| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Abteilung für Pathophysiologie, Zentrum Innere Medizin, Universitätsklinikum Essen, 45122 Essen, Germany
 |
ABSTRACT |
|---|
 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Endogenous opioids are
involved in ischemic preconditioning (IP) in several species.
Whether or not opioids are important for IP and short-term myocardial
hibernation (STMH) in pigs is currently unknown. In 34 enflurane-anesthetized pigs, the left anterior descending coronary
artery was flow constantly perfused. Subendocardial blood flow (Endo),
infarct size (IS; percent area at risk), and the free energy change of
ATP hydrolysis (
G) were determined. After 90-min severe
ischemia and 120-min reperfusion, IS averaged 28.3 ± 5.4% (means ± SE) (n = 8; Endo: 0.047 ± 0.009 ml · min
1 · g1). IP
by 10-min ischemia and 15-min reperfusion reduced IS to 9.9 ± 3.8% (P < 0.05, n = 8;
Endo: 0.044 ± 0.009 ml · min1 · g1). After
naloxone (1 mg/kg iv followed by 2 µg · kg1 · min1), IS
averaged 25.8 ± 7.0% (n = 6; Endo: 0.039 ± 0.008 ml · min1 · g1)
without and 24.7 ± 4.7% (n = 6; Endo: 0.044 ± 0.006 ml · min1 · g1)
with IP. At 5-min moderate ischemia in the presence of
naloxone, Endo decreased from 0.90 ± 0.07 to 0.28 ± 0.03 ml · min1 · g1and
G decreased from 
58.6 ± 1.0 to 52.6 ± 0.4 kJ/mol. Prolongation of ischemia to 90 min did not alter Endo,
but G recovered toward control values (57.7 ± 1.1 kJ/mol), and the myocardium remained viable. These responses are
identical to those of nonnaloxone-treated pigs. Endogenous opioids are
involved in IP but not in STMH in pigs.
infarction; myocardial ischemia; free energy change
| |
INTRODUCTION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
-ENDORPHINE
PLASMA CONCENTRATIONS are increased in patients during acute
myocardial ischemia, such as during percutaneous transluminal
coronary angioplasty (PTCA) (15, 30) and after myocardial
infarction (36). In these experiments, there is good evidence that opioids attenuate the consequences of
ischemia-reperfusion. Blockade of opioid receptors with
naloxone abolishes 1) the ischemia-induced decrease
in mean arterial pressure (16) and 2) the
morphine-induced decreases in heart rate and arterial pressure and the
ischemia-induced arrhythmias in anesthetized pigs
(5).
Ischemic preconditioning is the earliest stress response that
occurs during episodes of brief ischemia and reperfusion, and it can render the myocardium more tolerant to subsequent
lethal ischemic injury (39).
Ischemic preconditioning occurs in two different phases: first,
an early immediate effect [classic ischemic preconditioning
(IP)] and, second, a late effect (late phase of preconditioning)
(3, 20, 57). Naloxone abolishes the infarct size reduction
achieved by IP in rats (17, 45, 46) and rabbits (13,
34), and it prevents the attenuation of electrocardiogram changes during repeated PTCA in humans (52).
Conversely, activation of opioid receptors reduces infarct size during
subsequent ischemia to the same extent as IP in rats (27,
42, 44); the important opioid receptor for such cardioprotection
in rats appears to be the 
-opioid receptor (1, 43). The
activation of -opioid receptors also induces the late phase of
preconditioning in rats (17). The signal cascade after
activation of opioid receptors involves activation of pertussis
toxin-sensitive G proteins in rats (44), protein kinase C
in rabbits (34), and ATP-dependent potassium channels in
rats (27, 42, 44) and isolated cardiomyocytes from chick
embryos (31). Whether or not endogenous opioids are also
involved in infarct size reduction by IP in pigs is unclear at present,
because certain species differences in the mechanisms of
ischemic preconditioning exist (12).
During more moderate ischemia, the myocardium does not inevitably undergo necrosis but can adapt to reduced blood flow through a regulatory reduction in contractile function (22, 38). Therefore, loss of contractile function in patients with coronary artery disease frequently does not indicate infarction but a downregulated state of myocardial "hibernation" (38). A close relationship between reduced myocardial blood flow and contractile function, i.e., perfusion-contraction matching, is a key feature of "short-term myocardial hibernation" (STMH) in the experimental setting (40). Further characteristics of myocardial hibernation are recovery of energy metabolism during ongoing ischemia, persistence of an inotropic reserve, recovery of contractile function on reperfusion, and, almost by definition, absence of necrosis (22). No mechanism underlying myocardial hibernation, other than reduced calcium responsiveness (24), has so far been identified.
