(Circulation. 1999;99:1249-1254.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Preconditioning in Immature Rabbit Hearts
Role of KATP Channels
From the Division of Cardiothoracic Surgery (J.E.B., P.H.) and Department of Pharmacology and Toxicology (J.E.B., G.J.G.), Medical College of Wisconsin, Milwaukee, Wis.
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Abstract |
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Background—The protective effects of ischemic preconditioning have been shown to occur in adult hearts of all species studied. We determined whether immature hearts normoxic or chronically hypoxic from birth could be preconditioned, the time window or memory of the cardioprotective effect, and the involvement of the KATP channel.
Methods and Results—Isolated immature rabbit hearts (7 to 10 days old) were subjected to 0, 1, or 3 cycles of preconditioning consisting of 5 minutes of global ischemia plus 10 minutes of reperfusion. This was followed by 30 minutes of global ischemia and 35 minutes of reperfusion. Normoxic hearts (FIO2=0.21) subjected to 1 cycle of preconditioning recovered 70±7% of left ventricular developed pressure compared with 43±8% recovery in nonpreconditioned controls. Three cycles of preconditioning did not result in additional recovery (63±8%). Hearts from rabbits raised from birth in hypoxic conditions (FIO2=0.12) and subjected to 1 and 3 preconditioning cycles did not show increased recovery (68±8% and 65±5%) compared with nonpreconditioned hypoxic controls (63±9%), although the recovery was greater in chronically hypoxic hearts than in age-matched normoxic controls. Increasing the recovery period after the preconditioning stimulus from 10 to 30 minutes resulted in a loss of cardioprotection. Pretreatment of normoxic hearts for 30 minutes with the KATP channel blocker 5-hydroxydecanoate (300 µmol/L) completely abolished preconditioning (70±7% to 35±9%) but had no effect on nonpreconditioned hearts (40±8%).
Conclusions—Immature hearts normoxic from birth can be preconditioned, whereas immature hearts hypoxic from birth cannot. Preconditioning in normoxic immature hearts is associated with activation of the KATP channel.
Key Words: cardiovascular diseases • heart defects, congenital • hypoxia • ions • ischemia
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Introduction |
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Ischemic preconditioning results in a reduction in infarct size, the severity of postischemic arrhythmias, and postischemic contractile dysfunction.1 The protective effects of ischemic preconditioning have been shown to occur in adult hearts of all species, including humans.2 Preconditioning may be able to serve a protective role in cardiac surgery in which delivery of cardioplegia in patients with severe coronary stenosis and ventricular hypertrophy may be limited.
In children with congenital heart disease, in whom ventricular hypertrophy, pulmonary atresia with intact ventricular septum, and coronary sinusoids are present, adequate access to all regions of the heart may be denied to cardioplegic solutions, which represents an increased risk factor for cardiac surgery.3 4 5 Protection of ischemic immature myocardium with cardioplegia is less than optimal despite its well-known benefits in adults, as shown by depletion of ATP,6 7 the generation of free radicals,8 and histological injury.9 Thus, in pediatric cardiac surgery, additional cardioprotection by endogenous mechanisms such as preconditioning may be useful when conventional myocardial protection with cardioplegia is inadequate. Preconditioning of isolated chick ventricular myocytes results in reduced enzyme leakage.10 However, it is unknown whether intact neonatal hearts can be preconditioned, thereby resulting in improved postischemic contractile function.
In contrast to adults with acquired heart disease, the myocardium of children with congenital heart disease may be chronically perfused with blood that is hypoxic before corrective cardiac surgery.11 We recently demonstrated that increased tolerance to ischemia in the intact and chronically hypoxic neonatal rabbit heart is associated with increased activation of the KATP channel and suggested that adaptation to chronic hypoxia may represent a unique form of preconditioning.12
The aims of the present study were to determine (1) whether immature hearts normoxic or hypoxic from birth could be preconditioned, (2) how long the memory of preconditioning persisted, and (3) the involvement of the ATP-sensitive potassium (KATP) channel in mediating preconditioning in immature hearts.
