© 1995 American Heart Association, Inc.
Articles |
Role of Bradykinin in Protection of Ischemic Preconditioning in Rabbit Hearts
From the Departments of Medicine (M.V.C.) and Physiology, University of South Alabama, College of Medicine, Mobile.
Correspondence to Michael V. Cohen, MD, Department of Physiology, MSB 3050, University of South Alabama, College of Medicine, Mobile, AL 36688.
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Abstract |
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Abstract Bradykinin receptor activation has been proposed to be involved in ischemic preconditioning. In the present study, we further investigated the role of this agent in preconditioning in both isolated and in situ rabbit hearts. All hearts were subjected to 30 minutes of regional ischemia followed by reperfusion for 2 hours (in vitro hearts) and 3 hours (in situ hearts). Infarct size was measured by tetrazolium staining and expressed as a percentage of the size of the risk zone. Preconditioning in situ hearts with 5 minutes of ischemia and 10 minutes of reperfusion significantly reduced infarct size to 10.2±2.2% of the risk region (P<.0005 versus control infarct size of 36.7±2.6%). Pretreatment with HOE 140 (26 µg/kg), a bradykinin B2 receptor blocker, did not alter infarct size in nonpreconditioned hearts (40.6±5.3% infarction) but abolished protection from ischemic preconditioning (34.1±1.6% infarction). However, when HOE 140 was administered during the initial reflow period following 5 minutes of ischemia, protection was no longer abolished (15.6±3.9% infarction versus 13.3±3.8% without HOE 140, P=NS). Bradykinin infusion in isolated hearts mimicked preconditioning, and protection was not affected by pretreatment with the nitric oxide synthase inhibitor N
-nitro-L-arginine methyl ester
or the prostaglandin synthesis inhibitor
indomethacin but could be completely abolished by the
protein kinase C (PKC) inhibitors polymyxin B and
staurosporine as well as by HOE 140. HOE 140 could not
block the protection of ischemic preconditioning in isolated
hearts. That failure was apparently due to the absence of blood-borne
kininogens rather than autonomic nerves. When the preconditioning
stimulus in the in situ model was amplified with four cycles of
5-minute ischemia/10-minute reperfusion, HOE 140 pretreatment
could no longer block protection (infarct size was 10.7±3.5% versus
6.4±2.0% without HOE 140, P=NS). We propose that
bradykinin receptors protect by coupling to PKC as do adenosine
receptors, and blockade of either receptor will diminish the total
stimulus of PKC below threshold and prevent protection. A more intense
preconditioning ischemic stimulus can overcome bradykinin
receptor blockade, however, by simply enhancing the amount of
adenosine and possibly other agonists released.
Key Words: adenosine • bradykinin • ischemic preconditioning • HOE 140 • protein kinase C
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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During ischemia, numerous metabolites, neurotransmitters, and peptides are released locally by the myocardium. Several of them, including adenosine,1 catecholamines,2 and bradykinin,3 have been proposed as triggers of ischemic preconditioning. The roles of adenosine4 5 and catecholamines6 7 8 9 in ischemic preconditioning have previously been extensively examined in various animal models. Studies from this laboratory using the rabbit infarct–size model have shown that adenosine acts both as a trigger and mediator of this protection.10 We have also proposed that adenosine receptors initiate intracellular signaling, resulting in activation of protein kinase C (PKC)11 12 to provide protection. The involvement of bradykinin in ischemic preconditioning has been suggested by Parratt and colleagues13 14 15 in studies involving their arrhythmia model. They proposed that bradykinin released from endothelium during ischemia might act as the trigger for ischemic preconditioning. They demonstrated that HOE 140, a bradykinin B2 receptor antagonist, prevents15 and local infusion of bradykinin mimics13 14 the antiarrhythmic effect of ischemic preconditioning. It was further proposed that bradykinin stimulates nitric oxide release, which then increases cGMP production to provide protection.15 16 Wall et al17 confirmed the importance of bradykinin in the preconditioning phenomenon by demonstrating infarct size reduction after its infusion in rabbits and abolition of the protective effect of ischemic preconditioning by HOE 140.
Although Wall et al17 documented the involvement of bradykinin in ischemic preconditioning, there was no attempt to determine the mechanism or possible pathway of signal transduction. Obviously, the ultimate clinical application of the preconditioning phenomenon will depend on an understanding of its intracellular signaling. Because Parratt15 had suggested that nitric oxide was central to the salutary effect of the peptide against arrhythmias and we had proposed instead that the protection against infarction afforded by preconditioning was dependent on PKC activation,11 12 the present study aimed to carefully determine how bradykinin initiated the protection and whether its action was independent or somehow dependent on other agonists released during ischemia. Experiments were performed to evaluate the importance of PKC, nitric oxide, prostaglandins, circulating kininogens, and cardiac denervation in the protective action of exogenously administered and endogenously produced bradykinin. Furthermore, the present study was also designed to determine whether bradykinin serves as a trigger and/or a mediator of the preconditioning phenomenon in the rabbit heart and to search for possible interaction between this agonist and others, such as adenosine, that are released by ischemic tissue.
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Materials and Methods |
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Surgical Procedures
All experiments were performed in accordance with the "Guide for the Care and Use of Laboratory Animals" (publication No. [NIH] 85-23) and were approved by the institutional animal care and use committee of the University of South Alabama.
In Situ Experiments
New Zealand White rabbits of either sex, weighing between 1.3
and 2.4 kg, were anesthetized with intravenous
sodium pentobarbital (30 mg/kg). The trachea was intubated through a
cervical incision. Mechanical ventilation was achieved with a
positive-pressure respirator (MD Industries) and 100%
O2, a tidal volume of 15 mL, and a rate of 30
breaths per minute. The respiratory rate was adjusted to keep blood pH
in the physiological range. Body temperature was
maintained near 38°C with a heating pad. The left carotid artery and
jugular vein were cannulated for blood pressure monitoring and
additional anesthesia and drug administration,
respectively. A left thoracotomy was performed in the fourth
intercostal space, and the pericardium was opened to expose the heart.
A 2-0 silk suture on a curved taper needle was passed around a
prominent branch of the left coronary artery, and the ends were
pulled through a small vinyl tube to form a snare. The coronary
branch was occluded by pulling the snare, which was then fixed by
clamping the tube with a small hemostat. Myocardial ischemia
was confirmed by regional cyanosis. Reperfusion was achieved by
releasing the snare and was confirmed by visible hyperemia over
the surface.