Whereas the term hibernation was initially borrowed from zoology as a paradigm to characterize the endogenous cardiac protection during ischemia, recent studies indicate that the serum of truly hibernating mammals does indeed contain an opioid-like protein (25) that acts to preserve myocardial ultrastructure (8, 27) and improve functional recovery from ischemia (7, 8, 27) when given to nonhibernating animals. However, whether or not the development of successful STMH during ischemia is also triggered by endogenous opioids is unclear at present. Pigs were used for the study of involvement of endogenous opioids in both IP and STMH because their coronary anatomy (55), extent of collateral flow (56), and time course of infarct development most closely resemble those observed in humans (41).
We therefore tested in an established pig model of IP and STMH whether or not blockade of opioid receptors with naloxone 1) abolishes infarct size reduction by IP and 2) interferes with the development of STMH.
| |
MATERIALS AND METHODS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Experimental Preparation
Thirty-four Göttinger minipigs (20-40 kg) of either sex were initially sedated using ketamine hydrochloride (1 g im) and then anesthetized with thiopental (Trapanal; 500 mg iv). Through a midline cervical incision, the trachea was intubated for connection to a respirator (Dräger; Lübeck, Germany). Anesthesia was then maintained using enflurane (1-1.5%) with an oxygen/nitrous oxide mixture (40:60%). Arterial blood gases were monitored frequently in the initial stages of the preparation until stable and then periodically throughout the study (Radiometer; Copenhagen, Denmark). Rectal temperature was monitored, and body temperature was kept between 37 and 38°C using heating pads. Pigs were instrumented for the measurement of left ventricular pressure and wall thickness (23, 47). After heparinization, the left anterior descending (LAD) coronary artery and vein were cannulated, and the artery was perfused by an extracorporeal circuit including an occlusive roller pump. Heart rate was held constant by left atrial pacing.Regional Myocardial Function, Blood Flow, and Metabolism
Regional systolic wall thickening (sonomicrometry) was calculated. Regional myocardial blood flow was measured with microspheres, and myocardial oxygen and lactate consumptions were calculated (23). Transmural biopsies were taken to determine the free energy change of ATP hydrolysis (32).Morphology
Six transverse myocardial slices from each heart were incubated in triphenyltetrazolium chloride (TTC) solution to identify necrotic tissue (47).Experimental Protocols: Ischemic Preconditioning
Group 1 (n = 8). After control measurements of systemic hemodynamics, regional myocardial function, blood flow, and metabolism were performed, coronary inflow was reduced to achieve a 90% reduction in regional myocardial function. At 5- and 85-min ischemia, measurements were repeated, and thereafter the myocardium was reperfused for 2 h.
Group 2 (n = 8). After control measurements of systemic hemodynamics, regional myocardial function, blood flow, and metabolism were performed, the myocardium was subjected to one cycle of 10-min preconditioning ischemia, with a 90% reduction in regional myocardial function, and 15-min reperfusion. During reperfusion, coronary arterial pressure was maintained at the level measured before ischemia by continuously adapting coronary inflow with the roller pump. After reperfusion, coronary inflow was once again reduced to the same level as during the preconditioning ischemia. Thereafter, the protocol of group 2 was identical to that of group 1.
Group 3 (n = 6).
After control measurements of systemic hemodynamics, regional
myocardial function, blood flow, and metabolism were performed, naloxone was given as a bolus of 1 mg/kg iv, followed by a continuous intravenous infusion of 2 µg · kg1 · min1 until the
end of the 90-min ischemic period. This dose of naloxone has
been previously shown to completely block the morphine-induced decreases in heart rate and blood pressure in anesthetized pigs (5). Thirty minutes after the bolus injection of naloxone
was given, all measurements were repeated before coronary inflow was reduced.
Group 4 (n = 6).
The protocol of group 4 was identical to that of group
2 except that the naloxone administration was started 30 min
before the first ischemia. Once again, naloxone was given as a
bolus of 1 mg/kg iv, followed by a continuous intravenous infusion of 2 µg · kg1 · min1 until the
end of the 90-min ischemic period.
Experimental Protocols: Short-Term Myocardial Hibernation
Group 5 (n = 6). After measurements of systemic hemodynamics, regional myocardial function, blood flow, and metabolism at baseline were performed, the naloxone administration (like in group 3) was started. Thirty minutes later, all measurements were repeated, and biopsies were taken before LAD inflow was decreased by 50% for 90 min; this decrease in coronary inflow has previously been shown to allow the development of myocardial hibernation in the absence of naloxone (23, 32). Measurements were repeated at 10- and 85-min ischemia. Thereafter, the myocardium was reperfused for 2 h.
