(Circulation. 1997;96:1641-1646.)
© 1997 American Heart Association, Inc.
Articles |
Ischemic Preconditioning at a Distance
Reduction of Myocardial Infarct Size by Partial Reduction of Blood Supply Combined With Rapid Stimulation of the Gastrocnemius Muscle in the Rabbit
From the Heart Institute, Good Samaritan Hospital, and the University of Southern California, Los Angeles.
Correspondence to Robert A. Kloner, MD, PhD, The Heart Institute, Good Samaritan Hospital, 1225 Wilshire Blvd, Los Angeles, CA 90017.
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Abstract |
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Background Limitation of myocardial infarct size by an earlier brief complete occlusion of a coronary artery is defined as ischemic preconditioning. However, myocardial protection also can be achieved by partial reduction of coronary flow, rapid cardiac pacing, or brief ischemia-reperfusion of a remote region of the heart. Our study assesses the effect on myocardial infarct size of preconditioning at a distance induced by partial reduction of blood flow to a hind limb with or without increase of demand by electrical stimulation of a skeletal muscle.
Methods and Results Anesthetized rabbits were randomized to 30 minutes of waiting period (controls), 55% to 65% reduction of femoral artery blood flow (stenosis), electrical stimulation of the gastrocnemius muscle at a rate of one per second (stimulation), or stenosis+stimulation. Thereafter, rabbits underwent 30 minutes of coronary artery occlusion and 4 hours of reperfusion. Each group included 8 rabbits. Risk zones were comparable among groups. However, the ratio of infarct size to risk zone was smaller in the stenosis+stimulation group (0.09±0.02) compared with the control (0.26±0.03), stenosis (0.36±0.05), and stimulation (0.30±0.05) groups (P=.0006). ANCOVA performed on the fraction of infarction (infarct size/left ventricular weight) and the fraction of risk zone revealed a significant group effect (P=.0004).
Conclusions Remote ischemia of a skeletal muscle induced by muscle stimulation combined with restriction of blood flow preconditioned the myocardium. The combination of muscle stimulation with reduction of femoral arterial blood flow but not muscle stimulation without blood flow restriction or of flow restriction without muscle stimulation reduced myocardial infarct size considerably.
Key Words: angina • claudication • myocardial infarction • ischemia
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Introduction |
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The original experimental models of ischemic myocardial preconditioning involved brief complete obstruction of the infarct-related coronary artery before a long episode of ischemia.1 2 However, myocardial protection simulating preconditioning can be achieved by partial coronary artery stenosis,3 4 5 6 by rapid cardiac pacing,7 8 9 10 11 or by stimulation of the left stellate cardiac nerve combined with restriction of the increase in coronary flow by a pneumatic occluder, thus interfering with the supply-demand balance.12 Moreover, it has been demonstrated that myocardial protection can be conferred by an earlier brief ischemia of a remote myocardial region ("preconditioning at a distance")13 or even by brief ischemia of a remote organ, such as the kidney14 or mesentery.15 However, it is unclear whether ischemia of a remote organ induced by imbalance between myocardial oxygen demand and supply can protect the myocardium from ischemia-reperfusion injury. The purpose of this study was to assess the effect on myocardial infarct size of preconditioning at a distance induced by partial reduction of blood flow to a hind limb with or without increase of oxygen demand by rapid electrical stimulation of the gastrocnemius muscle.