Denervation
Cardiac decentralization, the interruption of all extracardiac
autonomic afferent and efferent inputs to the heart, was accomplished
by sequential dissection around the major intrapericardial vessels. For
each vessel, pericardial attachments and adventitia were cleared;
simultaneously, all associated intrapericardial neural
tissues were severed. Cardiac decentralization was accomplished in a
four-stage procedure: (1) dissection around the ascending aorta; (2)
dissection at the root of the superior vena cava and in the region
between vena cava and ascending aorta, including adjacent segments of
the right pulmonary artery; (3) dissection around the right
pulmonary vein complex, including removal of the fatty tissue
between the dorsal surface of the pulmonary veins and the right
atrium; and (4) dissection around the main pulmonary artery
from its origin to its bifurcation into right and left
pulmonary arteries. Concentrated phenol (88%, Mallinckrodt)
was then carefully applied to each of the four dissection sites. To
confirm cardiac decentralization, right and left cervical
vagosympathetic complexes were isolated and individually stimulated
electrically (30-Hz pulses for 5 milliseconds at 10 V). If residual
changes in atrial rate, atrioventricular conduction, or
systemic blood pressure were noted during supramaximal autonomic
stimulation, further dissections around the major vessels were
performed until all responses to vagosympathetic stimulation were
eliminated. Adequacy of this sympathetic decentralization has been
confirmed in a similarly prepared group of rabbits in which myocardial
norepinephrine levels were reduced by 99.6% at 1 to 2
weeks after the procedure.18
In Vitro Experiments
Rabbits were anesthetized and intubated as described
above. After a left thoracotomy and placement of a suture around the
coronary artery, the hearts were quickly excised, mounted on a
Langendorff apparatus, and perfused at 75 mm Hg pressure
with nonrecirculating Krebs' buffer containing (mmol/L) NaCl 118.5,
KCl 4.7, MgSO4 1.2, KH2PO4 1.2,
NaHCO3 24.8, CaCl2 2.5, and glucose 10. The
Krebs' buffer was gassed with 95% O2/5%
CO2, resulting in a pH of 7.4 to 7.5. The
temperature of the perfusate was maintained at 37°C. A fluid-filled
latex balloon connected to a transducer with PE240 tubing was inserted
into the left ventricle. Balloon volume was adjusted to set the left
ventricular end-diastolic pressure equal to 5
to 10 mm Hg at the beginning of the experiment. Total coronary
artery flow was measured by timed collection of perfusate dripping from
the right heart into a graduated cylinder.
Infarct Size Measurement
At the end of the experiment, in situ hearts were quickly
removed from the chest, mounted on a modified Langendorff
apparatus, and perfused at room temperature with saline for
1 minute to wash out blood. Then in all in situ hearts as well as in
vitro hearts already suspended from an aortic cannula, the
coronary artery was reoccluded, and 1 to 10 µm zinc cadmium
sulfide fluorescent particles (Duke Scientific) were infused
into the perfusate to demarcate the risk zone as the tissue without
fluorescence. The heart was weighed, frozen, and then cut into
2-mm-thick slices. The slices were thawed and stained by incubation for
20 minutes at 37°C in 1%
triphenyltetrazolium chloride (TTC) in pH
7.4 buffer. The areas of infarct (TTC negative) and risk zone
(nonfluorescent under ultraviolet light) were determined by
planimetry. Infarct and risk zone volumes were then calculated by
multiplying each area by the slice thickness and summing the
products. Infarct size was expressed as a percentage of the risk
zone infarcted.
Chemicals
HOE 140 was a gift from Hoechst. Bradykinin,
N-nitro-L-arginine methyl ester
(L-NAME), indomethacin, and staurosporine
were purchased from Sigma Chemical Co. Polymyxin B was obtained from
Calbiochem.
Protocols
In Situ
Intact animals. Eight groups of rabbits were studied,
and the protocols are summarized in Fig 1
. All rabbits
experienced 30 minutes of regional ischemia followed by 180
minutes of reperfusion. The control group (CONT) of rabbits was
subjected only to the above ischemia/reperfusion sequence. The
second group was the one-cycle ischemic preconditioning group
(PC10), in which rabbit hearts were subjected to 5 minutes of
ischemia and 10 minutes of reperfusion before the 30-minute
ischemia. The third group of rabbits was treated with an
intravenous bolus of HOE 140 (26 µg/kg) 30 minutes before
the 30-minute ischemia (HOE-CONT). In the fourth group
(HOE-PC10), the same dose of HOE 140 was administered 15 minutes before
the ischemic preconditioning protocol of the PC10
group.
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To determine whether B2 receptor activation is required during the 30-minute ischemia to achieve myocardial protection, HOE 140 was administered after ischemic preconditioning but before the 30-minute ischemia. Because studies involving HOE 140 always used a 15-minute or longer pretreatment with this drug to allow adequate time for development of bradykinin receptor antagonism, animals in the fifth (PC20) and sixth (PC20-HOE) groups were preconditioned with 5 minutes of ischemia and 20 minutes of reperfusion. In the PC20-HOE group, HOE 140 was infused 15 minutes before the 30-minute ischemia and therefore 5 minutes after release of the 5-minute coronary occlusion. The seventh (PC10x4) and eighth (HOE-PC10x4) groups were preconditioned with four cycles of 5-minute ischemia/10-minute reperfusion. After the fourth 5-minute ischemia, there were 10 minutes of reflow before the prolonged coronary occlusion. The animals in the HOE-PC10x4 group also received HOE 140 15 minutes before the first 5-minute period of ischemia.
Denervated animals. Experiments were performed 120 minutes
after completion of the surgical denervation to allow animals to
stabilize after the surgical stress. Experimental protocols are also
depicted in Fig 1
. Animals in the DN-CONT group were subjected to 30
minutes of ischemia followed by 180 minutes of reperfusion.
Animals in the DN-PC10 and DN-HOE-PC10 groups were preconditioned with
5-minute ischemia/10-minute reperfusion followed by the
30-minute ischemia/180-minute reperfusion. In the DN-HOE-PC10
group, HOE 140 (26 µg/kg) was also administered
intravenously as a bolus 15 minutes before the
5-minute ischemia.
In Vitro
In all experiments, infarcts were induced by 30 minutes of
regional ischemia. Subsequently, all hearts experienced 120
minutes of reperfusion. Animals were divided into 15 groups (Fig 2). After 20 minutes of equilibration, the control group
experienced only ischemia and reperfusion as noted. The PC
group was preconditioned with 5 minutes of global ischemia and
10 minutes of reperfusion before the 30-minute regional
ischemia. In the BK group, bradykinin was included in the
perfusate (400 nmol/L) for 5 minutes, starting 15 minutes before the
30-minute regional ischemia. In the POLY group, polymyxin B (50
µmol/L), a PKC inhibitor, was included in the perfusate
for 50 minutes, starting 20 minutes before regional ischemia.
In the BK+POLY group, bradykinin and polymyxin B were present as
noted above. In the L-NAME group, rabbits were infused with buffer
containing this nitric oxide synthesis inhibitor (100
µmol/L) for 50 minutes, starting 20 minutes before regional
ischemia. In the BK+L-NAME group, bradykinin and L-NAME were
given as already described. The IM group was perfused with
indomethacin (10 µmol/L), a
cyclooxygenase inhibitor, for 50
minutes in the buffer, starting 20 minutes before regional
ischemia. Indomethacin was dissolved in 99.5%
ethanol, and the final concentration of ethanol in the perfusate was
<0.2%. In the BK+IM group, bradykinin and
indomethacin were present as noted above. In the
BK+POLY, BK+L-NAME, and BK+IM groups, infusion of the blocker was
always started 5 minutes before bradykinin was added and continued
until the end of the ischemic period. In the PC+STAURO(E) and
PC+STAURO(L) groups, infusion of staurosporine (100 nmol/L)
was either begun 5 minutes before and ended 5 minutes after the
5-minute preconditioning ischemia (E protocol) or started 10
minutes after PC, ie, 5 minutes before the long ischemia, and
continued for 15 minutes (L protocol). The BK+STAURO(L) animals were
treated with bradykinin as already indicated, and
staurosporine was initiated just before the 30-minute
coronary occlusion. The HOE group was exposed to HOE 140 (20
nmol/L) for 60 minutes, starting 30 minutes before regional
ischemia. In the BK+HOE group, bradykinin and HOE 140 were
given as described. In the PC+HOE group, preconditioning was performed
as in the PC group, and HOE 140 was infused as above.