Data Analysis and Statistics
Data are reported as mean values ± SE. Statistical analysis for groups 1-4 comprised two-way ANOVA for repeated measures and Fisher's least significant difference tests when significant overall effects were detected. Data in group 5 were analyzed by one-way ANOVA and Fisher's least significant difference tests. A P value < 0.05 was accepted as indicating a significant difference in mean values.In groups 1-4, linear regression analyses between subendocardial blood flow at 5-min ischemia in the left ventricular area at risk and infarct size (expressed as a percentage of the area at risk) were performed. Regression lines were compared by analysis of covariance.
| |
RESULTS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Data on systemic hemodynamics, regional myocardial function, blood
flow, and metabolism in groups 1-5 are summarized in
Tables 1 and
2. Heart rate was held constant by left
atrial pacing. Regional myocardial function of the posterior control
wall remained stable throughout the experimental protocol in each
group.
|
|
Ischemic Preconditioning
Systemic hemodynamics, regional myocardial function, blood flow, and metabolism were not different among groups 1-4 at baseline. Naloxone did not alter any of the measured parameters at baseline.Systemic hemodynamics, regional myocardial function, blood flow, and metabolism were not different among groups 1-4 during ischemia except for a tendency toward a better-preserved left ventricular peak pressure and maximum first derivative of left ventricular pressure during ischemia in groups 1 and 3 (Table 1).
Infarct Size
The area at risk was comparable between groups 1 and 4, averaging 43.6 ± 3.1, 48.7 ± 3.4, 47.3 ± 2.5, and 42.0 ± 3.5%, respectively (Fig. 1). After 90-min severe myocardial ischemia and 120-min reperfusion, infarct size averaged 28.3 ± 5.4% (group 1) (Fig. 1). IP by one cycle of 10-min ischemia and 15-min reperfusion reduced infarct size to 9.9 ± 3.8% (P < 0.05, group 2). The relationship between infarct size and subendocardial blood flow in group 2 was significantly shifted downward compared with the relationship obtained in group 1 (Fig. 2).
|
|
In the presence of naloxone after 90-min sustained ischemia and
120-min reperfusion (group 3), 25.8 ± 7.0% of the
area at risk was infarcted, and infarct size was unchanged (24.7 ± 4.7%) with IP (group 4) (Fig. 1). Also, the
relationships between infarct size and subendocardial blood flow in
groups 3 and 4 were superimposable (Fig.
3).
|
Short-Term Myocardial Hibernation
Naloxone did not alter any of the measured parameters at baseline. Left ventricular pressure slightly decreased with the initiation of ischemia and decreased further when ischemia was prolonged to 90 min.With the reduction in coronary inflow, mean coronary arterial pressure,
anterior systolic wall thickening, transmural and subendocardial blood
flows, myocardial oxygen consumption, and the free energy change of ATP
hydrolysis in the anterior wall were decreased (Table 2 and Fig.
4). Myocardial lactate consumption was
reversed to net lactate production. Prolongation of ischemia to
85 min did not result in a further change (Table 2) except that the
free energy change of ATP hydrolysis recovered toward control values
(Fig. 4). Myocardial necrosis (TTC staining) was absent in all animals
after 90-min moderate ischemia and 120-min reperfusion.
|
This is exactly the same pattern of responses as seen in previous studies (23, 32) on STMH with the use of the same animal model in the absence of naloxone.
| |
DISCUSSION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
The major findings of the present study are that blockade of opioid receptors with naloxone completely abolished the infarct size reduction achieved by IP and that the same dose of naloxone did not interfere with the development of STMH.
Critique of Methods
The strengths and limitations of the experimental model have been discussed in detail elsewhere (23, 47). Pigs were used for the study of involvement of endogenous opioids in both IP and STMH because their coronary anatomy (55), extent of collateral flow (56), and time course of infarct development most closely resemble those observed in humans (41).Naloxone was given at a dose of 1 mg/kg iv, followed by a continuous
infusion of 2 µg · kg1 · min1,
resulting in a total dose of ~1.2 mg/kg. This dose of naloxone did
not alter baseline systemic hemodynamics or regional myocardial function. Similarly, naloxone at concentrations of up to 10 mg/kg had
no effect on systemic hemodynamics in squirrel monkeys
(11). This dose of naloxone, however, effectively blocks
opioid receptors, as previously shown by blockade of the
morphine-induced decreases in heart rate and blood pressure in
anesthetized pigs (5) and evidenced by loss of the infarct
size reduction by IP in the present study. Naloxone had no direct
unspecific effect on the myocardium, because infarct size in untreated
(group 1) and naloxone-treated (group 3) pigs was
similar after 90-min ischemia and 120-min reperfusion.