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Methods |
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Animals
Animals used in this study received humane care in compliance with the "Guide for the Care and Use of Laboratory Animals" formulated by the National Research Council, 1996.
Creation of Hypoxia From Birth
Pregnant New Zealand White rabbits were obtained from a
commercial breeder. For the hypoxic studies, the kits were born in a
normoxic environment and then transferred to a hypoxic environmental
chamber (FIO2=0.12) immediately after
their first feeding. The oxygen level in the chamber was maintained at
FIO2=0.12 throughout the remainder of
the study. For the normoxic studies, the kits were raised under
identical conditions except that FIO2
in the environmental chamber remained at 0.21 for the duration of
the study.12
Perfusion System
Isolated rabbit hearts were instrumented as previously
described.12 A 3-way tap, located immediately above the
site of cannulation, allowed the entire perfusate to be
diverted away from the heart to produce global, no-flow
ischemia. Reperfusion was achieved by repositioning of the tap
to allow perfusate to be delivered to the heart.
Perfusion Media
The standard perfusate was modified Krebs-Henseleit
bicarbonate buffer13 (mmol/L): NaCl 118.5;
NaHCO3 25.0; KCl 4.8; MgSO4
0.6; H2O 1.2;
KH2PO4 1.2 (pH 7.4 when
gassed with 95% O2-5%
CO2), in which the calcium content was reduced to
1.8. Glucose (11.1 mmol/L) was added to the perfusate.
Before use, all perfusion fluids were filtered through cellulose
acetate membranes with a pore size of 5.0 µm to remove
particulate matter. KATP blockers were added to
this perfusate as needed.
Assessment of Ventricular Function
Left and right ventricular function was monitored
continuously throughout each experiment as previously
described.12 End-diastolic pressure was
initially set to 3 mm Hg for 2 minutes. The balloons were then
progressively inflated with a microsyringe to set
end-diastolic pressures to 8 mm Hg for the left
ventricle and 4 mm Hg for the right ventricle, and developed
pressure was recorded during steady-state conditions.
Coronary-flow rate was measured throughout the experiment by
timed collections of the coronary effluent from the right side
of the heart into a graduated cylinder. Coronary flow rate was
expressed as milliliters per minute.
Perfusion Sequence
Preconditioning Studies
We performed the following experiments in a random order using
10 hearts from 6 groups to test the null hypothesis that immature
hearts normoxic or chronically hypoxic from birth cannot be
preconditioned. The 6 experimental groups were as follows: group 1,
normoxic, nonpreconditioned; group 2, normoxic, 1x5
minutes of preconditioning; group 3, normoxic, 3x5 minutes of
preconditioning; group 4, hypoxic, nonpreconditioned;
group 5, hypoxic, 1x5 minutes of preconditioning; and group 6,
hypoxic, 3x5 minutes of preconditioning. Figure 1
illustrates the experimental protocol.
Immediately after aortic cannulation, hearts were perfused in the
Langendorff mode14 at constant perfusion pressure of
42 mm Hg15 with balloons placed in the left and
right ventricles. Biventricular function and
coronary flow rate were recorded under steady-state
conditions. Hearts were subjected to 0, 1, or 3 cycles of
preconditioning, each consisting of 5 minutes of global, no-flow
ischemia plus 10 minutes of reperfusion. In each instance, this
was followed by 30 minutes of global, no-flow ischemia and 35
minutes of reperfusion. The rationale for investigating >1
preconditioning cycle was to determine if the threshold (the minimum
stimulus necessary to produce preconditioning) was higher in
chronically hypoxic hearts than in normoxic controls. During the
reperfusion period, indexes of cardiac function were measured under
steady-state conditions. In this way, each heart served as its own
control.