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Statistics
All data are presented as mean±SEM. One-way ANOVA
combined with Scheffé's post hoc test was used to test for
differences in infarct size between groups. ANOVA with replication was
used to test for differences in hemodynamics in any
given group. A value of P<.05 was considered to be
significant.
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Results |
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In Situ
Intact Animals
Fifty-seven rabbits were initially entered into this part of the study. Because we have previously shown that small risk zones are associated with a disproportionately small percentage of infarction,19 six animals with risk zone volumes of <0.5 cm3 were eliminated to avoid the associated artifact. Thus, data from 51 rabbits were included in the analysis.
Hemodynamic data from all the groups are summarized in
Table 1. Baseline values of heart rate and mean
arterial blood pressure were comparable among groups. These
values were also very stable during ischemia and reperfusion.
HOE 140 did not affect either heart rate or blood pressure.
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To test the potency and duration of HOE 140 antagonism, four rabbits (two from the HOE-CONT group and two from the HOE-PC10 group) were challenged with intravenous bolus injections of bradykinin (0.5 µg/kg) before and 10, 60, and 120 minutes after HOE 140 administration. The transient (<1 minute) hypotensive effect of bradykinin (mean arterial pressure, from 80±3 to 60±4 mm Hg) was completely abolished by 26 µg/kg of HOE 140 for up to 2 hours.
Table 2 presents animal body weight, heart weight,
and risk zone volume data. There were no significant differences in
these parameters among groups. Table 2 also summarizes mean
data for group infarct sizes; Fig 3 depicts the data for
individual animals. Thirty minutes of regional ischemia induced
36.7±2.6% infarction of the risk zone in the CONT group, whereas
preconditioning with one cycle of 5-minute ischemia/10-minute
reperfusion (PC10 group) dramatically reduced infarct size to
10.2±2.2% (P<.0005 versus CONT group). Pretreatment with
HOE 140 abolished the protective effect of ischemic
preconditioning: infarct size in the HOE-PC10 group was 34.1±1.6%
(P=NS versus CONT group), whereas HOE 140 alone had no
effect on infarct size. Prolongation of the reflow period from 10 to 20
minutes after the 5-minute coronary occlusion in the PC20 group
did not affect the protection of ischemic preconditioning.
Administration of HOE 140 at 5 minutes after the 5-minute
ischemia but 15 minutes before the 30-minute coronary
occlusion did not alter the protective effect of ischemic
preconditioning (15.6±3.9% infarction, P<.005 versus
HOE-CONT group). When the hearts were ischemically
preconditioned by four cycles of 5-minute ischemia/10-minute
reperfusion (PC10x4), HOE 140 administered before ischemic
preconditioning (HOE-PC10x4) also failed to block protection
(10.7±3.5% infarction, P=NS versus PC10x4).
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Denervated Animals
Bradykinin, a very active neuropeptide, is known to have multiple
interactions with sympathetic and parasympathetic neurons. Because HOE
140 failed to block the protective effect of ischemic
preconditioning in the isolated heart (see below) but did block it in
the in situ heart, we wanted to test whether the innervation of the
heart might be responsible for the different behavior in the two
models. Fifteen rabbits were included in this part of the study.
Hemodynamic data, body and heart weights, and risk zone
and infarct volumes are presented in Tables 1 and 2. Baseline
heart rates and mean blood pressures were not significantly different
among the three groups, and these values were stable during the
experiments. The baseline heart rate and mean blood pressure values in
the decentralized animals were also comparable to those in the intact
rabbits. There were no significant differences in group body weights,
heart weights, and risk zone sizes. Group infarct data are
presented in Table 2, and individual animal data are depicted
in Fig 4. Acute surgical denervation of the hearts did
not alter infarct size in control animals (36.3±2.0% in DN-CONT
group, P=NS versus CONT group) or the ability of
ischemic preconditioning to protect the heart (14.3±2.2% in
DN-PC10 group, P<.005 versus DN-CONT group). HOE 140
administered 15 minutes before ischemic preconditioning
abolished the protection associated with preconditioning (35.4±2.2%
infarction, P=NS versus DN-CONT group), as it did in the
intact rabbits.
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In Vitro
Eighty-six hearts were included in this part of the study. Table 3 presents hemodynamic data.
Baseline heart rates, left ventricular developed pressures,
and coronary flows were comparable among the 15 experimental
groups. In the BK group, administration of bradykinin tended to
increase coronary flow, but this change was not significant.
Polymyxin B alone significantly decreased developed pressure and tended
to decrease coronary flow, but these effects were not observed
in the BK+POLY group. Staurosporine also caused pressure to
fall. L-NAME alone significantly decreased developed pressure and
coronary flow. In the BK+L-NAME group, a modest decrease in
coronary flow was again observed, although developed pressure
was unchanged. Indomethacin alone significantly
decreased developed pressure and tended to decrease coronary
flow. These changes were attenuated by the simultaneous
administration of bradykinin. Staurosporine also diminished
developed pressure, although coronary flow was unaffected. HOE
140 decreased coronary flow with and without bradykinin, but
the change was not significant. In the PC+HOE group, developed pressure
after treatment with HOE 140 and PC was significantly decreased, but
coronary flow was unaffected. None of the
hemodynamic changes could satisfactorily explain the
effects of the drugs on infarct size. In all groups, developed pressure
and coronary flow during occlusion were significantly lower
than baseline values with partial recovery during reperfusion.
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Table 4 presents the weights of the animals, risk
zone size, and infarct data. There were no significant differences in
body weight, heart weight, or risk zone size among the various groups.
Infarct size as a percentage of risk zone was 34.7±1.9% in the
control group (Fig 5). A brief 5-minute infusion of
bradykinin significantly limited infarction to 13.9±1.3%. Neither
L-NAME nor indomethacin was able to block the
protection of a bradykinin infusion. In contrast, HOE 140 aborted the
protective effect of bradykinin (29.7±5.4% infarction). Polymyxin B,
which itself did not modify infarct size, completely blocked the
protective effect of bradykinin (32.9±5.9% infarction) (Fig 6). Preconditioning these isolated hearts significantly
protected them (7.3±1.8% infarction) (Fig 6).
Staurosporine had no effect on the protection of
ischemic preconditioning when administered just before and
during the 5-minute global ischemia [PC+STAURO(E)]
(14.1±1.7% infarction) but completely blocked protection when infused
during the long ischemia [PC+STAURO(L)] (33.7±2.6%
infarction). Staurosporine was equally effective at
blocking the protection afforded by bradykinin [BK+STAURO(L)]
(31.8±1.9% infarction). Unlike observations in the in situ hearts,
the salutary effect of ischemic preconditioning in the isolated
heart was unaffected by HOE 140 (8.9±1.0% infarction) (Fig 5).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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These data in isolated and in situ rabbit hearts provide important new insights into the pathways by which bradykinin salvages ischemic myocardium. Although bradykinin had previously been observed to reduce infarct size in rabbits,17 there had been no prior attempt to elucidate a mechanism. The results demonstrate the central importance of PKC to the protection afforded by bradykinin and exclude several other possibilities. These observations support a unifying hypothesis for the preconditioning phenomenon and make eventual clinical extrapolation more likely.