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Methods |
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Animal Preparation
Male New Zealand White rabbits (2.0 to 3.0 kg) were anesthetized with a mixture of ketamine (
130 mg/kg
IM) and xylazine (65 mg/kg IM). Repeated injections of
ketamine and xylazine were given during the protocol as
required to maintain a deep level of anesthesia. The
rabbits were intubated and mechanically ventilated with room air
enriched with 100% oxygen delivered at a rate of 1.0 L/min. The left
jugular vein and carotid artery were cannulated with fluid-filled
catheters. The right femoral artery was exposed below the right
inguinal ligament. An ultrasonic flow probe for continuous measurement
of mean blood flow and an occluder balloon cuff were placed around the
femoral artery. In the rabbits randomized to flow reduction, the
occluder balloon was inflated with glycerol. The femoral flow was kept
constant by an occlusive pressure maintained with an angioplasty
inflator. The right gastrocnemius muscle was exposed through proximal
and distal skin incisions, and pacing electrodes were attached by a 4-0
silk suture to this muscle. The chest was opened through the left
fourth intercostal space. The pericardium was incised and the heart
exposed. Near the base of the heart, a large anterolateral branch of
the left circumflex artery or the artery itself was encircled with a
4-0 silk suture. The ends of the suture were threaded through a piece
of tubing, forming a snare that could be tightened to occlude the
artery. A 21-gauge butterfly catheter was inserted into the left atrial
appendage and fixed by a metal clip for injection of radioactive
microspheres to measure regional myocardial blood flow and blue
dye at the end of the protocol to delineate the ischemic zone
at risk. Systemic arterial pressure and heart rate were
recorded throughout the protocol. Blood flow in the right femoral
artery was monitored until coronary artery occlusion.
Experimental Protocols
After a 10-minute stabilization period, baseline heart rate,
blood pressure, and right femoral flow rate were measured and rabbits
were randomized to one of four treatment groups (Fig 1
):
(1) control: 30-minute waiting period without inflation of the vascular
occluder or electrical stimulation of the gastrocnemius muscle; (2)
stenosis without muscle stimulation: reduction of the femoral
blood flow by 55% to 65% for 30 minutes without electrical
stimulation of the gastrocnemius muscle; (3) muscle stimulation without
stenosis: electrical stimulation of the gastrocnemius muscle,
at a rate of one per second, with a stimulus of 9 V and 20-ms duration
for 30 minutes without reduction of femoral blood flow; and (4) muscle
stimulation with stenosis: reduction of the femoral blood flow
by 55% to 65% followed by electrical stimulation of the gastrocnemius
muscle at a rate of one per second with a stimulus of 9 V and 20-ms
duration for 30 minutes.
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After 30 minutes, the coronary artery was ligated for 30 minutes by tightening of the snare. Thereafter, the vascular occluder was released and muscle stimulation stopped. Measurement of regional myocardial blood flow was obtained at 25 minutes of ischemia. After 30 minutes of coronary artery occlusion, the snare was released and the heart reperfused for 4 hours. Thirty minutes after reperfusion, regional myocardial blood flow measurement was repeated to verify reperfusion.
Heart rate and systemic pressure were measured at baseline, 2 minutes before coronary artery occlusion (28 minutes of treatment), 25 minutes of coronary artery occlusion, 30 and 60 minutes after reperfusion, and every 60 minutes thereafter. Heart rate and arterial blood pressure were recorded at a paper speed of 25 mm/s. Three to five beats were averaged at each time point.
At the end of the protocol, after 4 hours of reperfusion, the coronary artery was reoccluded, and 4 mL of a 50% solution of Unisperse blue dye (CIBA-Geigy) was injected through the left atrial catheter to delineate the ischemic region at risk of necrosis. The deeply anesthetized rabbit was then killed by an injection of potassium chloride into the left atrium, and the heart was excised.
Analysis of Myocardium at Risk of Infarction
and Infarct Size
The heart was sliced transversely into six to eight sections
2 mm thick and photographed with magnification to identify the
ischemic risk zones (uncolored by the blue dye) and the
nonischemic zones (colored by blue dye). The slices were then
incubated for 10 minutes in a 1% solution of buffered
triphenyltetrazolium chloride (TTC)
preheated to 37°C, immersed in 10% phosphate-buffered formalin, and
rephotographed. The second photograph showed the necrotic zone
(unstained by TTC) and the noninfarcted region (stained red by TTC).
The photographic slides were later projected with a magnification
of x3 in a random order and traced without knowledge of the treatment
group. The areas of ischemic and normally perfused zones and
the areas of necrotic and nonnecrotic zones in each slice were
determined by computerized planimetry (Summagraphics). These areas were
multiplied by the weight of each slice, and the results were summed to
obtain the weight of the ischemic zone (IZ) at risk and the
weight of the necrotic zone (NZ). Infarct size was defined as the ratio
of the weight of the necrotic zone to the ischemic zone
(NZ/IZ).