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Memory Studies
We assessed the effect of the period of time between the
preconditioning stimulus and the prolonged ischemic insult on
postischemic recovery in immature normoxic hearts. The
duration of this period determines whether the myocardium
retains the memory of the preconditioning stimulus that confers
protection during subsequent sustained
ischemia.16 17 We performed the following
experiments in random order using 10 hearts from 4 groups. The 4
experimental groups were as follows: group 7,
nonpreconditioned; group 8, 1x5 minutes of
preconditioning with 10 minutes of reperfusion; group 9, 1x5 minutes
of preconditioning with 20 minutes of reperfusion; and group 10, 1x5
minutes of preconditioning with 30 minutes of reperfusion. In each
instance, the preconditioning event was followed by 30 minutes of
global, no-flow ischemia and 35 minutes of reperfusion.
Mechanism Studies
Preconditioning in mature hearts is mediated by activation of
KATP channels.18 19 We determined
whether blockade of the KATP channel before the
preconditioning stimulus influences postischemic recovery
in immature hearts. We performed the following experiments in random
order using 10 hearts in 5 groups of normoxic rabbits. The 5
experimental groups were as follows: group 11,
nonpreconditioned before ischemia; group 12,
nonpreconditioned, 30 minutes of perfusion with
5-hydroxydecanoate (300 µmol/L) before ischemia; group
13, preconditioned; group 14, 30 minutes of perfusion with
5-hydroxydecanoate (100 µmol/L) before preconditioning; and
group 15, 30 minutes of perfusion with 5-hydroxydecanoate (300
µmol/L) before preconditioning. In each instance, the preconditioning
stimulus consisted of 5 minutes of global, no-flow ischemia
followed by 10 minutes of recovery. This was followed by 30 minutes of
global, no-flow ischemia and 35 minutes of reperfusion.
All hearts that were entered into the study were included in the analysis. Recovery of developed pressure was expressed as a percentage of its predrug, preischemic value. Ten hearts were used for each of the 15 conditions studied. Results are expressed as mean±SD. Statistical analysis was performed by use of repeated-measures ANOVA with the Greenhouse-Geisser adjustment used to correct for the inflated risk of a type I error,20 and where this proved significant, the Mann-Whitney test was used as a second step to identify which groups were significantly different. After ANOVA was performed, the data were reanalyzed for differences related to multiple comparisons.12 Significance was accepted at a level of P<0.05.
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Results |
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Preconditioning in Immature Hearts
The Table
gives
hemodynamic data for immature hearts before
preconditioning, after the first preconditioning cycle, and after 35
minutes of reperfusion. Coronary flow rate in chronically
hypoxic hearts was higher than in normoxic hearts as an adaptive
response to increase oxygen delivery to the myocardium.
Right ventricular developed pressure was higher in hypoxic
ventricles than in normoxic ventricles as a consequence of right
ventricular hypertrophy. The preconditioning
stimulus depressed left and right ventricular developed
pressures during the recovery period in all groups. The Table
also shows that hearts from chronically hypoxic rabbits were more
tolerant of ischemia than normoxic controls, as shown by
improved recovery of postischemic left
ventricular developed pressure. Figure 2 shows that normoxic hearts subjected to
1 cycle of preconditioning (group 2) exhibited an increased recovery of
left ventricular developed pressure, from 43±8% in
nonpreconditioned hearts (group 1) to 70±7%.
Increasing the number of preconditioning cycles from 1 to 3 (group 3)
did not result in additional increased recovery of developed pressure
(63±8%). In contrast, Figure 3 shows
that chronically hypoxic hearts subjected to 1 cycle of preconditioning
(group 5) did not show increased recovery of developed pressure
compared with nonpreconditioned hearts (group 4)
(63±9% versus 68±8%). Increasing the number of preconditioning
cycles from 1 to 3 in chronically hypoxic hearts (group 6) did not
result in additional protection (65±5%). Thus, neither 1 or 3 cycles
of preconditioning resulted in greater protection than that afforded by
chronic hypoxia. Our data indicate that left ventricle from
immature hearts normoxic from birth could be preconditioned, whereas
left ventricle from immature hearts chronically hypoxic from birth
could not be preconditioned. Recovery of developed pressure in the
right ventricle was not increased by preconditioning in either normoxic
or chronically hypoxic hearts.