In the present study, we have confirmed that HOE 140, a bradykinin B2 receptor antagonist, blocks the protection from one cycle of ischemic preconditioning in rabbit hearts in situ when it is administered before the 5-minute ischemic period. However, HOE 140 does not block protection when its administration is delayed until after ischemic preconditioning but before the prolonged ischemia. Neither can HOE 140 block protection when hearts are preconditioned by four cycles of 5-minute ischemia/10-minute reperfusion, even when the antagonist is given before ischemic preconditioning. These results suggest that bradykinin produced during ischemia participates in the endogenous triggering of ischemic preconditioning but plays no role in the subsequent second ischemic phase. Furthermore, the importance of bradykinin as a trigger is minimized if the preconditioning stimulus is more profound.
During myocardial ischemia, numerous metabolites and neurotransmitters are released locally, and several of them have been shown to play an important role in ischemic preconditioning.4 20 Intracardiac production of bradykinin, a nonapeptide of the kinin family, has been shown to be increased during myocardial ischemia.21 22 Nolly et al23 have demonstrated that rat cardiac tissue contains mRNA coding for kallikrein as well as the enzyme itself. This enzyme is responsible for degradation of kininogen into bradykinin. Although the blood is a very rich source of kininogen, this precursor can also be isolated from the heart. The presence of a local kallikrein-kinin system apparently ensures the ability of the heart to produce bradykinin. Presumably ischemia results in pH and other changes that cause activation of kallikrein and the subsequent availability of bradykinin. The cardioprotective effect of bradykinin was first suggested when studies showed that several angiotensin-converting enzyme inhibitors such as ramiprilat could protect hearts against the deleterious consequences of ischemia and reperfusion.3 24 25 26 27 28 29 30 It was proposed that angiotensin-converting enzyme inhibitors acted by inhibiting the breakdown of bradykinin, since HOE 140 reversed the protective effect.24 26 Furthermore, it was reported that direct intracoronary infusion of bradykinin could reduce infarct size in dogs.24 Parratt and colleagues13 14 15 16 reported that intracoronary infusion of bradykinin mimicked preconditioning by profoundly reducing the severity of ischemia-induced arrhythmias in dogs13 14 and suggested that the protective effects were mediated through prostacyclin (prostaglandin I2) and/or nitric oxide and increasing cGMP.15 16
The possible involvement of bradykinin in the protective effect of ischemic preconditioning has also been investigated by Parratt's group.15 They reported that HOE 140 prevented the antiarrhythmic effect of ischemic preconditioning in anesthetized dogs. More recently, Wall et al17 reported that in anesthetized rabbits the administration of HOE 140 before ischemic preconditioning abolished the anti-infarct effect associated with preconditioning. They also showed that a brief infusion of bradykinin substituting for ischemia could mimic ischemic preconditioning.
Our results confirm that bradykinin may act as a trigger for
ischemic preconditioning in rabbit hearts. HOE 140 given before
ischemic preconditioning blocked protection (Fig 3). However,
in contrast to adenosine, bradykinin does not appear to
participate during the subsequent 30 minutes of ischemia,
because HOE 140 failed to alter protection when B2
receptors were blocked only during the prolonged ischemia. We
found that adenosine receptors must be occupied during the
preconditioning ischemia (presumably acting as a trigger) as
well as during the subsequent prolonged ischemia (serving as a
mediator) in order for protection to occur.10
The signal transduction pathway for ischemic preconditioning is still controversial. Parratt and colleagues15 16 have proposed that the antiarrhythmic effect of ischemic preconditioning is triggered by bradykinin, which in turn induces prostaglandin and nitric oxide release. Prostaglandin and nitric oxide would then increase cGMP, which they postulated provides protection. However, Patel et al31 found that inhibition of nitric oxide actually limited infarct size in the open-chest rabbit heart.
To further investigate the mechanism by which bradykinin induced
protection in these ischemic hearts, we used an isolated heart
model in which drugs could be administered at specific times and at
known concentrations. In this model, bradykinin infusion resulted in as
much myocardial salvage as ischemic preconditioning with 5
minutes of global ischemia (Fig 5). This protection could not
be blocked by either L-NAME or indomethacin, both
administered in doses known to block nitric oxide32 and
prostaglandin33 34 synthesis, respectively,
thus effectively excluding nitric oxide synthesis or
prostaglandin production as necessary steps in the
protection cascade responsible for the anti-infarct effect. As
expected, HOE 140 blocked protection from bradykinin, confirming that a
B2 receptor is involved. Perhaps most important is the
observation that polymyxin B, a selective inhibitor of PKC,
completely aborted the protection afforded by bradykinin (Fig 6).
Although polymyxin B is specific for PKC among the cellular
kinases,35 its ability to also close ATP-sensitive
K+ channels,36 proposed mediators of
ischemic preconditioning,37 38 39 makes its site of
action less clear. However, staurosporine, a second kinase
blocker that aborted the salutary effect of ischemic
preconditioning only when present during the long ischemia,
also prevented the protection by bradykinin when included during
ischemia. Since staurosporine blocks
phosphorylation but not translocation of PKC, it is not
surprising that staurosporine administered only at the time
of the preconditioning ischemia failed to block protection. It
is equally apparent that the salutary effect of bradykinin is dependent
on the ability of the cell to phosphorylate at the
beginning of the 30-minute ischemia. Hence, PKC, rather than
cGMP, most likely mediates the protection.
We have previously proposed that ischemic preconditioning is
triggered by endogenous adenosine release, which
upregulates PKC through receptor-mediated cell-signaling
pathways.40 The second episode of ischemia again
releases adenosine, which reactivates PKC, resulting in
phosphorylation of some end effector and thus causing
protection. The PKC theory predicts that any receptor coupling to PKC
should be able to protect ischemic myocardium.
Indeed, 
1-adrenergic,9
M2-muscarinic,41 42 43 44 and
AT1-angiotensin II45 agonists can
all substitute for ischemia and trigger the protection of
preconditioning. Bradykinin has also been shown to activate PKC
in a number of nonmyocardial cells. Although much of the evidence is
biochemical, Murray et al46 have demonstrated that the PKC
inhibitors sphingosine and H-7 block the increased
permeability observed in hamster endothelial cells
after exposure to bradykinin, and Bascands et al47 have
shown that bradykinin-induced contractions of rat mesangial
cells could be attenuated by H-7 and calphostin C. Bradykinin increases
diacylglycerol and inositol phosphate production in many cell
types, including a neuronal cell line,48 rat mesenteric
arterial smooth muscle cells,49 canine
tracheal smooth muscle cells,50 and rat
mesangial cells.47 Bradykinin can also
stimulate phospholipase C and D, thus providing alternate pathways for
activation of PKC.50 Furthermore, bradykinin induces
phosphorylation of the MARCKS protein, an
endogenous PKC substrate in arterial smooth
muscle cells.49 Finally, bradykinin has been noted to
cause translocation of multiple PKC isoforms from the cytosol to cell
membranes in neuroblastoma NCB-20 cells51 and Chinese
hamster ovary cells.52 Therefore, the most likely
explanation for bradykinin-mediated protection of ischemic
rabbit hearts is the ability of the peptide to activate PKC in
the cardiomyocytes as well.
Although the role of PKC in preconditioning has been supported by many,53 54 55 56 57 58 it is acknowledged that a few have been unable to confirm the role of PKC.59 60 61 62 However, in their canine studies, Przyklenk and Kloner59 were never able to confirm that the doses of the PKC antagonist that they claimed did not block protection were indeed sufficient to block PKC activity, and the dose of phorbol myristate acetate intended to activate PKC and hence protect porcine myocardium in the study of Vogt et al60 was in the range noted by us63 to be too high to be protective, presumably because cellular reactions other than the one accounting for protection of ischemic tissue, such as coronary constriction and leukocyte activation, were affected. Therefore, evidence denying a role for PKC in the preconditioning phenomenon is hardly conclusive.
