(Hypertension. 1997;30:735.)
© 1997 American Heart Association, Inc.
Articles |
Role of Kinins in the Cardioprotective Effect of Preconditioning
Study of Myocardial Ischemia/Reperfusion Injury in B2 Kinin Receptor Knockout Mice and Kininogen-Deficient Rats
From the Hypertension and Vascular Research Division and the Electrophysiology Laboratory (C.R.W.), Division of Cardiology, Department of Medicine, Henry Ford Hospital, Detroit, Mich.
Correspondence to Xiao-Ping Yang, MD, Hypertension and Vascular Research Division, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI 48202.
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Abstract |
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Abstract Kinins acting on the B2 receptor appear to be involved in the cardioprotective effect of preconditioning on myocardial ischemia/reperfusion injury. We tested the hypothesis that in mice lacking the gene encoding for the B2 kinin receptor (B2 knockout mice; B2-KO) as well as in rats deficient in high-molecular-weight (HMW) kininogen (Brown Norway Katholiek rats; BNK), the cardioprotective effect of preconditioning is diminished or abolished. 129SvEvTac (SV129) mice and Brown Norway rats (BN) served as controls. We confirmed that plasma HMW kininogen in BNK rats was 100-fold lower than in BN and 140-fold lower than in Sprague-Dawley rats (33±4 versus 1814±253 and 2397±302 ng/mL, P<.01). Each strain of mice was divided into (1) controls (without preconditioning); (2) one cycle of preconditioning (3 minutes ligation and 5 minutes reperfusion); and (3) three cycles of preconditioning. Each strain of rats was divided into (1) controls; and (2) three cycles of preconditioning. All animals were subjected to 30 minutes of ischemia and 120 minutes of reperfusion. In SV129 controls, the ratio of infarct size to risk area (IS/AR) was 55.6±4.6%. One and three cycles of preconditioning reduced IS/AR to 38.6±3.2% and 31.1±2.3%, respectively (P<.05 and P<.01 versus control). This protective effect was absent in B2-KO mice: IS/AR was 54.8±2.9% in controls, 58.5±3.6% with one cycle of preconditioning, and 58.5±3.4% with three cycles. In BN rats without preconditioning, IS/AR was 84.7±3.9%; preconditioning reduced it to 61.6±3.4% (P<.01). In BNK rats, IS/AR was 87.1±4.8% in controls and 84.3±4.1% with preconditioning. Preconditioning also prevented reperfusion arrhythmias in BN but not BNK rats. Within species, risk area, mean blood pressure, and heart rate were similar between strains. We concluded that (1) preconditioning protects the heart against ischemia/reperfusion injury in mice and rats; (2) activation of prekallikrein, which in turn generates kinins from HMW kininogen, may contribute to the effect of preconditioning; and (3) an intact kallikrein-kinin system is necessary for the cardioprotective effect of preconditioning.
Key Words: mice, kinin B2 receptor, knockout • rats • kininogens • ischemia/reperfusion injury
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Introduction |
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In 1986, Murry et al1 reported that repeated brief coronary occlusion renders the myocardium more resistant to injury from subsequent prolonged ischemia. They termed this phenomenon "ischemic preconditioning." To date, preconditioning has been documented to be the most powerful strategy known for protecting the heart against ischemia/reperfusion injury in various species of animals, such as dogs, pigs, rabbits, and rats.2 3 4 Recently, the concept of preconditioning has been adapted to human studies. It has been shown that repetitive balloon inflations or intermittent aortic clamping during angioplasty or coronary bypass surgery provides similar cardioprotection in patients.5 6 However, the precise mechanisms by which preconditioning protects the heart against ischemia/reperfusion injury are not fully understood. Several potential hypotheses, such as release of adenosine7 8 and heat shock protein,9 activation of protein kinase C (PKC),10 11 and opening ATP-sensitive potassium channels (KATP),3 12 have been studied intensively.