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Persistence of Memory
We then examined the relationship between the duration of the
reperfusion period after a single 5-minute preconditioning stimulus
before sustained ischemia and recovery of
postischemic function. Figure 4 shows the results of an increase in the
reperfusion period between the preconditioning stimulus and the
prolonged ischemic insult from 10 to 30 minutes. Ten minutes of
reperfusion after the preconditioning stimulus (group 8) resulted in a
recovery of left ventricular developed pressure of 72±6%.
The memory of preconditioning was retained after 20 minutes of
reperfusion (group 9), with a recovery of 67±6%. However, after 30
minutes of reperfusion (group 10), the memory of preconditioning was
lost, resulting in a recovery of developed pressure to 42±4%, which
was no different than in nonpreconditioned hearts
(42±6%; group 7). There were no differences in
hemodynamics between groups before sustained
ischemia.
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Role of KATP Channels
Figure 5 shows that in hearts
nonpreconditioned before ischemia, recovery of
developed pressure was 43±6% (group 11). Blockade of the
KATP channel for 30 minutes before
ischemia in nonpreconditioned hearts with
300 µmol/L 5-hydroxydecanoate (group 12) had no effect on
tolerance to ischemia, with recovery of 40±8%. Preconditioned
hearts (group 13) recovered 70±7% of preischemic
developed pressure compared with 43±6% in
nonpreconditioned controls (group 11). Pretreatment of
hearts for 30 minutes with 100 µmol/L 5-hydroxydecanoate (group
14) and 300 µmol/L 5-hydroxydecanoate (group 15) before
preconditioning completely abolished preconditioning, with recoveries
of 45±8% and 35±9%, respectively, which were no different than
recoveries in nonpreconditioned hearts.
5-Hydroxydecanoate (100 and 300 µmol/L) depressed
preischemic coronary flow rate and developed
pressure in both the preconditioned and
nonpreconditioned groups. Thus, 5-hydroxydecanoate was
able to completely abolish preconditioning in immature normoxic
hearts.
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Discussion |
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We demonstrated that hearts from immature rabbits normoxic from birth can be preconditioned. In contrast, hearts from immature rabbits hypoxic from birth were resistant to preconditioning. Chronically hypoxic hearts were also more resistant to sustained ischemia than were normoxic hearts, consistent with our previous results.11 12 The memory of preconditioning in immature normoxic hearts was lost 30 minutes after the preconditioning stimulus. The KATP channel blocker 5-hydroxydecanoate completely abolished the cardioprotective effects of preconditioning in immature normoxic hearts, whereas 5-hydroxydecanoate did not affect recovery of postischemic function in nonpreconditioned normoxic hearts.
Preconditioning of Immature Hearts
Adaptation to chronic hypoxia from birth confers tolerance
to subsequent ischemia compared with age-matched normoxic
controls.11 We previously suggested that there are
similarities between adaptation to chronic hypoxia and
preconditioning regarding the ability of these 2 processes to protect
the heart against a subsequent ischemic insult.12
In the present study, we demonstrate for the first time that left
ventricle of immature rabbit hearts normoxic from birth could be
preconditioned, whereas immature hearts chronically hypoxic from birth
could not be preconditioned. Our data suggest that chronically hypoxic
immature hearts are already protected by adaptation to hypoxia
and that additional cardioprotection by ischemic
preconditioning is not possible. In our previous study,12
in which hearts were subjected to 18 minutes of global no-flow
ischemia, recovery of right ventricular function
was greater in chronically hypoxic hearts than in normoxic controls. In
the present study, in which hearts were subjected to 30 minutes of
global no-flow ischemia, recovery of right
ventricular function in chronically hypoxic hearts was no
different from normoxic controls. We attribute the observed differences
between the present and previous studies to the increased duration
of ischemia. The right ventricle was resistant to
preconditioning in our study. This raises the possibility that
the right ventricle may already be preconditioned or that the
preconditioning stimulus was insufficient to protect the right
ventricle against the subsequent period of prolonged
ischemia.