Although exogenous agonists
phenylisopropyladenosine,5
phenylephrine,9 carbachol,43
acetylcholine,41 42 44 and angiotensin
II45 infused in lieu of ischemia can trigger
preconditioning, a physiological role for each of
these receptor systems in ischemic preconditioning cannot be
assumed. For example, adenosine receptor–blocking agents can
block the protection of ischemic preconditioning in rabbit
hearts,4 5 whereas BE 22546 and
phenoxybenzamine,9 1-adrenergic
antagonists, cannot. Hence, when preconditioning with 5
minutes of ischemia, adenosine but not
catecholamines participate in triggering the protection.
However, changes in conditions could alter the significance of any
released agonist. For example, the protection after preconditioning
hearts with 10 minutes of hypoxia could be aborted only by
simultaneous blockade of adenosine and
1-adrenergic receptors, indicating that both
adenosine and norepinephrine were released in
amounts sufficient to precondition.64
In our in vivo rabbit model, blockade of either bradykinin or
adenosine4 5 receptors can abort the protection of
ischemic preconditioning. Thus, we propose that 5 minutes of
ischemia produces only enough bradykinin, adenosine,
and perhaps other activators of PKC such that their
additive effect is required to activate sufficient PKC to
trigger preconditioning (Fig 7). It should be
appreciated that 5 minutes of ischemia is very near the
threshold for protection.65 Blockade of either the
bradykinin or the adenosine component would prevent that
threshold from being reached. As demonstrated in the present study,
however, bradykinin blockade was no longer able to abort protection if,
rather than one preconditioning cycle, four were used. As diagrammed in
Fig 7, we propose that repeated episodes of ischemia simply
increase the amounts of adenosine and perhaps other agonists
released to attain the threshold level even when bradykinin receptors
are blocked. Adenosine and purine release continues to be
observed after at least three occlusions in the dog,66 six
in the rat,67 and two in the rabbit (authors' unpublished
data, 1994), albeit at a diminished rate.
|
The interaction between adenosine and bradykinin receptors may not simply be additive. The ability of adenosine and bradykinin receptors to activate phospholipase C was studied by Gerwins and Fredholm,68 who found that stimulation of adenosine A1 and bradykinin receptors raised inositol 1,4,5-trisphosphate and intracellular free calcium in DDT1 MF-2 smooth muscle cells in a synergistic rather than an additive manner. It is uncertain whether similar changes occur in the cardiocyte.
It is equally important to note that bradykinin receptor activation is
not at all necessary during the prolonged ischemic phase.
Previous studies have documented that the adenosine
antagonist 8-(p-sulfophenyl)theophylline
can abort protection if infused 5 minutes before the long
ischemia.10 A similar blockade of protection could
not be duplicated with HOE 140. We have no explanation for why
bradykinin does not seem to participate during the long
ischemia whereas adenosine does. Adenosine,
like bradykinin, also stimulates production of inositol
phosphate compounds,69 suggesting that it too is coupled
to PKC. We do not think that adenosine receptors are
particularly unique among receptors putatively coupled to PKC and
certainly are not the only ones whose occupancy can mediate protection
during the long ischemia. Recently, we showed that in hearts
exposed to adenosine receptor–blocking agents during the
prolonged ischemia, protection could be restored by simple
coinfusion of the 1-adrenergic agonist
phenylephrine.9
Unexpectedly, HOE 140 failed to block the anti-infarct effect of
ischemic preconditioning in isolated rabbit hearts, even when
HOE 140 was present during the entire preconditioning and prolonged
ischemic periods (Fig 5). In the isolated heart, neuronal input
is eliminated, and because bradykinin is a potent
neuropeptide,70 71 it was considered that perhaps the
protection of bradykinin was dependent on an intact autonomic nervous
system. However, our finding that HOE 140 had the same effect in intact
and denervated in situ rabbit hearts (Fig 4) argues against such a
possibility. The absence of blood elements in the perfusate of the
isolated heart is the more likely explanation. It has been shown that
kininogen in the blood is the major precursor of bradykinin and that
elimination of blood could reduce its effective production,
although significant increases of bradykinin have been detected during
ischemia even in buffer-perfused isolated rat
hearts.22 Although absence of a blood-borne enzyme might
also affect bradykinin production, the identification of
kallikrein in cardiac tissue23 makes enzyme deficiency a
less likely possibility. Apparently, enough additional
adenosine is released in the isolated heart model to make up
for the reduced bradykinin release.
In summary, we have demonstrated that bradykinin participates in the trigger phase of ischemic preconditioning but not in the mediation phase and that PKC but not nitric oxide or prostaglandins plays a critical role in the signal transduction cascade of bradykinin. Apparently, a threshold level of PKC stimulation must be reached before protection can be triggered. We propose that both adenosine and bradykinin are released by ischemia and that their effects in activating PKC are additive. These redundant pathways for PKC increase the likelihood that exposure to ischemia will induce a protective adaptation.
|
Acknowledgments |
|---|
This study was supported in part by grants HL-20648 and HL-50688 from the National Institutes of Health, Heart, Lung, and Blood Institute.
Received November 11, 1994; accepted May 23, 1995.