Recently, it has been suggested that kinins, which are vasoactive
peptides, are involved in the cardioprotective mechanism(s) of
preconditioning. For example, in patients undergoing angioplasty,
balloon inflation for 1 minute increased kinin concentration from the
coronary sinus 50 times more than the pre-inflation
period.13 Animal studies also showed that during the
preconditioning procedure, outflow of kinins from the coronary
sinus is rapidly increased,14 15 along with increased
release of cGMP, an indicator of nitric oxide production, and
6-keto-PGF1
, a metabolite of
prostacyclin.16 17 Furthermore, direct infusion of
bradykinin into the coronary circulation mimics the
cardioprotective action of preconditioning, such as reducing infarct
size and occurrence of arrhythmias.18 19 In
addition, blockade of kinins with a specific kinin receptor
antagonist diminishes the cardioprotective effect of
preconditioning.19 20 21 Using rats genetically lacking in
kininogen, Linz et al16 found that recovery of left
ventricular function and metabolism following
ischemia/reperfusion injury was slowed or deteriorated compared
to normal controls; however, it is not known whether the
cardioprotective effect of preconditioning in kininogen-deficient rats
is still preserved. Nevertheless, these results suggest that activation
of the kallikrein-kinin system is an important component in the
cardioprotective effect of preconditioning.
Two subtypes of kinin receptors, B1 and B2, have been characterized. Most of the known effects of kinins are mediated via activation of the B2 receptor.22 23 Using homologous recombination, Borkowski et al24 recently developed a mouse model in which the gene encoding for the B2 kinin receptor was knocked out (B2-KO). We previously reported that the blood pressure response to intra-arterial bradykinin in these mice was absent, whereas the response to acetylcholine was conserved.25 Since it is well known that pharmacological probes by themselves may alter the cardiovascular response to various pathophysiological events, which emphasizes the complexity of data presentation and interpretation, genetically altered mice and rats would provide a useful tool to overcome these limitations. In the present study, we tested the hypothesis that in animals with a genetic kinin-kallikrein deficiency, such as B2-KO and HMW kininogen-deficient rats, the cardioprotective effect of preconditioning is diminished or abolished.
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Methods |
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Animals
Mice
B2 kinin receptor knockout mice (B2-KO) were derived from a breeding pair of homozygous (-/-) mice24 and are currently being bred in our Mutant Mouse Facilities. 129SvEvTac (SV129) mice were purchased from Taconic Farms (Germantown, NY) and served as controls, since the -/- mice were bred from a 129/SvJ genetic background.
Rats
Brown Norway Katholiek rats (BNK), which are deficient in
high-molecular-weight (HMW) kininogen, are currently being bred in our
animal facilities. Control Brown Norway rats (BN) were purchased from
Charles River (Wilmington, MA).
Animals were housed in an air-conditioned room with a 12-hour light/dark cycle, received standard mouse (or rat) chow, and drank tap water. This study was approved by the Henry Ford Hospital Care of Experimental Animals Committee.
Surgical Procedures
Male mice weighing 25 to 30 g and male rats weighing 250 to
300 g were anesthetized with sodium pentobarbital (50
mg/kg, IP), intubated, and ventilated with room air using a
positive-pressure respirator. A polyethylene catheter (PE10 fused to
PE50) was inserted into the left carotid artery (in mice) or the left
femoral artery (in rats) to measure mean blood pressure and heart rate.
A left thoracotomy was performed via the fourth intercostal space, and
the heart was exposed and the pericardium was opened as described
previously in rats.26 The left anterior descending
coronary artery (LAD) was ligated with a 9-0 silk suture (for
mice) or 7-0 silk suture (for rats) near its origin between the
pulmonary outflow tract and the edge of the left atrium. Acute
myocardial ischemia was deemed successful when the anterior
wall of the left ventricle (LV) became cyanotic. After 30 minutes of
sustained ischemia, the suture was released and the heart was
reperfused for 120 minutes. Successful reperfusion was identified by
return of the original color, accompanied by obvious ST-segment
elevation. The lungs were inflated by increasing positive
end-expiratory pressure, and the thoracotomy site was closed. Animals
were kept on a heating pad throughout the experiment.