The ability of ischemic preconditioning to provide additional protection in chronically hypoxic hearts during subsequent postnatal development is unknown. Evidence to support this possibility, however, is based on the observation by Tajima et al21 that hearts from chronically hypoxic adult rats could be preconditioned, although no mechanisms were uncovered to explain the additive protective effect of preconditioning on adaptation to chronic hypoxia. Additional studies are needed to define the relationship between age, adaptation to hypoxia, and ischemic preconditioning, as well as the mechanisms involved.
We considered the possibility that the threshold for preconditioning was higher in chronically hypoxic hearts than in normoxic controls. However, increasing the number of preconditioning cycles from 1 to 3 did not result in additional cardioprotection in either normoxic or chronically hypoxic hearts. There was a trend toward a slight reduction in cardioprotection with multiple preconditioning cycles in both normoxic and chronically hypoxic hearts, although the effect was not significant. Our finding is in agreement with Iliodromitis et al,22 who demonstrated that multiple cycles of preconditioning resulted in a loss of protection in an in situ rabbit model of myocardial necrosis. Thus, our data do not support the idea of an increased threshold for preconditioning in chronically hypoxic hearts.
Memory of Preconditioning
In adult rabbit hearts preconditioned by a single 5-minute period
of occlusion, a time delay of 15 to 30 minutes between the
preconditioning stimulus and the prolonged ischemic insult
results in a loss of cardioprotection.16 17 Similarly, we
have shown that in immature rabbit hearts preconditioned by a single
5-minute period of occlusion, the memory of preconditioning is also
lost after a time delay of 30 minutes between the preconditioning
stimulus and the prolonged ischemic insult. Our data suggest
there is no age-related difference in the memory of preconditioning
between immature and mature rabbit hearts. The protective effects of
ischemic preconditioning elicited by a single 5-minute period
of occlusion reappear 24 to 72 hours after the preconditioning stimulus
in adult rabbits.23 Additional studies are needed to
determine whether this "second window of protection" is present
in immature rabbit hearts.
Involvement of KATP Channel
In adult rabbit hearts, blockade of the KATP
channel with glibenclamide abolished the protective effect of
preconditioning.18 19 Our present study shows that
pretreatment of immature hearts with 100 and 300 µmol/L of the
ischemia-selective KATP channel blocker
5-hydroxydecanoate completely abolishes the protective effect of
preconditioning. Our study is the first to demonstrate preconditioning
in immature rabbit hearts and the involvement of the
KATP channel. 5-Hydroxydecanoate alone had no
effect on recovery from ischemia in
nonpreconditioned hearts. This finding is in agreement
with previous studies24 that showed 5-hydroxydecanoate had
no effect on injury during the cycle of ischemia and
reperfusion.
Adaptation of immature rabbits to chronic hypoxia from birth increases tolerance of the heart to subsequent ischemia.11 The KATP channel blocker glibenclamide abolished this cardioprotective effect.12 Ischemic preconditioning in immature rabbit hearts also increased tolerance to ischemia. 5-Hydroxydecanoate abolished this cardioprotective effect. Thus, ischemic preconditioning and adaptation to chronic hypoxia in immature hearts appear to share a final common effector, the KATP channel, although the signal transduction pathway in the immature heart that results in increased activation of the KATP channel is unknown.
The cardioprotective effect of KATP channel openers, used at concentrations that do not shorten action potential duration, is abolished by the KATP channel blocker 5-hydroxydecanoate.24 This suggests that 5-hydroxydecanoate may not act on the sarcolemmal KATP channel. Potassium channels are also found in the inner mitochondrial membrane,25 26 where they control mitochondrial volume and energetics. Diazoxide, a KATP channel opener, is 1000 times more selective for opening mitochondrial KATP channels than sarcolemmal KATP channels.27 The cardioprotective effect of diazoxide during ischemia is completely abolished by 5-hydroxydecanoate,28 which indicates a role for the mitochondrial KATP channel in protection of ischemic myocardium. 5-Hydroxydecanoate completely abolished the cardioprotective effects of preconditioning in immature hearts, which suggests a cardioprotective role for mitochondrial KATP channels in immature hearts.