Ischemic Preconditioning
In rats and rabbits, naloxone has been previously shown to block the infarct size reduction achieved by IP (13, 34, 45, 46). In naloxone-treated patients, S-T segment changes and cardiac pain severity during a second PTCA balloon inflation were similar to those observed during the first inflation, whereas they were significantly attenuated in patients given placebo (52). This effect on S-T segment changes has been regarded as evidence for IP in the human heart; however, experiments in rabbits revealed that electrocardiogram changes associated with IP protocols are, rather, epiphenomena and do not reflect the protection of IP (6).Our data confirm, for the first time in pigs, those previous findings
of a protective effect of endogenous opioids during severe myocardial
ischemia. The signal cascade of IP in pigs involves several
endogenous triggers such as adenosine (49) and bradykinin (47), subsequent activation of protein kinase C and a
protein tyrosine kinase (54), and activation of
ATP-dependent potassium channels (48). More recently, the
activation of p38 and extracellular signal-regulated kinases
(ERK)/mitogen-activated protein kinases (MAPK) has also been
demonstrated during IP in pigs (2, 4). The present study
adds one more endogenous trigger to those involved in the signal
cascade of IP in pigs, i.e., opioids. Infusion of opioid receptor
agonists reduced infarct size to the same extent as IP in rats
(27, 42). The important opioid receptor for such
cardioprotection was identified as the -opioid receptor (1,
43), whereas activation of the 
-opioid receptor appears to be
even detrimental (1) with the possibility of putting the
heart into an "antipreconditioning" state (14).
Blockade of opioid receptors with naloxone in the present and other
studies worsened the outcome of ischemia and reperfusion,
indicating that endogenous opioids act primarily on -opioid
receptors rather than -opioid receptors.
The interaction of triggers of IP is rather complex (19). Bradykinin appears to be an important trigger with a weaker/more short-lasting IP stimulus, whereas adenosine gains more importance with stronger/longer stimuli (19, 47). In pigs, infarct size reduction achieved by 3-min preconditioning ischemia and 15-min reperfusion is completely abolished by blockade of bradykinin receptors, whereas the infarct size reduction after 10-min preconditioning ischemia and 15-min reperfusion is largely attenuated by destruction of adenosine with adenosine deaminase (47, 49). As blockade of opioid receptors (present paper) also almost completely abolishes infarct size reduction by IP in swine, both adenosine and opioids appear to trigger IP in an interactive fashion. Whether both signals are oriented in parallel or back-to-back remains to be established. The latter explanation has recently been suggested from a study (26) in isolated rat hearts in which the fentanyl-induced increase in contractile function after ischemia-reperfusion was abolished by pretreatment with an adenosine receptor antagonist.
The mechanisms involved in infarct size reduction by opioid receptor
activation in other species involve activation of pertussis toxin-sensitive G proteins in rats (44), protein kinase C
in rabbits (34), and ATP-dependent potassium channels in
rats (27, 42) and isolated cardiomyocytes from chick
embryos (31). The further signal cascade leading finally
to cardioprotection has not yet been established. In vitro data in
transfected COS-7 cells (African green monkey kidney cells) suggested
that opioid receptor activation, especially that of the - and
-subtype, is associated with increased phosphorylation of ERK but
not p38 MAPK (21). While ERK are activated during
ischemia-reperfusion in rabbits (37) and pigs
(4) in vivo, their importance for the infarct size
reduction by IP remains controversial (29, 51). The signal cascade of opioid receptor activation-induced protection in pigs is
entirely unknown; however, in a recent study (51),
blockade of ERK abolished IP in pigs.
Short-Term Myocardial Hibernation
We used an established model of STMH in which regional low-flow ischemia was induced by controlled hypoperfusion of the LAD (23, 32). Myocardial blood flow was reduced by ~50% such that regional contractile function decreased to ~50% of baseline. Under these conditions, the initially impaired metabolism recovered over time, and necrosis was absent even when ischemia was extended to 90 min. The hemodynamic and metabolic data in the animals used for the present study in the presence of naloxone are comparable to previously published data in the absence of naloxone (23, 32).Opioids appear to be involved in true mammalian hibernation. Plasma
from a hibernating bear caused ground squirrels, normally active during
the summer, to hibernate. This induction of summer hibernation is
effectively blocked by naloxone (25). Similarly, infusion
of a -opioid receptor agonist induces hibernation in ground
squirrels (25). The hibernation-inducing trigger or
hibernation-related factor has been identified as an opioid-like 88-kDa
protein (25), which may be either a precursor or a potent
releaser of endogenous opioids (10, 35). Whereas blockade
of opioid receptors with naloxone thus abolishes the induction of true
mammalian hibernation, it had no effect on the development of STMH in
vivo in the present study.