Experimental Protocols
Since the mouse model of ischemic preconditioning has
not been established and it is not known how many cycles of
preconditioning are needed, we performed 1 or 3 cycles in mice. For
rats, only 3 cycles were employed, since it has been well documented
that multiple cycles of preconditioning are needed to achieve
protection. Prior to a sustained period of 30 minutes of LAD occlusion
and 120-minute reperfusion, each strain of mice was divided into three
groups: (1) controls (without preconditioning); (2) one cycle of
preconditioning (3-minute LAD occlusion and 5-minute reperfusion); and
(3) three cycles of preconditioning. Each strain of rats was divided
into controls (without preconditioning) and preconditioning. Mean blood
pressure and heart rate were measured with a pressure transducer
connected to a recorder (Brush 220, Gould, Cleveland, OH)
throughout the experimental period. Electrocardiograms
(ECG) were monitored by subcutaneously inserting needle electrodes into
the limbs. One minute before prolonged reperfusion and continuing for
30 minutes, ECGs were recorded and stored on a computerized Window
Graphic recorder (WindoGraf 480, Gould, Cleveland, OH). Reperfusion
arrhythmias such as the total number of ventricular
premature beats and the duration of ventricular
tachycardia were analyzed. Ventricular
tachycardia was defined as a run of 4 or more consecutive
premature beats.
Measurement of Myocardial Infarct Size
After 120 minutes of reperfusion, animals were reintubated and
the chest reopened. The LAD was retightened and the ascending aorta
clamped, after which 5% Evans blue was directly injected into the left
ventricular chamber by needle puncture to separate the
nonischemic area from the area at risk. The heart was then
excised, and the atria, great vessels, and right ventricle were
dissected. The left ventricle was cut into 3 slices (in mice) and 4
slices (in rats) proceeding transversely from base to apex. The slices
were incubated with triphenyltetrazolium
chloride (TTC, 10 mg/mL) in 0.2 mol/L phosphate buffer
solution for 30 minutes. Noninfarcted myocardium, which
contains dehydrogenase, stained brick red by reacting with TTC, whereas
the necrotic (infarcted) tissue remained unstained due to lack of
enzymes. Each slice was photographed, magnified, and projected onto
a screen; infarcted area (uncolored), area at risk (uncolored+brick
red), and nonoccluded areas (blue) were measured with a planimeter and
calculated. The following parameters were averaged across
the three slices for each heart and expressed as (1) ratio of infarct
size to area at risk (IS/AR); (2) ratio of infarct size to the left
ventricle (IS/LV); and (3) ratio of area at risk to the left ventricle
(AR/LV).
Measurement of Plasma Kininogens in Rats
Kininogen levels were measured by a modification of a previously
reported method.27 For HMW kininogen, plasma was incubated
with glass powder in the presence of o-phenanthroline
(kininase inhibitor) to activate plasma
prekallikrein through stimulation of coagulation factor
XII. HMW kininogen was converted to kinin by plasma kallikrein, and the
bradykinin released was measured by radioimmunoassay (RIA). For
low-molecular-weight (LMW) kininogen, plasma was incubated with glass
powder in the absence of o-phenanthroline. Thus kinins
converted from HMW kininogen by plasma kallikrein were destroyed by
kininases in plasma. After degrading peptidases, kallikrein
inhibitors, and plasma prekallikrein by
acidification at pH 2, further incubation with glandular kallikrein
released kinins only from LMW kininogen. Kinins were assayed by RIA as
described previously.28
Statistical Analysis
Results are expressed as mean±SEM. Comparisons were done using
a multiple Student’s t test or a Wilcoxon
two-sample test with Bonferroni’s correction. An adjusted level of
<.01 indicates statistical significance because of the larger
number of comparisons. P
.01 but <.05 was considered
significant.
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Results |
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Hemodynamics
Mice
Basal mean blood pressure (MBP) and heart rate were not statistically different between B2-KO and SV129 mice. MBP decreased during the 30-minute occlusion period and returned to baseline after 2 hours of reperfusion, whereas heart rate was slightly increased during ischemia and remained unchanged during reperfusion in all groups. There was no significant difference among groups (Table).
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Rats
MBP and HR were similar between BN and BNK rats during basal,
ischemia, and reperfusion periods. During reperfusion, MBP
tended to decrease and heart rate tended to increase in all groups.
There was no difference among groups (Table).
Myocardial Infarct Size
Mice
In the control SV129 mice, the cardioprotective effect of
preconditioning was present. In SV129 mice without preconditioning
(n=8), IS/AR was 55.6±4.6% and IS/LV was 26.3±2.2%. One cycle of
preconditioning (n=8) reduced IS/AR to 38.6±3.2% (P<.05)
and IS/LV to 16.8±0.8% (P<.01). Three cycles (n=8)
decreased infarct size further (IS/AR, 31.1±2.3%; IS/LV, 15.0±1.3%;
P<.01) (Fig 1).