Clinical Relevance
Clinically, adult human myocardium can be
preconditioned by brief periods of planned or unplanned
ischemia, with protection mediated by
KATP channel activation. During coronary
angioplasty, the severity of ST-segment depression is diminished during
a second balloon inflation compared with the first. Administration of
glibenclamide, a KATP channel blocker, 90 minutes
before angioplasty eliminated this cardioprotective
effect.29 Angina that precedes a myocardial infarction
within 48 hours confers endogenous
cardioprotection.30 Preconditioning also preserves
high-energy phosphates in patients undergoing coronary artery
bypass surgery.2
Cardiopulmonary bypass operations in children to correct congenital heart defects represent a planned ischemic insult for which ischemic preconditioning may be beneficial. In children with some forms of congenital heart disease, adequate access to all regions of the heart may be denied to cardioplegic solutions. Incomplete cardioprotection with cardioplegia in infants and children after surgical repair of congenital hearts defects has been demonstrated by a deterioration in systolic function.31 We have shown that protection of ischemic immature rabbit myocardium with traditional cardioplegia may be inadequate.15 Thus, the potential exists for clinical application of ischemic myocardial preconditioning before cardiac surgery in children with congenital heart disease. Another potential area of application for ischemic preconditioning in children would be in the setting of cardiac transplantation.
In conclusion, we have shown that isolated, crystalloid-perfused, immature hearts normoxic from birth can be preconditioned, whereas immature hearts chronically hypoxic from birth cannot be preconditioned. The response of blood-perfused immature hearts to a preconditioning stimulus remains unknown. The mechanism of preconditioning in immature hearts is associated with activation of the KATP channel. Additional studies are needed to define the relative contributions of the sarcolemmal and mitochondrial KATP channels as well as the signal transduction mechanism responsible for KATP channel activation.
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Acknowledgments |
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This work was supported in part by grants HL-54075 and HL-08311 from the National Institutes of Health, Ronald McDonald's Children's Charities, and the Children's Hospital of Wisconsin Research Foundation. We are grateful to Ara K. Pridjian, MD, for stimulating discussion and to Mary Lynne Koenig for secretarial assistance.
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Footnotes |
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Reprint requests to John E. Baker, PhD, Division of Cardiothoracic Surgery, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226.
Received May 26, 1998; revision received October 9, 1998; accepted October 22, 1998.
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 I. Malagon, K. Hogenbirk, J. van Pelt, M. G. Hazekamp, and J. G. Bovill Effect of three different anaesthetic agents on the postoperative production of cardiac troponin T in paediatric cardiac surgery Br. J. Anaesth., June 1, 2005; 94(6): 805 - 809. [Abstract] [Full Text] [PDF]
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 A. K. Gamperl and A. P. Farrell Cardiac plasticity in fishes: environmental influences and intraspecific differences J. Exp. Biol., July 1, 2004; 207(15): 2539 - 2550. [Abstract] [Full Text] [PDF]
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A. K. Gamperl, H. A. Faust, B. Dougher, and K. J. Rodnick Hypoxia tolerance and preconditioning are not additive in the trout (Oncorhynchus mykiss) heart J. Exp. Biol., June 15, 2004; 207(14): 2497 - 2505. [Abstract] [Full Text] [PDF]