Therefore, endogenous opioids have a role similar to that of endogenous adenosine and ATP-dependent potassium channels in that they are involved in the endogenous cardioprotection provided by IP in pigs (48, 49) but not in the development of STMH (50). The present data once more support the notion that IP and STMH, although both are cardioprotective phenomena initiated during ischemia, are mechanistically different.
Clinical Implications
Given the experimental data, one can assume that patients receiving opioid receptor agonists during cardiac surgery involving ischemia-reperfusion (33, 53) will potentially benefit apart from and in addition to pain relief. Conversely, patients receiving opioid receptor antagonists for detoxification after a narcotic overdose or as part of the treatment of drug abuse (9, 18, 28) are potentially at increased risk.| |
ACKNOWLEDGEMENTS |
|---|
We thank Dr. Claus Martin for the chemical analyses and A. Hörsting for technical support.
| |
FOOTNOTES |
|---|
Address for reprint requests and other correspondence: G. Heusch, Abteilung für Pathophysiologie, Zentrum Innere Medizin, Universitätsklinikum Essen, Hufelandstraße 55, 45122 Essen, Germany (E-mail: gerd.heusch{at}uni-essen.de).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 23 October 2000; accepted in final form 27 November 2000.
| |
REFERENCES |
|---|
|
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
1.
Aitchison, KA,
Baxter GF,
Moneeb Awan M,
Smith RM,
Yellon DM,
and
Opie LH.
Opposing effects on infarction of delta and kappa opioid receptor activation in the isolated rat heart: implications for ischemic preconditioning.
Basic Res Cardiol
95:
1-10,
2000[ISI][Medline].
2.
Barancik, M,
Htun P,
Strohm C,
Kilian S,
and
Schaper W.
Inhibition of the cardiac p38-MAPK pathway by SB203580 delays ischemic cell death.
J Cardiovasc Pharmacol
35:
474-483,
2000[ISI][Medline].
3.
Baxter, GF,
Goma FM,
and
Yellon DM.
Characterisation of the infarct-limiting effect of delayed preconditioning: time-course and dose-dependency studies in rabbit myocardium.
Basic Res Cardiol
92:
159-167,
1997[ISI][Medline].
4.
Behrends, M,
Schulz R,
Post H,
Alexandrov A,
Belosjorow S,
Michel MC,
and
Heusch G.
Inconsistent relation of MAPK activation to infarct size reduction by ischemic preconditioning in pigs.
Am J Physiol Heart Circ Physiol
279:
H1111-H1119,
2000
5.
Bergey, JL,
and
Beil ME.
Antiarrhythmic evaluation of naloxone against acute coronary occlusion-induced arrhythmias in pigs.
Eur J Pharmacol
90:
427-431,
1983[ISI][Medline].
6.
Birincioglu, M,
Yang XM,
Critz SD,
Cohen MV,
and
Downey JM.
S-T segment voltage during sequential coronary occlusions is an unreliable marker of preconditioning.
Am J Physiol Heart Circ Physiol
277:
H2435-H2441,
1999
7.
Bolling, SF,
Benedict MB,
Tramontini NL,
Kilgore KS,
Harlow HH,
Su TP,
and
Oeltgen PR.
Hibernation triggers and myocardial protection.
Circulation
98, Suppl19:
II-220-II-224,
1998.
8.
Bolling, SF,
Tramontini NL,
Kilgore KS,
Su TP,
Oeltgen PR,
and
Harlow HH.
Use of "natural" hibernation induction triggers for myocardial protection.
Ann Thorac Surg
64:
623-627,
1997
9.
Bradberry, JC,
and
Raebel MA.
Continuous infusion of naloxone in the treatment of narcotic overdose.
Drug Intell Clin Pharmacol
15:
945-950,
1981[Abstract].
10.
Bruce, DS,
Cope GW,
Elam TR,
Ruit KA,
Oeltgen PR,
and
Su TP.
Opioids and hibernation. I. Effects of naloxone on bear HIT's depression of guinea pig ileum contractility and on induction of summer hibernation in the ground squirrel.
Life Sci
41:
2107-2111,
1987[ISI][Medline].
11.
Byrd, LD.
Cardiovascular effects of naloxone, naltrexone and morphine in the squirrel monkey.
Life Sci
32:
391-398,
1983[ISI][Medline].
12.
Cave, AC,
Collis CS,
Downey JM,
and
Hearse DJ.