Measurement of Regional Myocardial Blood Flow
Regional myocardial blood flow was measured by use of 11-µm
radioactive microspheres (New England Nuclear),
5x105 microspheres per injection, labeled with
141Ce, 96Nb, or 103Ru.
Microspheres were injected into the left atrium via the left
atrial catheter, and a reference blood sample was obtained from the
carotid artery at a fixed rate of 2.06 mL/min. At the end of the
protocol, samples were cut from the center of ischemic and
nonischemic regions (determined by the absence and presence of
the blue dye, respectively), weighed, and counted with the reference
blood samples in a well gamma counter. Blood flow was then computed and
expressed in mL·min-1·g
tissue-1.
Exclusion Criteria
We decided prospectively to exclude from the study rabbits with
an ischemic risk zone of <10% of the left
ventricular weight, rabbits with an ischemic
regional myocardial blood flow >0.2
mL·min-1·g
tissue-1 during coronary artery
occlusion, or rabbits that failed to reperfuse (regional myocardial
blood flow 
0.4 mL·min-1·g
tissue-1 30 minutes after release of the
coronary artery snare).
Additional Group
Because the mean heart rate of the rabbits randomized to
electrical muscle stimulation and reduction of femoral blood flow was
lower than the control and the muscle stimulation without
stenosis groups, an additional group was added post hoc,
without randomization. These rabbits were subjected to reduction of the
femoral blood flow by 55% to 65% followed by electrical stimulation
of the gastrocnemius muscle at a rate of one per second, with a
stimulus of 9 V and 20-ms duration for 30 minutes. Atrial pacing at a
rate of 180 bpm was initiated immediately after coronary artery
occlusion and continued throughout the protocol. Regional myocardial
blood flow was not measured in this group because it was not feasible
to achieve stable atrial pacing with a 21-gauge butterfly catheter
inserted into the left atrium.
Statistical Analyses
All data summary and statistical analyses were performed
with SAS version 6.04. Heart rate and mean blood pressure were
analyzed by repeated-measures ANOVA. Data on the necrotic and
ischemic zones, femoral artery blood flow, and regional
myocardial blood flow were evaluated by ANOVA. Tukey's test was used
to test for a difference among the individual means. ANCOVA was used to
test for group effect on the weight of the ischemic zone versus
the weight of the necrotic zone. Data are expressed as mean±SEM.
Values of P.05 were considered statistically
significant.
The rabbits used in this study were maintained in accordance with the policies of the American Heart Association (1985)16 and in accordance with the guidelines prepared by the Committee on Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources, National Research Council (Department of Health, Education, and Welfare publication 85-230). Good Samaritan Hospital is accredited by the American Association for Accreditation of Laboratory Animal Care.
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Results |
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Thirty-four rabbits were randomized into the first four groups. Two rabbits were excluded for regional myocardial blood flow >0.2 mL·min-1·g-1 during coronary artery occlusion. Data are reported on the remaining 32 animals, 8 in each group.
Femoral Artery Blood Flow
Femoral artery blood flow was comparable among groups at baseline
(Table 1). Although femoral artery blood flow did not
change much in the control group, it increased to 5.96 mL/min (58±17%
increase) in the muscle stimulation group compared with 4.76 mL/min
(14±17%) in the control group (P<.05). Femoral artery
blood flow was reduced by 60±1% and 64±1% in the stenosis
and muscle stimulation+stenosis groups, respectively
(P<.01 versus the control and muscle stimulation
groups).
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Hemodynamics
Mean blood pressure was comparable among groups throughout the
duration of the protocol (P=.97) (Fig 2).
Throughout the entire duration of the protocol, heart rate was slower
in the muscle stimulation+stenosis and stenosis groups
than in the control and muscle stimulation alone groups
(P=.0008 for the difference among groups), which was related
primarily to postreperfusion differences (Fig 2). During
coronary artery occlusion, however, there was no significant
difference in heart rate among groups (P=.087).