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 J. Forkel, X. Chen, S. Wandinger, F. Keser, A. Duschin, U. Schwanke, S. Frede, P. Massoudy, R. Schulz, H. Jakob, et al. Responses of chronically hypoxic rat hearts to ischemia: KATP channel blockade does not abolish increased RV tolerance to ischemia Am J Physiol Heart Circ Physiol, February 1, 2004; 286(2): H545 - H551. [Abstract] [Full Text] [PDF]
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 P. Rafiee, Y. Shi, K. A. Pritchard Jr., H. Ogawa, A. L. W. Eis, R. A. Komorowski, C. M. Fitzpatrick, J. S. Tweddell, S. B. Litwin, K. Mussatto, et al. Cellular Redistribution of Inducible Hsp70 Protein in the Human and Rabbit Heart in Response to the Stress of Chronic Hypoxia: ROLE OF PROTEIN KINASES J. Biol. Chem., October 31, 2003; 278(44): 43636 - 43644. [Abstract] [Full Text] [PDF]
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A. Rosa, J.-P. Maury, J. Terrand, X. Lyon, P. Kucera, L. Kappenberger, and E. Raddatz Ectopic pacing at physiological rate improves postanoxic recovery of the developing heart Am J Physiol Heart Circ Physiol, June 1, 2003; 284(6): H2384 - H2392. [Abstract] [Full Text] [PDF]
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 D. Zhu, M. Medhora, W. B. Campbell, N. Spitzbarth, J. E. Baker, and E. R. Jacobs Chronic Hypoxia Activates Lung 15-Lipoxygenase, Which Catalyzes Production of 15-HETE and Enhances Constriction in Neonatal Rabbit Pulmonary Arteries Circ. Res., May 16, 2003; 92(9): 992 - 1000. [Abstract] [Full Text] [PDF]
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J. Neckar, O. Szarszoi, L. Koten, F. Papousek, B. Ost'adal, G. J Grover, and F. Kolar Effects of mitochondrial KATP modulators on cardioprotection induced by chronic high altitude hypoxia in rats Cardiovasc Res, August 15, 2002; 55(3): 567 - 575. [Abstract] [Full Text] [PDF]
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 P. Rafiee, Y. Shi, X. Kong, K. A. Pritchard Jr, J. S. Tweddell, S. B. Litwin, K. Mussatto, R. D. Jaquiss, J. Su, and J. E. Baker Activation of Protein Kinases in Chronically Hypoxic Infant Human and Rabbit Hearts: Role in Cardioprotection Circulation, July 9, 2002; 106(2): 239 - 245. [Abstract] [Full Text] [PDF]
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M. Tonkovic-Capin, G. J. Gross, Z. J. Bosnjak, J. S. Tweddell, C. M. Fitzpatrick, and J. E. Baker Delayed cardioprotection by isoflurane: role of KATP channels Am J Physiol Heart Circ Physiol, July 1, 2002; 283(1): H61 - H68. [Abstract] [Full Text] [PDF]
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 A. K. Gamperl, A. E. Todgham, W. S. Parkhouse, R. Dill, and A. P. Farrell Recovery of trout myocardial function following anoxia: preconditioning in a non-mammalian model Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2001; 281(6): R1755 - R1763. [Abstract] [Full Text] [PDF]
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J. T. Eells, M. M. Henry, G. J. Gross, and J. E. Baker Increased Mitochondrial KATP Channel Activity During Chronic Myocardial Hypoxia : Is Cardioprotection Mediated by Improved Bioenergetics? Circ. Res., November 10, 2000; 87(10): 915 - 921. [Abstract] [Full Text] [PDF]
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J. E. Baker, E. A. Konorev, G. J. Gross, W. M. Chilian, and H. J. Jacob Resistance to myocardial ischemia in five rat strains: is there a genetic component of cardioprotection? Am J Physiol Heart Circ Physiol, April 1, 2000; 278(4): H1395 - H1400. [Abstract] [Full Text] [PDF]
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 M. Gonzalez-Zulueta, A. B. Feldman, L. J. Klesse, R. G. Kalb, J. F. Dillman, L. F. Parada, T. M. Dawson, and V. L. Dawson Requirement for nitric oxide activation of p21ras/extracellular regulated kinase in neuronal ischemic preconditioning PNAS, January 4, 2000; 97(1): 436 - 441. [Abstract] [Full Text] [PDF]
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