Improved functional recovery by ischaemic preconditioning is not mediated by adenosine in the globally ischaemic isolated rat heart.
Cardiovasc Res
27:
663-668,
1993
13.
Chien, GL,
Mohtadi K,
Wolff RA,
and
van Winkle DM.
Naloxone blockade of myocardial ischemic preconditioning does not require central nervous system participation.
Basic Res Cardiol
94:
136-143,
1999[ISI][Medline].
14.
Downey, JM.
Anti-preconditioning.
Basic Res Cardiol
95:
11,
2000[ISI].
15.
Falcone, C,
Guasti L,
Ochan M,
Codega S,
Tortorici M,
Angoli L,
Bergamaschi R,
and
Montemartini C.
Beta-endorphins during coronary angioplasty in patients with silent or symptomatic myocardial ischemia.
J Am Coll Cardiol
22:
1614-1620,
1993[Abstract].
16.
Flacke, JW,
Flacke WE,
Bloor BC,
and
Olewine S.
Effects of fentanyl, naloxone, and clonidine on hemodynamics and plasma catecholamine levels in dogs.
Anesth Analg
62:
305-313,
1983
17.
Fryer, RM,
Hsu AK,
Eells JT,
Nagase H,
and
Gross GJ.
Opioid-induced second window of cardioprotection.
Circ Res
84:
846-851,
1999
18.
Gold, CG,
Cullen DJ,
Gonzales S,
Houtmeyers D,
and
Dwyer MJ.
Rapid opioid detoxification during general anesthesia.
Anesthesiology
91:
1639-1647,
1999[ISI][Medline].
19.
Goto, M,
Liu Y,
Yang XM,
Ardell JL,
Cohen MV,
and
Downey JM.
Role of bradykinin in protection of ischemic preconditioning in rabbit hearts.
Circ Res
77:
611-621,
1995
20.
Guo, Y,
Wu WJ,
Qiu Y,
Tang XL,
Yang Z,
and
Bolli R.
Demonstration of an early and a late phase of ischemic preconditioning in mice.
Am J Physiol
44:
H1375-H1387,
1998.
21.
Gutstein, HB,
Rubie EA,
Mansour A,
Akil H,
and
Woodgett JR.
Opioid effects on mitogen-activated protein kinase signaling cascades.
Anesthesiology
87:
1118-1126,
1997[ISI][Medline].
22.
Heusch, G.
Hibernating myocardium.
Physiol Rev
78:
1055-1085,
1998
23.
Heusch, G,
Post H,
Michel MC,
Kelm M,
and
Schulz R.
Endogenous nitric oxide and myocardial adaptation to ischemia.
Circ Res
87:
146-152,
2000
24.
Heusch, G,
Rose J,
Skyschally A,
Post H,
and
Schulz R.
Calcium responsiveness in regional myocardial short-term hibernation and stunning in the in situ porcine heart-inotropic responses to postextrasystolic potentiation and intracoronary calcium.
Circulation
93:
1556-1566,
1996
25.
Horton, ND,
Kaftani DJ,
Bruce DS,
Bailey EC,
Krober AS,
Jones JR,
Turker M,
Khattar N,
Su TP,
Bolling SF,
and
Oeltgen PR.
Isolation and partial characterization of an opioid-like 88 kDa hibernation-related protein.
Comp Biochem Physiol
119:
787-805,
1998.
26.
Kato, R,
Ross S,
and
Foex P.
Fentanyl protects the heart against ischaemic injury via opioid receptors, adenosine A1 receptors and KATP channel linked mechanisms in rats.
Br J Anaesth
84:
204-214,
2000
27.
Kevelaitis, E,
Peynet J,
Mouas C,
Launay JM,
and
Menasché P.
Opening of potassium channels. The common cardioprotective link between preconditioning and natural hibernation?
Circulation
99:
3079-3085,
1999
28.
Kienbaum, P,
Thurauf N,
Michel MC,
Scherbaum N,
Gastpar M,
and
Peters J.
Profound increase in epinephrine concentration in plasma and cardiovascular stimulation after mu-opioid receptor blockade in opioid-addicted patients during barbiturate-induced anesthesia for acute detoxification.
Anesthesiology
88:
1154-1161,
1998[ISI][Medline].
29.
Kim, SO,
Baines CP,
Critz SD,
Pelech SL,
Katz S,
Downey JM,
and
Cohen MV.
Ischemia induced activation of heat shock protein 27 kinases and casein kinase 2 in the preconditioned rabbit heart.
Biochem Cell Biol
77:
559-567,
1999[ISI][Medline].
30.
Kurita, A,
Takase B,
Uehata A,
Sugahara H,
Nishioka H,
Maruyama T,
Satomura K,
Mizuno K,
and
Nakamura H.