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References |
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 S. Ghosh and M. Galinanes Protection of the human heart with ischemic preconditioning during cardiac surgery: role of cardiopulmonary bypass J. Thorac. Cardiovasc. Surg., July 1, 2003; 126(1): 133 - 142. [Abstract] [Full Text] [PDF]
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J. N. Peart and G. J. Gross Adenosine and opioid receptor-mediated cardioprotection in the rat: evidence for cross-talk between receptors Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H81 - H89. [Abstract] [Full Text] [PDF]
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 M. Singh and H. K. Saini Resident Cardiac Mast Cells and Ischemia-Reperfusion Injury Journal of Cardiovascular Pharmacology and Therapeutics, June 1, 2003; 8(2): 135 - 148. [Abstract] [PDF]
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 E. o. Cosar and C. J. O'Connor Hibernation, Stunning, and Preconditioning: Historical Perspective, Current Concepts, Clinical Applications, and Future Implications Seminars in Cardiothoracic and Vascular Anesthesia, June 1, 2003; 7(2): 115 - 140. [Abstract] [PDF]
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S. K. Jain, R. B. Schuessler, and J. E. Saffitz Mechanisms of Delayed Electrical Uncoupling Induced by Ischemic Preconditioning Circ. Res., May 30, 2003; 92(10): 1138 - 1144. [Abstract] [Full Text] [PDF]
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 F. Kehl, P. S. Pagel, J. G. Krolikowski, W. Gu, W. Toller, D. C. Warltier, and J. R. Kersten Isoflurane Does Not Produce a Second Window of Preconditioning Against Myocardial Infarction In Vivo Anesth. Analg., November 1, 2002; 95(5): 1162 - 1168. [Abstract] [Full Text] [PDF]
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L. M. Schwartz, T. S. Welch, and M. S. Crago Cardioprotection by multiple preconditioning cycles does not require mitochondrial KATP channels in pigs Am J Physiol Heart Circ Physiol, October 1, 2002; 283(4): H1538 - H1544. [Abstract] [Full Text] [PDF]
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H. K Reddy, S. K.G Koshy, and H. Shukia Triggers and promoters of ischaemic preconditioning Cardiovasc Res, October 1, 2002; 56(1): 1 - 3. [Full Text] [PDF]
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O. Oldenburg, M. V Cohen, D. M Yellon, and J. M Downey Mitochondrial KATP channels: role in cardioprotection Cardiovasc Res, August 15, 2002; 55(3): 429 - 437. [Abstract] [Full Text] [PDF]
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R. M Fryer, J. A Auchampach, and G. J Gross Therapeutic receptor targets of ischemic preconditioning Cardiovasc Res, August 15, 2002; 55(3): 520 - 525. [Abstract] [Full Text] [PDF]
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Y.-P. Wang, H. Maeta, K. Mizoguchi, T. Suzuki, Y. Yamashita, and M. Oe Intestinal ischemia preconditions myocardium: role of protein kinase C and mitochondrial KATP channel Cardiovasc Res, August 15, 2002; 55(3): 576 - 582. [Abstract] [Full Text] [PDF]
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C. Weinbrenner, M. Nelles, N. Herzog, L. Sarvary, and R. H Strasser Remote preconditioning by infrarenal occlusion of the aorta protects the heart from infarction: a newly identified non-neuronal but PKC-dependent pathway Cardiovasc Res, August 15, 2002; 55(3): 590 - 601. [Abstract] [Full Text] [PDF]
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P. Gres, R. Schulz, J. Jansen, C. Umschlag, and G. Heusch Involvement of endogenous prostaglandins in ischemic preconditioning in pigs Cardiovasc Res, August 15, 2002; 55(3): 626 - 632. [Abstract] [Full Text] [PDF]
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A. T Saurin, D. J Pennington, N. J.H Raat, D. S Latchman, M. J Owen, and M. S Marber Targeted disruption of the protein kinase C epsilon gene abolishes the infarct size reduction that follows ischaemic preconditioning of isolated buffer-perfused mouse hearts Cardiovasc Res, August 15, 2002; 55(3): 672 - 680. [Abstract] [Full Text] [PDF]
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H. Y. Zhang, B. C. McPherson, H. Liu, T. S. Baman, P. Rock, and Z. Yao H2O2 opens mitochondrial KATP channels and inhibits GABA receptors via protein kinase C-epsilon in cardiomyocytes Am J Physiol Heart Circ Physiol, April 1, 2002; 282(4): H1395 - H1403. [Abstract] [Full Text] [PDF]
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 D.L. MANN The Yin/Yang of Innate Stress Responses in the Heart Cold Spring Harb Symp Quant Biol, January 1, 2002; 67(0): 363 - 370. [Abstract] [PDF]
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L.K.K. Teoh, R. Grant, J.A. Hulf, W.B. Pugsley, and D.M. Yellon The effect of preconditioning (ischemic and pharmacological) on myocardial necrosis following coronary artery bypass graft surgery Cardiovasc Res, January 1, 2002; 53(1): 175 - 180. [Abstract] [Full Text] [PDF]
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R. A. Kloner and R. B. Jennings Consequences of Brief Ischemia: Stunning, Preconditioning, and Their Clinical Implications: Part 2 Circulation, December 18, 2001; 104(25): 3158 - 3167. [Abstract] [Full Text] [PDF]
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R. Schulz, M. V Cohen, M. Behrends, J. M Downey, and G. Heusch Signal transduction of ischemic preconditioning Cardiovasc Res, November 1, 2001; 52(2): 181 - 198. [Full Text] [PDF]
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R. M Bell and D. M Yellon The contribution of endothelial nitric oxide synthase to early ischaemic preconditioning: the lowering of the preconditioning threshold. An investigation in eNOS knockout mice Cardiovasc Res, November 1, 2001; 52(2): 274 - 280. [Abstract] [Full Text] [PDF]
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 J. M. Abadie, G. T. Malcom, J. R. Porter, and F. Svec Dehydroepiandrosterone Alters Zucker Rat Soleus and Cardiac Muscle Lipid Profiles Exp Biol Med, September 1, 2001; 226(8): 782 - 789. [Abstract] [Full Text] [PDF]
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Z. Ebrahim, D. M Yellon, and G. F Baxter Bradykinin elicits "second window" myocardial protection in rat heart through an NO-dependent mechanism Am J Physiol Heart Circ Physiol, September 1, 2001; 281(3): H1458 - H1464. [Abstract] [Full Text] [PDF]
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T. Miura, S. Kawamura, H. Tatsuno, Y. Ikeda, S. Mikami, H. Iwamoto, T. Okamura, M. Iwatate, M. Kimura, Y. Dairaku, et al. Ischemic Preconditioning Attenuates Cardiac Sympathetic Nerve Injury via ATP-Sensitive Potassium Channels During Myocardial Ischemia Circulation, August 28, 2001; 104(9): 1053 - 1058. [Abstract] [Full Text] [PDF]
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Y. Zhang, J. W. Bissing, L. Xu, A. J. Ryan, S. M. Martin, F. J. Miller Jr, K. C. Kregel, G. R. Buettner, and R. E. Kerber Nitric oxide synthase inhibitors decrease coronary sinus-free radical concentration and ameliorate myocardial stunning in an ischemia-reperfusion model J. Am. Coll. Cardiol., August 1, 2001; 38(2): 546 - 554. [Abstract] [Full Text] [PDF]
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E. Kevelaitis, A. P. Patel, A. Oubenaissa, J. Peynet, C. Mouas, D. M. Yellon, and P. Menasche Backtable heat-enhanced preconditioning: a simple and effective means of improving function of heart transplants Ann. Thorac. Surg., July 1, 2001; 72(1): 107 - 112. [Abstract] [Full Text] [PDF]
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H. Liu, B. C. McPherson, X. Zhu, M. L. A. Da Costa, V. Jeevanandam, and Z. Yao Role of nitric oxide and protein kinase C in ACh-induced cardioprotection Am J Physiol Heart Circ Physiol, July 1, 2001; 281(1): H191 - H197. [Abstract] [Full Text] [PDF]