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Regional Myocardial Blood Flow
Regional myocardial blood flow measurements were not available in
two rabbits because of technical difficulty. All groups were equally
ischemic during coronary artery occlusion (Table 2). Regional myocardial blood flow in the previously
ischemic zone at 30 minutes of reperfusion tended to be higher
in the muscle stimulation+stenosis group, but without
statistical significance. Regional myocardial blood flow in the
nonischemic zone during both ischemia and reperfusion
was similar among groups (Table 2).
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Myocardium at Risk and Infarct Size
Mean body weight, left ventricular weight, and the
size of the risk region (expressed either in weight or as a fraction of
the left ventricular weight) were comparable among the
groups (Table 3). However, the weight of the necrotic
zone, the size of the necrotic zone (expressed as a fraction of the
left ventricle), and infarct size (the ratio between the weight of the
necrotic zone and that of the ischemic risk zone) were
significantly lower in the muscle stimulation+stenosis group
(P<.01 for the difference in infarct size between the
muscle stimulation+stenosis versus the stenosis group
and versus the muscle stimulation group; P<.05 versus the
control group) (Table 3).
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Fig 3 shows the relationship between the volume of
necrosis (divided by the left ventricular weight) and the
volume of the ischemic zone (divided by the left
ventricular weight) by groups. ANCOVA testing for group
effect performed on the fraction of the left ventricle that developed
necrosis and the fraction of the left ventricle that composed the
ischemic area at risk revealed a significant group effect
(P=.0004). The slope of the regression line of the muscle
stimulation+stenosis group was lower than that of the other
three groups. Hence, for the same ischemic zone at risk, the
muscle stimulation+stenosis group developed a smaller infarct
size than the other three groups.
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Additional Group
The group that was added post hoc and was subjected to
gastrocnemius muscle stimulation+stenosis+atrial pacing
included seven rabbits. Of seven rabbits entered into the study, one
demonstrated persistent epicardial cyanosis during the reperfusion
period and therefore was eliminated. Six rabbits successfully completed
the protocol. The mean blood pressure of the rabbits that were
subjected to atrial pacing was comparable to that of the other four
groups. Heart rate, however, was maintained at 180 bpm during
coronary artery occlusion and the 4 hours of reperfusion (Fig 2
). Mean body weight of the rabbits subjected to atrial pacing in
addition to muscle stimulation+stenosis was comparable to that
of the other four groups (2.43±0.06 kg). Left ventricular
weight (3.88±0.09 g) and the size of the ischemic area at risk
(0.34±0.05 of the left ventricular weight) were also
comparable to those of the other four groups. The infarct size of these
rabbits was relatively small (0.06±0.02 of the left ventricle;
0.17±0.04 of the ischemic risk zone).
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Discussion |
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The main finding in the present study is that by alteration of the supply-demand balance in a remote skeletal muscle, myocardial protection was conferred. After 30 minutes of coronary artery occlusion and 4 hours of reperfusion, infarct size expressed as a fraction of the ischemic risk zone was reduced by 65% in the rabbits subjected to reduction of flow in the femoral artery combined with rapid muscle stimulation compared with the control group (Table 3
). Further evidence that muscle stimulation+stenosis had an
infarct size–reducing effect was provided by ANCOVA testing for group
effect performed on the fraction of the left ventricle that developed
necrosis and the fraction of the left ventricle that was
ischemic (Fig 3). A significant group effect was found. The
slope of the regression line of the muscle stimulation+stenosis
group was lower than that of the other three groups. Skeletal muscle
stimulation (using the same rate, amplitude, and stimulus duration as
in the muscle stimulation+stenosis group) without reduction of
femoral blood flow, and reduction of femoral artery flow without
electrical stimulation of the gastrocnemius muscle, did not alter
infarct size, probably because the magnitude of the impairment in the
supply-demand balance of the skeletal muscle was not severe enough to
provide a preconditioning-like stimulus. The magnitude of infarct size reduction found in our study is comparable to that achieved with ischemic preconditioning produced by brief occlusion of the same coronary artery that is subjected later to a prolonged occlusion.17 18 19 20
Although mean blood pressure was comparable among the groups throughout the protocol, heart rate was slower in the stenosis group and muscle stimulation+stenosis group than in the muscle stimulation and control groups. However, during coronary artery occlusion, the difference was not statistically significant (P=.087). Moreover, mean infarct size in the stenosis without muscle stimulation group was the highest among groups (0.36±0.05), despite the lower heart rate. In the additional six rabbits that were subjected to atrial pacing at a rate of 180 bpm during coronary artery occlusion and throughout reperfusion, infarct size was also relatively small. Thus, the infarct size reduction seen in the muscle stimulation+stenosis group cannot be explained by relative bradycardia. In the latter group, atrial pacing was initiated immediately after coronary artery occlusion to eliminate the possibility of preconditioning the myocardium by atrial pacing.7 8 9 10 11
All groups were equally ischemic during coronary artery occlusion. Therefore, augmentation of collateral flow is not the mechanism of protection. The trend toward higher regional myocardial blood flow 30 minutes after reperfusion in the postischemic zone in the muscle stimulation+stenosis group is explained by the smaller infarct size. Thus, the postreperfusion hyperemia is not blunted by no-reflow.