Differences in plasma beta-endorphin and bradykinin levels between patients with painless or with painful myocardial ischemia.
Am Heart J
123:
304-309,
1992[ISI][Medline].
31.
Liang, BT,
and
Gross GJ.
Direct preconditioning of cardiac myocytes via opioid receptors and KATP channels.
Circ Res
84:
1396-1400,
1999
32.
Martin, C,
Schulz R,
Rose J,
and
Heusch G.
Inorganic phosphate content and free energy change of ATP hydrolysis in regional short-term hibernating myocardium.
Cardiovasc Res
39:
318-326,
1998
33.
Maxam-Moore, VA,
Wilkie DJ,
and
Woods SL.
Analgesics for cardiac surgery patients in critical care: describing current practice.
Am J Crit Care
3:
31-39,
1994.
34.
Miki, T,
Cohen MV,
and
Downey JM.
Opioid receptor contributes to ischemic preconditioning through protein kinase C activation in rabbits.
Mol Cell Biochem
186:
3-12,
1998[ISI][Medline].
35.
Oeltgen, PR,
Welborn JR,
Nuchols PA,
Spurrier WA,
Bruce DS,
and
Su TP.
Opioids and hibernation. II. Effects of kappa opioid U69593 on induction of hibernation in summer-active ground squirrels by "Hibernation Induction Trigger" (HIT).
Life Sci
41:
2115-2110,
1987[ISI][Medline].
36.
Oldroyd, KG,
Harvey K,
Gray CE,
Beastall GH,
and
Cobbe SM.
-Endorphin release in patients after spontaneous and provoked acute myocardial ischaemia.
Br Heart J
1992:
230-235,
1999.
37.
Ping, P,
Zhang J,
Li RCX,
Kong D,
Tang XL,
Qiu Y,
Manchikalapudi S,
Auchampach JA,
Blacl RG,
and
Bolli R.
PKC-dependent activation of p44/p42 MAPKs during myocardial ischemia-reperfusion in conscious rabbits.
Am J Physiol Heart Circ Physiol
276:
H1468-H1481,
1999
38.
Rahimtoola, SH.
A perspective on the three large multicenter randomized clinical trials of coronary bypass surgery for chronic stable angina.
Circulation
72, Suppl V:
V-123-V-135,
1985.
39.
Reimer, KA,
Murry CE,
and
Jennings RB.
Cardiac adaptation to ischemia. Ischemic preconditioning increases myocardial tolerance to subsequent ischemic episodes.
Circulation
82:
2266-2268,
1990
40.
Ross, J, Jr.
Myocardial perfusion-contraction matching. Implications for coronary heart disease and hibernation.
Circulation
83:
1076-1083,
1991
41.
Schaper, W,
Görge G,
Winkler B,
and
Schaper J.
The collateral circulation of the heart.
Prog Cardiovasc Dis
31:
57-77,
1988[ISI][Medline].
42.
Schultz, JEJ,
Hsu AK,
and
Gross GJ.
Morphine mimics the cardioprotective effect of ischemic preconditioning via a glibenclamide-sensitive mechanism in the rat heart.
Circ Res
78:
1100-1104,
1996
43.
Schultz, JEJ,
Hsu AK,
and
Gross GJ.
Ischemic preconditioning in the intact rat heart is mediated by 1- but not µ- or -opioid receptors.
Circulation
97:
1282-1289,
1998
44.
Schultz, JEJ,
Hsu AK,
Nagase H,
and
Gross GJ.
TAN-67, a 1-opioid receptor agonist, reduces infarct size via activation of Gi/o proteins and KATP channels.
Am J Physiol Heart Circ Physiol
274:
H909-H914,
1998
45.
Schultz, JEJ,
Rose E,
Yao Z,
and
Gross GJ.
Evidence for involvement of opioid receptors in ischemic preconditioning in rat hearts.
Am J Physiol Heart Circ Physiol
268:
H2157-H2161,
1995
46.
Schultz, JJ,
Hsu A,
and
Gross GJ.
Ischemic preconditioning is mediated by a peripheral opioid receptor mechanism in the intact rat heart.
J Mol Cell Cardiol
29:
1355-1362,
1997[ISI][Medline].
47.
Schulz, R,
Post H,
Vahlhaus C,
and
Heusch G.
Ischemic preconditioning in pigs: a graded phenomenon. Its relation to adenosine and bradykinin.
Circulation
98:
1022-1029,
1998
48.
Schulz, R,
Rose J,
and
Heusch G.
Involvement of activation of ATP-dependent potassium channels in ischemic preconditioning in swine.