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As expected, the protective effect of preconditioning was absent in B2-KO mice. IS/AR was 58.5±3.6% in B2-KO mice with one cycle of preconditioning (n=7) and 58.5±3.4% with three cycles (n=7), which did not differ from B2-KO mice without preconditioning (54.8±2.9%; n=7) but was significantly larger than in SV129 mice with preconditioning (Fig 1, upper panel). IS/LV followed a similar pattern (Fig 1, lower panel). Without preconditioning, infarct size was similar in both strains. AR/LV was similar among all groups.
Rats
IS/AR in BN rats without preconditioning was 84.7±3.9% (n=8);
preconditioning reduced it to 61.6±3.4% (n=10, P<.01)
(Fig 2). This protective effect was
absent in BNK rats: IS/AR was 87.1±4.8% without preconditioning and
84.3±4.1% with preconditioning. AR/LV did not differ among the
various groups.
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Reperfusion Arrhythmias
Mice
No ventricular arrhythmias occurred during the
experimental period in either strain of mice. Intermittent A-V block
(first-, second-, or third-degree) occurred mainly during the
ischemic period in both strains. High-degree A-V block was the
major cause of death.
Rats
Without preconditioning, the total number of
ventricular premature beats (VPBs) and duration of
ventricular tachycardia (DVT) were 36±13 beats
and 5.4±2.0 seconds in BN rats and 35±14 beats and 5.6±2.4 seconds
in BNK rats. Preconditioning completely prevented
ventricular arrhythmias in BN rats (zero occurrence
for both VPB and VT; P<.01 compared to BN controls) but not
in BNK (VPBs, 50±14 beats; DVT, 3.0±1.1 seconds; P<.05
compared to BN rats with preconditioning) (Fig 3).
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Plasma Kininogens in Rats
Plasma HMW kininogen in BNK rats was 100-fold lower than in BN
rats and 140-fold lower than in SD rats (17±3 versus 1814±253 and
2397±302 ng/mL, respectively; P<.01) (Fig 4). LMW
kininogen was slightly lower in BNK rats than in BN and SD rats, but
the disparity did not reach statistical significance (1551±319 versus
1773±74 and 1781±140 ng/mL, respectively).
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Discussion |
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Murry et al1 first reported in 1986 that ischemic preconditioning protects the heart against sustained ischemic injury in dogs. In the decade that followed, a number of investigators demonstrated similar protection in rabbits and rats. We can now show that the cardioprotective action of preconditioning is also observed in smaller rodents such as mice, as demonstrated by reduction of myocardial infarct size. This protection is greater when using multiple cycles of preconditioning instead of just one. More importantly, we found that in mice lacking the gene encoding for the B2 kinin receptor as well as rats deficient in HMW kininogen, the cardioprotective effect of preconditioning was abolished, whereas under basal conditions (without preconditioning), myocardial injury in these genetically altered animals was no different from their controls. We interpret these data as indicating that kinins generated from HMW kininogen during ischemic preconditioning may play an important role in protecting the heart against ischemia/reperfusion injury; in other words, existence of an intact kallikrein-kinin system is necessary for achievement of cardioprotection by preconditioning.
Kinins are oligopeptides containing the sequence of bradykinin. They are generated from precursor HMW and LMW kininogen by kininogenases known as plasma and tissue (glandular) kallikrein.29 Most known effects of bradykinin are thought to be mediated via the B2 kinin receptor. Since kinins circulate at low levels in plasma, it has been suggested that they may be generated locally and act as autocrine/paracrine hormones at the tissue level, regulating regional blood flow and function.29 Whether the heart is capable of generating kinins locally is another question. Previously we found that kallikrein mRNA is present in vascular tissue and myocardium and that kallikrein is synthesized and released by the heart.30 We also reported that cardiac tissue contains and releases kininogens,31 although the data did not allow us to distinguish between HMW and LMW forms. Nevertheless, the presence of a local kallikrein-kinin system apparently ensures the ability of the heart to generate kinins. A number of studies have demonstrated that kinins are released from the heart and that their release is rapidly increased during ischemia or preconditioning.14 15 32 However, we were concerned with the site of kinin generation under ischemic conditions, ie, whether they are generated by myocardial tissue kallikrein or released from vascular tissue by plasma kallikrein. Our present data showed that in rats with lower levels of HMW kininogen, the cardioprotective effect of preconditioning was abolished and yet LMW kininogen was almost normal; thus we hypothesized that during ischemia kinins are mainly released from HMW kininogen by plasma kallikrein. It is possible that ischemia produces endothelial damage, which activates plasma prekallikrein; in turn, plasma kallikrein generates kinins from HMW kininogen. Although we do not have direct evidence for this hypothesis, it may be supported by the present data.