Liauw et al21 reported that 5 hours of gracilis muscle ischemia (induced by complete reduction of blood flow) followed by 48 hours of reperfusion resulted in significant muscle salvage after 5 hours of ischemia and 48 hours of reperfusion of the contralateral gracilis muscle. Przyklenk et al13 demonstrated that four episodes of 5 minutes of left circumflex coronary artery occlusion protected the canine myocardium supplied by the left anterior descending coronary artery. After 60 minutes of left anterior descending coronary artery occlusion, infarct size was 6±2% of the ischemic zone in the dogs subjected to preceding left circumflex ischemia versus 16±5% in the controls (P<.05). McClanahan et al14 occluded the left renal artery in rabbits for 10 minutes. After 10 minutes of reperfusion, the coronary artery was ligated for 30 minutes, followed by 3 hours of reperfusion. Additional groups were subjected to preconditioning by 5 minutes of coronary artery occlusion (classic preconditioning), no preceding ischemia (controls), or permanent renal artery occlusion. Infarct size was 43±3% of the ischemic risk zone in the control rabbits, 8±2% in the classic preconditioning group (P=.0001 versus controls), and 11±2% in the transient renal ischemia group (P=.0001 versus controls). Infarct size was 31±4% (P=NS) in the group subjected to preceding permanent renal artery occlusion.14 Gho et al15 found that 15 minutes of anterior mesenteric artery occlusion in normothermic rats followed by 10 minutes of reperfusion and then 60 minutes of coronary artery occlusion resulted in reduction of infarct size to 50±3% of the risk zone compared with 68±2% of the risk zone in the control group (P<.001). A 15-minute coronary artery occlusion followed by 10 minutes of reperfusion and then 60 minutes of coronary reocclusion was equally protective (infarct size, 50±3%, P<.001), whereas 15 minutes of renal artery occlusion failed to limit infarct size (72±5%) in normothermic rats. Only in rats subjected to hypothermia (body temperature, 30°C to 31°C) did 15 minutes of renal artery occlusion protect the heart (46±6% compared with 67±3% in rats subjected to hypothermia alone, P<.01).15 However, myocardial protection by partial reduction of blood flow to a stimulated peripheral muscle has not been described previously. Moreover, in the studies by McClanahan et al14 and Gho et al,15 permanent peripheral artery occlusion without an intervening reperfusion period before coronary artery occlusion was not protective. In contrast to the previous studies, in our study there was no intervening reperfusion period. Peripheral ischemia was induced by partial stenosis of the femoral artery. Therefore, residual flow through the ischemic muscle continued and the potential mediators of protection could be continuously released into the circulation. Ischemia of the lower limbs caused by an increase of demand in muscles supplied by stenotic arteries is common in the daily life of patients with peripheral vascular disease or patients with reduced cardiac output due to severe heart failure. This type of ischemia may be more common than transient complete obstruction of mesenteric or renal arteries. Myocardial protection induced by such an ischemic event may partially explain the phenomenon of warm-up angina and especially walk-through angina.22 23 24 25 Walk-through angina refers to the paradoxical disappearance of anginal pain despite continuation of exertion.22 24 In this phenomenon, there is no intervening rest (as in the present protocol); thus, improvement of blood supply to the ischemic myocardium probably does not occur.