Am J Physiol Heart Circ Physiol
267:
H1341-H1352,
1994
49.
Schulz, R,
Rose J,
Post H,
and
Heusch G.
Involvement of endogenous adenosine in ischaemic preconditioning in swine.
Pflügers Arch
430:
273-282,
1995[ISI][Medline].
50.
Schulz, R,
Rose J,
Post H,
and
Heusch G.
Regional short-term hibernation in swine does not involve endogenous adenosine or KATP channels.
Am J Physiol Heart Circ Physiol
268:
H2294-H2301,
1995
51.
Strohm, C,
Barancik M,
v. Brühl ML,
Kilian SAR,
and
Schaper W.
Inhibition of the ER-kinase casade by PD98059 and UO126 counteracts ischemic preconditioning in pig myocardium.
J Cardiovasc Pharmacol
36:
218-229,
2000[ISI][Medline].
52.
Tomai, F,
Crea F,
Gaspardone A,
Versaci F,
Ghini AS,
Ferri C,
Desideri G,
Chiariello L,
and
Gioffré PA.
Effects of naloxone on myocardial ischemic preconditioning in humans.
J Am Coll Cardiol
33:
1863-1869,
1999
53.
Tsang, J,
and
Brush B.
Patient-controlled analgesia in postoperative cardiac surgery.
Anaesth Intensive Care
27:
464-470,
1999[ISI][Medline].
54.
Vahlhaus, C,
Schulz R,
Post H,
Rose J,
and
Heusch G.
Prevention of ischemic preconditioning only by combined inhibition of protein kinase C and protein tyrosine kinase in pigs.
J Mol Cell Cardiol
30:
197-209,
1998[ISI][Medline].
55.
Weaver, ME,
Pantely GA,
Bristow JD,
and
Ladley HD.
A quantitative study of the anatomy and distribution of coronary arteries in swine in comparison with other animals and man.
Cardiovasc Res
20:
907-917,
1986
56.
White, FC,
and
Bloor CM.
Coronary collateral circulation in the pig: correlation of collateral flow with coronary bed size.
Basic Res Cardiol
76:
189-196,
1981[ISI][Medline].
57.
Yellon, DM,
Baxter GF,
Garcia-Dorado D,
Heusch G,
and
Sumeray MS.
Ischaemic preconditioning: present position and future directions.
Cardiovasc Res
37:
21-33,
1998
This article has been cited by other articles:
|
|
 |
|
  H. H. Patel, B. P. Head, H. N. Petersen, I. R. Niesman, D. Huang, G. J. Gross, P. A. Insel, and D. M. Roth Protection of adult rat cardiac myocytes from ischemic cell death: role of caveolar microdomains and {delta}-opioid receptors Am J Physiol Heart Circ Physiol, July 1, 2006; 291(1): H344 - H350. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Heusch, R. Schulz, and S. H. Rahimtoola Myocardial hibernation: a delicate balance Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H984 - H999. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Okubo, Y. Tanabe, K. Takeda, M. Kitayama, S. Kanemitsu, R. C. Kukreja, and N. Takekoshi Ischemic preconditioning and morphine attenuate myocardial apoptosis and infarction after ischemia-reperfusion in rabbits: role of {delta}-opioid receptor Am J Physiol Heart Circ Physiol, October 1, 2004; 287(4): H1786 - H1791. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. White, P. E. Constantin, and W. C. Claycomb Cardiac physiology at the cellular level: use of cultured HL-1 cardiomyocytes for studies of cardiac muscle cell structure and function Am J Physiol Heart Circ Physiol, March 1, 2004; 286(3): H823 - H829. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Kuzume, R. A. Wolff, K. Amakawa, K. Kuzume, and D. M. Van Winkle Sustained exogenous administration of Met5-enkephalin protects against infarction in vivo Am J Physiol Heart Circ Physiol, December 1, 2003; 285(6): H2463 - H2470. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
J. A. Coles Jr., D. C. Sigg, and P. A. Iaizzo Role of kappa -opioid receptor activation in pharmacological preconditioning of swine Am J Physiol Heart Circ Physiol, June 1, 2003; 284(6): H2091 - H2099. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
D. C. Sigg, J. A. Coles Jr., P. R. Oeltgen, and P. A. Iaizzo Role of delta -opioid receptor agonists on infarct size reduction in swine Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H1953 - H1960. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
R. Schulz, H. Post, T. Neumann, P. Gres, H. Luss, and G. Heusch Progressive loss of perfusion-contraction matching during sustained moderate ischemia in pigs Am J Physiol Heart Circ Physiol, May 1, 2001; 280(5): H1945 - H1953. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