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 Y. Suematsu, T. Ohtsuka, Y. Hirata, K. Maeda, K. Imanaka, and S. Takamoto L-Arginine given after ischaemic preconditioning can enhance cardioprotection in isolated rat hearts Eur. J. Cardiothorac. Surg., June 1, 2001; 19(6): 873 - 879. [Abstract] [Full Text] [PDF]
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M. T. Jaberansari, G. F. Baxter, C. A. Muller, S. E. Latouf, E. Roth, L. H. Opie, and D. M. Yellon Angiotensin-converting enzyme inhibition enhances a subthreshold stimulus to elicit delayed preconditioning in pig myocardium J. Am. Coll. Cardiol., June 1, 2001; 37(7): 1996 - 2001. [Abstract] [Full Text] [PDF]
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R. Schulz, P. Gres, and G. Heusch Role of endogenous opioids in ischemic preconditioning but not in short-term hibernation in pigs Am J Physiol Heart Circ Physiol, May 1, 2001; 280(5): H2175 - H2181. [Abstract] [Full Text] [PDF]
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Z. Yao, B. C. McPherson, H. Liu, Z. Shao, C. Li, Y. Qin, T. L. Vanden Hoek, L. B. Becker, and P. T. Schumacker Signal transduction of flumazenil-induced preconditioning in myocytes Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H1249 - H1255. [Abstract] [Full Text] [PDF]
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 H. T. LEE and C. W. EMALA Protein Kinase C and Gi/o Proteins Are Involved in Adenosine- and Ischemic Preconditioning--Mediated Renal Protection J. Am. Soc. Nephrol., February 1, 2001; 12(2): 233 - 240. [Abstract] [Full Text]
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G.-Y. Wang, S. Wu, J.-M. Pei, X.-C. Yu, and T.-M. Wong {kappa}- but not {delta}-opioid receptors mediate effects of ischemic preconditioning on both infarct and arrhythmia in rats Am J Physiol Heart Circ Physiol, January 1, 2001; 280(1): H384 - H391. [Abstract] [Full Text] [PDF]
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S. Shigematsu, S. Ishida, D. C. Gute, and R. J. Korthuis Postischemic anti-inflammatory effects of bradykinin preconditioning Am J Physiol Heart Circ Physiol, January 1, 2001; 280(1): H441 - H454. [Abstract] [Full Text] [PDF]
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S. Pepe Dysfunctional ischemic preconditioning mechanisms in aging Cardiovasc Res, January 1, 2001; 49(1): 11 - 14. [Full Text] [PDF]
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S. P. Bell, M. N. Sack, A. Patel, L. H. Opie, and D. M. Yellon Delta opioid receptor stimulation mimics ischemic preconditioning in human heart muscle J. Am. Coll. Cardiol., December 1, 2000; 36(7): 2296 - 2302. [Abstract] [Full Text] [PDF]
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 A. T. SAURIN, J. L. MARTIN, R. J. HEADS, C. FOLEY, J. W. MOCKRIDGE, M. J. WRIGHT, Y. WANG, and M. S. MARBER The role of differential activation of p38-mitogen-activated protein kinase in preconditioned ventricular myocytes FASEB J, November 1, 2000; 14(14): 2237 - 2246. [Abstract] [Full Text]
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Q. Zhang and Z. Yao Flumazenil preconditions cardiomyocytes via oxygen radicals and KATP channels Am J Physiol Heart Circ Physiol, October 1, 2000; 279(4): H1858 - H1863. [Abstract] [Full Text] [PDF]
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T. Yoshida, R. M. Engelman, D. T. Engelman, J. A. Rousou, N. Maulik, M. Sato, G. T. Elliott, and D. K. Das Preconditioning of swine heart with monophosphoryl lipid A improves myocardial preservation Ann. Thorac. Surg., September 1, 2000; 70(3): 895 - 900. [Abstract] [Full Text] [PDF]
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R. R. Morrison, R. Jones, A. M. Byford, A. R. Stell, J. Peart, J. P. Headrick, and G. P. Matherne Transgenic overexpression of cardiac A1 adenosine receptors mimics ischemic preconditioning Am J Physiol Heart Circ Physiol, September 1, 2000; 279(3): H1071 - H1078. [Abstract] [Full Text] [PDF]
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M. Kitakaze, K. Node, H. Asanuma, S. Takashima, Y. Sakata, M. Asakura, S. Sanada, Y. Shinozaki, H. Mori, T. Kuzuya, et al. Protein Tyrosine Kinase Is Not Involved in the Infarct Size-Limiting Effect of Ischemic Preconditioning in Canine Hearts Circ. Res., August 18, 2000; 87(4): 303 - 308. [Abstract] [Full Text] [PDF]
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P. Abete, C. Calabrese, N. Ferrara, A. Cioppa, P. Pisanelli, F. Cacciatore, G. Longobardi, C. Napoli, and F. Rengo Exercise training restores ischemic preconditioning in the aging heart J. Am. Coll. Cardiol., August 1, 2000; 36(2): 643 - 650. [Abstract] [Full Text] [PDF]
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G. R. Gaudette, I. B. Krukenkamp, A. E. Saltman, H. Horimoto, and S. Levitsky Preconditioning with PKC and the ATP-sensitive potassium channels: a codependent relationship Ann. Thorac. Surg., August 1, 2000; 70(2): 602 - 608. [Abstract] [Full Text] [PDF]
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T. Miki, T. Miura, A. Tsuchida, A. Nakano, T. Hasegawa, T. Fukuma, and K. Shimamoto Cardioprotective Mechanism of Ischemic Preconditioning Is Impaired by Postinfarct Ventricular Remodeling Through Angiotensin II Type 1 Receptor Activation Circulation, July 25, 2000; 102(4): 458 - 463. [Abstract] [Full Text] [PDF]
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W. E. Johnston Preconditioning the Brain and Heart: Implications for Cardiac Surgery Seminars in Cardiothoracic and Vascular Anesthesia, July 1, 2000; 4(2): 70 - 79. [Abstract] [PDF]
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H.-L. Pan, S.-R. Chen, G. M. Scicli, and O. A. Carretero Cardiac interstitial bradykinin release during ischemia is enhanced by ischemic preconditioning Am J Physiol Heart Circ Physiol, July 1, 2000; 279(1): H116 - H121. [Abstract] [Full Text] [PDF]
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R. G. Schoemaker and C. L. van Heijningen Bradykinin mediates cardiac preconditioning at a distance Am J Physiol Heart Circ Physiol, May 1, 2000; 278(5): H1571 - H1576. [Abstract] [Full Text] [PDF]
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 D M Yellon and G F Baxter Protecting the ischaemic and reperfused myocardium in acute myocardial infarction: distant dream or near reality? Heart, April 1, 2000; 83(4): 381 - 387. [Full Text]
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R. D. Rakhit, R. J. Edwards, J. W. Mockridge, A. R. Baydoun, A. W. Wyatt, G. E. Mann, and M. S. Marber Nitric oxide-induced cardioprotection in cultured rat ventricular myocytes Am J Physiol Heart Circ Physiol, April 1, 2000; 278(4): H1211 - H1217. [Abstract] [Full Text] [PDF]
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S. ZAHLER, C. KUPATT, and B. F. BECKER Endothelial preconditioning by transient oxidative stress reduces inflammatory responses of cultured endothelial cells to TNF-{alpha} FASEB J, March 1, 2000; 14(3): 555 - 564. [Abstract] [Full Text]
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 H. T. Lee and C. W. Emala Protective effects of renal ischemic preconditioning and adenosine pretreatment: role of A1 and A3 receptors Am J Physiol Renal Physiol, March 1, 2000; 278(3): F380 - F387. [Abstract] [Full Text] [PDF]
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S. Ghosh, N. B Standen, and M. Galinanes Evidence for mitochondrial KATP channels as effectors of human myocardial preconditioning Cardiovasc Res, March 1, 2000; 45(4): 934 - 940. [Abstract] [Full Text] [PDF]
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T. Matsubara, S. Minatoguchi, H. Matsuo, K. Hayakawa, T. Segawa, Y. Matsuno, S. Watanabe, M. Arai, Y. Uno, M. Kawasaki, et al. Three minute, but not one minute, ischemia and nicorandil have a preconditioning effect in patients with coronary artery disease J. Am. Coll. Cardiol., February 1, 2000; 35(2): 345 - 351. [Abstract] [Full Text] [PDF]