It might be that mediators released from ischemic limbs can attenuate myocardial ischemia. The mechanism of this type of myocardial protection was not studied in the present protocol. It remains to be determined whether the mechanisms are similar to the proposed mechanisms for the classic forms of ischemic myocardial preconditioning. Stimulation of mechanoreceptors by vigorous muscle contraction is probably not the trigger for myocardial protection, because infarct size was not limited in the group subjected to muscle stimulation alone. However, ischemic skeletal muscle or stimulated skeletal chemoreceptors may trigger release of substances via humoral or neurogenic pathways. A humoral factor, such as adenosine, bradykinin, or other substance, released from the ischemic skeletal muscle may trigger this form of protection.26 27 Myocardial protection by remote ischemia may be related to a catecholamine effect, because pretreatment with certain catecholamines can mimic the effect of preconditioning.28 29 These catecholamines may be released into the circulation from the ischemic muscle or may be released by the intramyocardial sympathetic nerve endings as a result of a stimulation of the sympathetic nervous system. Gho et al15 reported that hexamethonium (20 mg/kg IV), a ganglion blocker, abolished the protection by 15 minutes of mesenteric artery occlusion but not the protection by cardiac ischemic preconditioning. Their findings support involvement of the neurogenic pathway in the protection afforded by ischemia at a distance. However, in the studies by McClanahan et al14 and by Gho et al,15 myocardial infarct size was not reduced if the peripheral organ was not reperfused before the coronary artery occlusion. This fact may point to a release of humoral mediator from the ischemic organ by reperfusion, because activation of the nervous system may not be dependent on reperfusion. It should be determined whether this type of protection occurs in the denervated heart. Future studies using measurements of various potential mediators released after muscle stimulation and various potential blocking agents of either humoral or neurogenic pathways to inhibit the protective effect may clarify the mechanism.
In conclusion, remote ischemia of skeletal muscle induced by muscle stimulation combined with partial restriction of blood flow preconditioned the myocardium. Infarct size after such a procedure but not after muscle stimulation without restriction of blood flow or of flow restriction without muscle stimulation reduced infarct size considerably after 30 minutes of coronary artery occlusion and 4 hours of reperfusion. This form of preconditioning at a distance may be an important and common form of myocardial protection in the clinical setting, especially in patients with peripheral vascular disease. The results of this study also strengthen the concept that preconditioning at a distance can occur and is possibly related to either a hormonal or catecholamine-related mechanism.
Received January 6, 1997; revision received February 27, 1997; accepted March 5, 1997.
