D. J. Autelitano, B. H. Wang, C. Milano, X.-J. Du, and E. A. Woodcock Reduced Reperfusion–Induced Ins(1,4,5)P3 Generation and Arrhythmias in Hearts Expressing Constitutively Active {alpha}1B-Adrenergic Receptors Circ. Res., December 14, 1998; 83(12): 1232 - 1240. [Abstract] [Full Text] [PDF]
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B. C. Yang, M. I. Phillips, Y. C. Zhang, B. Kimura, L. P. Shen, P. Mehta, and J. L. Mehta Critical Role of AT1 Receptor Expression After Ischemia/Reperfusion in Isolated Rat Hearts : Beneficial Effect of Antisense Oligodeoxynucleotides Directed at AT1 Receptor mRNA Circ. Res., September 7, 1998; 83(5): 552 - 559. [Abstract] [Full Text] [PDF]
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