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Y.-H. Liu, X.-P. Yang, D. Mehta, M. Bulagannawar, G. M. Scicli, and O. A. Carretero Role of kinins in chronic heart failure and in the therapeutic effect of ACE inhibitors in kininogen-deficient rats Am J Physiol Heart Circ Physiol, February 1, 2000; 278(2): H507 - H514. [Abstract] [Full Text] [PDF]
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S. Ghosh, N. B Standen, and M. Galinanes Preconditioning the human myocardium by simulated ischemia: studies on the early and delayed protection Cardiovasc Res, January 14, 2000; 45(2): 339 - 350. [Abstract] [Full Text] [PDF]
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C. E. Ganote and S. C. Armstrong Adenosine and preconditioning in the rat heart Cardiovasc Res, January 1, 2000; 45(1): 134 - 140. [Full Text] [PDF]
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L. P. Perrault and P. Menasche Preconditioning: can nature’s shield be raised against surgical ischemic-reperfusion injury? Ann. Thorac. Surg., November 1, 1999; 68(5): 1988 - 1994. [Abstract] [Full Text] [PDF]
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T. Okamura, T. Miura, H. Iwamoto, K. Shirakawa, S. Kawamura, Y. Ikeda, M. Iwatate, and M. Matsuzaki Ischemic preconditioning attenuates apoptosis through protein kinase C in rat hearts Am J Physiol Heart Circ Physiol, November 1, 1999; 277(5): H1997 - H2001. [Abstract] [Full Text] [PDF]
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M. A. Leesar, M. F. Stoddard, S. Manchikalapudi, and R. Bolli Bradykinin-induced preconditioning in patients undergoing coronary angioplasty J. Am. Coll. Cardiol., September 1, 1999; 34(3): 639 - 650. [Abstract] [Full Text] [PDF]
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R. D Rakhit, R. J Edwards, and M. S Marber Nitric oxide, nitrates and ischaemic preconditioning Cardiovasc Res, August 15, 1999; 43(3): 621 - 627. [Full Text] [PDF]
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P. B. Anning, B. D. Prendergast, P. A. MacCarthy, A. M. Shah, D. C. Buss, and M. J. Lewis ATP is involved in myocardial and vascular effects of exogenous bradykinin in ejecting guinea pig heart Am J Physiol Heart Circ Physiol, August 1, 1999; 277(2): H818 - H825. [Abstract] [Full Text] [PDF]
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H.-S. V. Chen, S. C. Body, and S. K. Shernan Myocardial Preconditioning: Characteristics, Mechanisms, and Clinical Applications Seminars in Cardiothoracic and Vascular Anesthesia, July 1, 1999; 3(2): 85 - 97. [Abstract] [PDF]
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S. Shigematsu, S. Ishida, D. C. Gute, and R. J. Korthuis Bradykinin prevents postischemic leukocyte adhesion and emigration and attenuates microvascular barrier disruption Am J Physiol Heart Circ Physiol, July 1, 1999; 277(1): H161 - H171. [Abstract] [Full Text] [PDF]
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S. Takeo and Y. Nasa Role of energy metabolism in the preconditioned heart - a possible contribution of mitochondria Cardiovasc Res, July 1, 1999; 43(1): 32 - 43. [Abstract] [Full Text] [PDF]
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P. Ping, J. Zhang, X. Cao, R. C. X. Li, D. Kong, X.-L. Tang, Y. Qiu, S. Manchikalapudi, J. A. Auchampach, R. G. Black, et al. PKC-dependent activation of p44/p42 MAPKs during myocardial ischemia-reperfusion in conscious rabbits Am J Physiol Heart Circ Physiol, May 1, 1999; 276(5): H1468 - H1481. [Abstract] [Full Text] [PDF]
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C. P. Baines, G. S. Liu, M. Birincioglu, S. D. Critz, M. V. Cohen, and J. M. Downey Ischemic preconditioning depends on interaction between mitochondrial KATP channels and actin cytoskeleton Am J Physiol Heart Circ Physiol, April 1, 1999; 276(4): H1361 - H1368. [Abstract] [Full Text] [PDF]
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P. Ping, H. Takano, J. Zhang, X.-L. Tang, Y. Qiu, R. C. X. Li, S. Banerjee, B. Dawn, Z. Balafonova, and R. Bolli Isoform-Selective Activation of Protein Kinase C by Nitric Oxide in the Heart of Conscious Rabbits : A Signaling Mechanism for Both Nitric Oxide–Induced and Ischemia-Induced Preconditioning Circ. Res., March 19, 1999; 84(5): 587 - 604. [Abstract] [Full Text] [PDF]
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S. Hoshida, N. Yamashita, K. Kawahara, T. Kuzuya, and M. Hori Amelioration by Quinapril of Myocardial Infarction Induced by Coronary Occlusion/Reperfusion in a Rabbit Model of Atherosclerosis : Possible Mechanisms Circulation, January 26, 1999; 99(3): 434 - 440. [Abstract] [Full Text] [PDF]
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T. Haruna, M. Horie, I. Kouchi, R. Nawada, K. Tsuchiya, M. Akao, H. Otani, T. Murakami, and S. Sasayama Coordinate Interaction Between ATP-Sensitive K+ Channel and Na+,K+-ATPase Modulates Ischemic Preconditioning Circulation, December 22, 1998; 98(25): 2905 - 2910. [Abstract] [Full Text] [PDF]
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T. Miki, T. Miura, R. Bunger, K. Suzuki, J. Sakamoto, and K. Shimamoto Ecto-5'-nucleotidase is not required for ischemic preconditioning in rabbit myocardium in situ Am J Physiol Heart Circ Physiol, October 1, 1998; 275(4): H1329 - H1337. [Abstract] [Full Text] [PDF]
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R. Schulz, H. Post, C. Vahlhaus, and G. Heusch Ischemic Preconditioning in Pigs: A Graded Phenomenon : Its Relation to Adenosine and Bradykinin Circulation, September 8, 1998; 98(10): 1022 - 1029. [Abstract] [Full Text] [PDF]
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C. Weinbrenner, G. S Liu, J. M Downey, and M. V Cohen Cyclosporine A limits myocardial infarct size even when administered after onset of ischemia Cardiovasc Res, June 1, 1998; 38(3): 676 - 684. [Abstract] [Full Text] [PDF]
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R. A. Kloner, R. Bolli, E. Marban, L. Reinlib, and E. Braunwald Medical and Cellular Implications of Stunning, Hibernation, and Preconditioning : An NHLBI Workshop Circulation, May 19, 1998; 97(18): 1848 - 1867. [Full Text] [PDF]
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T. Miura, T. Miura, S. Kawamura, M. Goto, J. Sakamoto, A. Tsuchida, M. Matsuzaki, and K. Shimamoto Effect of protein kinase C inhibitors on cardioprotection by ischemic preconditioning depends on the number of preconditioning episodes Cardiovasc Res, March 1, 1998; 37(3): 700 - 709. [Abstract] [Full Text] [PDF]
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L. R.C Dekker Toward the heart of ischemic preconditioning Cardiovasc Res, January 1, 1998; 37(1): 14 - 20. [Full Text] [PDF]
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D. M Yellon, G. F Baxter, D. Garcia-Dorado, G. Heusch, and M. S Sumeray Ischaemic preconditioning: present position and future directions Cardiovasc Res, January 1, 1998; 37(1): 21 - 33. [Abstract] [Full Text] [PDF]
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J. Starkopf, T. V Andreasen, E. Bugge, and K. Ytrehus Lipid peroxidation, arachidonic acid and products of the lipoxygenase pathway in ischaemic preconditioning of rat heart Cardiovasc Res, January 1, 1998; 37(1): 66 - 75. [Abstract] [Full Text] [PDF]
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Y. Qiu, A. Rizvi, X.-L. Tang, S. Manchikalapudi, H. Takano, A. K. Jadoon, W.-J. Wu, and R. Bolli Nitric oxide triggers late preconditioning against myocardial infarction in conscious rabbits Am J Physiol Heart Circ Physiol, December 1, 1997; 273(6): H2931 - H2936. [Abstract] [Full Text] [PDF]
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