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 M. R. Schmidt, M. Smerup, I. E. Konstantinov, M. Shimizu, J. Li, M. Cheung, P. A. White, S. B. Kristiansen, K. Sorensen, V. Dzavik, et al. Intermittent peripheral tissue ischemia during coronary ischemia reduces myocardial infarction through a KATP-dependent mechanism: first demonstration of remote ischemic perconditioning Am J Physiol Heart Circ Physiol, April 1, 2007; 292(4): H1883 - H1890. [Abstract] [Full Text] [PDF]
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 P. W.G. Elbers, P. de Haan, I. Vanicky, D. Legemate, and M. Dzoljic Effect of Temporary Visceral Ischemia on Spinal Cord Ischemic Damage in the Rabbit. Ann. Thorac. Surg., March 1, 2006; 81(3): 910 - 917. [Abstract] [Full Text] [PDF]
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D. A. Liem, M. te Lintel Hekkert, O. C. Manintveld, F. Boomsma, P. D. Verdouw, and D. J. Duncker Myocardium tolerant to an adenosine-dependent ischemic preconditioning stimulus can still be protected by stimuli that employ alternative signaling pathways Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1165 - H1172. [Abstract] [Full Text] [PDF]
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C. Weinbrenner, F. Schulze, L. Sarvary, and R. H Strasser Remote preconditioning by infrarenal aortic occlusion is operative via {delta}1-opioid receptors and free radicals in vivo in the rat heart Cardiovasc Res, February 15, 2004; 61(3): 591 - 599. [Abstract] [Full Text] [PDF]
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P. D. Addison, P. C. Neligan, H. Ashrafpour, A. Khan, A. Zhong, M. Moses, C. R. Forrest, and C. Y. Pang Noninvasive remote ischemic preconditioning for global protection of skeletal muscle against infarction Am J Physiol Heart Circ Physiol, October 1, 2003; 285(4): H1435 - H1443. [Abstract] [Full Text] [PDF]
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 Z. Xia, P. Herijgers, T. Nishida, S. Ozaki, P. Wouters, and W. Flameng Remote preconditioning lessens the deterioration of pulmonary function after repeated coronary artery occlusion and reperfusion in sheep: Un preconditionnement eloigne diminue la deterioration de la fonction pulmonaire apres l'occlusion et la reperfusion repetees de l'artere coronaire Can J Anesth, May 1, 2003; 50(5): 481 - 488. [Abstract] [Full Text] [PDF]
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 R.K. Kharbanda, U.M. Mortensen, P.A. White, S.B. Kristiansen, M.R. Schmidt, J.A. Hoschtitzky, M. Vogel, K. Sorensen, A.N. Redington, and R. MacAllister Transient Limb Ischemia Induces Remote Ischemic Preconditioning In Vivo Circulation, December 3, 2002; 106(23): 2881 - 2883. [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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E. W. Dickson, R. J. Tubbs, W. A. Porcaro, W. J. Lee, D. J. Blehar, R. E. Carraway, C. E. Darling, and K. Przyklenk Myocardial preconditioning factors evoke mesenteric ischemic tolerance via opioid receptors and KATP channels Am J Physiol Heart Circ Physiol, July 1, 2002; 283(1): H22 - H28. [Abstract] [Full Text] [PDF]
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D. A. Liem, P. D. Verdouw, H. Ploeg, S. Kazim, and D. J. Duncker Sites of action of adenosine in interorgan preconditioning of the heart Am J Physiol Heart Circ Physiol, July 1, 2002; 283(1): H29 - H37. [Abstract] [Full Text] [PDF]
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 S. de Zeeuw, T. W. Lameris, D. J. Duncker, D. Hasan, F. Boomsma, A. H. van den Meiracker, and P. D. Verdouw Cardioprotection in Pigs by Exogenous Norepinephrine but not by Cerebral Ischemia-Induced Release of Endogenous Norepinephrine Stroke, March 1, 2001; 32(3): 767 - 774. [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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E. W. Dickson, M. Lorbar, W. A. Porcaro, R. A. Fenton, C. P. Reinhardt, A. Gysembergh, and K. Przyklenk Rabbit heart can be "preconditioned" via transfer of coronary effluent Am J Physiol Heart Circ Physiol, December 1, 1999; 277(6): H2451 - H2457. [Abstract] [Full Text] [PDF]
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E. Loh, T. R. Rebbeck, P. D. Mahoney, D. DeNofrio, J. L. Swain, and E. W. Holmes Common Variant in AMPD1 Gene Predicts Improved Clinical Outcome in Patients With Heart Failure Circulation, March 23, 1999; 99(11): 1422 - 1425. [Abstract] [Full Text] [PDF]
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T. J. Pell, G. F. Baxter, D. M. Yellon, and G. M. Drew Renal ischemia preconditions myocardium: role of adenosine receptors and ATP-sensitive potassium channels Am J Physiol Heart Circ Physiol, November 1, 1998; 275(5): H1542 - H1547. [Abstract] [Full Text] [PDF]
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P. D Verdouw, M. A van den Doel, S. de Zeeuw, and D. J Duncker Animal models in the study of myocardial ischaemia and ischaemic syndromes Cardiovasc Res, July 1, 1998; 39(1): 121 - 135. [Full Text] [PDF]
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