The underlying mechanism(s) by which kinins protect the heart against
myocardial ischemia/reperfusion injury is not fully understood.
Several possibilities have been proposed. First, the cardioprotective
effect of kinins may be partially mediated by release of prostacyclin
and nitric oxide (NO). Kinins are known to be potent stimulators of NO
release from the endothelium, either directly or via
prostaglandins.33 34 It has been shown that
myocardial ischemia increases kinin release, accompanied by an
increase in cGMP (an indicator of NO production) and
6-keto-PGF1 (a metabolite of
prostacyclin16 17 ), whereas inhibiting
prostaglandin and NO synthesis diminishes or blocks the
protective effect of kinins.35 36 37 Furthermore, a recent
study showed that incubation of coronary microvessels or
myocardial slices with ACE inhibitors or kininogen caused a
significant increase in NO production and a decrease in
myocardial oxygen consumption,38 both of which were
blocked by a B2 kinin receptor antagonist.
These data may indicate that NO-induced reduction of oxygen consumption
contributes significantly to the cardioprotective action of kinins.
Second, kinins may be involved in myocardial energy metabolism. It was found that perfusing the ischemic heart with bradykinin increases production of myocardial tissue high-energy phosphates and glycogen content, along with a reduction in lactate dehydrogenase and creatinine kinase activity.39 It is known that during ischemia, oxidative metabolism is suppressed and the heart relies primarily on glycolysis for ATP production. Presumably, kinins increase energy production by either (1) facilitating translocation of intracellular glucose transporters (GLUT1 and GLUT4),40 thereby increasing glucose uptake, or (2) stimulating glycolysis (glycolytic flux) by activation of protein kinase C (PKC), which potentiates phosphorylation of phosphofructokinase,41 42 43 a key enzyme of the glycolysis pathway. In addition, activation of PKC by kinins may cause further phosphorylation of a secondary effector, presumably the KATP channel. A number of studies have demonstrated that opening of the KATP channel is implicated in the cardioprotective action of preconditioning, adenosine, and kinins.12 19 36
It is unlikely that the beneficial cardiac effect of kinins is related to their hemodynamic actions, such as increasing coronary blood flow or decreasing vascular resistance.35 44 In the present study, we did not observe any difference in blood pressure or heart rate between kinin-deficient mice or rats and their controls during the experimental period; in addition, preconditioning had no effect on these parameters. Other investigators also reported that intracoronary infusion of bradykinin at a lower concentration had no effect on coronary blood flow, but did reduce the myocardial damage caused by ischemia/reperfusion.45 46 However, it is uncertain whether kinins had any influence on the microcirculation of the heart, which contributes to cardioprotection.
To our surprise, we did not observe ventricular arrhythmias during either ischemia or reperfusion in any of these mice, such as those we usually saw in larger animals. We do not have an explanation for this. However, bradycardia occurred as the result of A-V block and was the major cause of death in mice. Preconditioning did not appear to have any effect on this.
In summary, preconditioning protects the heart against ischemia/reperfusion injury in mice and rats; this effect was absent in mice and rats with a deficiency of the kallikrein-kinin system. It is possible that ischemic preconditioning activates plasma prekallikrein in endothelial cells to generate kinins from HMW kininogen. Kinins acting on the B2 receptor may trigger and/or mediate the stimulation of an intracellular signal transduction pathway which contributes to the cardioprotective effect of preconditioning.
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Acknowledgments |
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This work was supported by National Institutes of Health grant HL28982-15 and by American Heart Association, Michigan Affiliate, grant 28GS9789.
Received March 16, 1997; first decision April 15, 1997; accepted April 29, 1997.
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