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(Circulation. 1997;96:2171-2177.)
© 1997 American Heart Association, Inc.
Articles |
Phentolamine Prevents Adaptation to Ischemia During Coronary Angioplasty
Role of 
-Adrenergic Receptors in Ischemic Preconditioning
From the Servizio Speciale di Diagnosi e Cura di Emodinamica (F.T., A.G., F.V., A.S.G., R.De P., L.C., P.A.G.), Divisione di Cardiochirurgia, Università di Roma Tor Vergata, European Hospital; and Istituto di Cardiologia (F.C.), Università Cattolica del Sacro Cuore, Rome, Italy.
Correspondence to Dr Fabrizio Tomai, Divisione di Cardiochirurgia, Università di Roma Tor Vergata, European Hospital, via Portuense 700, 00149 Rome, Italy.
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionReferences |
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Background Experimental studies indicate that
-adrenergic receptors are involved in ischemic
preconditioning. Their role in humans is unknown. Methods and Results Eighteen patients undergoing angioplasty for an isolated stenosis of the left anterior descending coronary artery were randomized to receive intravenous infusion of phentolamine or placebo during the procedure. Intracoronary ECG and cardiac pain were determined at the end of the first two balloon inflations. Average peak velocity in the contralateral coronary artery during balloon occlusion, an index of collateral recruitment, was also assessed by using a Doppler guide wire. In both phentolamine- and placebo-treated patients, average peak velocity significantly increased from baseline to the end of the first inflation (P<.01), but it did not show any further increase during the second inflation. In phentolamine-treated patients, ST-segment changes and cardiac pain severity during the second inflation were similar to those observed during the first inflation (13±9 versus 12±8 mm, P=NS, and 51±34 versus 54±32 mm, P=NS, respectively), whereas in placebo-treated patients, they were significantly less (6±4 versus 13±7 mm, P<.01, and 26±20 versus 49±22 mm, P<.05, respectively).
Conclusions The adaptation to ischemia observed in
humans after two sequential coronary balloon inflations is
abolished by phentolamine and is independent of collateral
recruitment. Thus, it occurs due to ischemic preconditioning
and is, at least in part, mediated by -adrenergic receptors.
Key Words: angioplasty • receptors, adrenergic, alpha • collateral circulation
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Ischemic preconditioning, a powerful form of myocardial protection from irreversible ischemic injury, has been shown in all animal species investigated1 2 3 4 and, recently, in isolated human myocytes5 and atrial trabeculae.6 There is evidence indicating that ischemic preconditioning also occurs in humans in the setting of coronary angioplasty7 8 and coronary artery bypass graft surgery.9
It has recently been demonstrated that the ischemic
preconditioning observed during coronary angioplasty after
repeated balloon inflations is abolished by pretreatment with
glibenclamide,10 theophylline,11 and
bamifylline,12 suggesting that the activation of both
ATP-sensitive K+ (KATP) channels and
A1 adenosine receptors plays a role in this
phenomenon. Several experimental studies have shown, however, that
preconditioning results from a complex series of events, involving a
variety of G protein-coupled receptors.13 14 In
particular, recent studies have shown that activation of
1-adrenergic receptors mimics and their blockade
abolishes ischemic preconditioning.15 16 17 Moreover,
in cardiomyocytes, 1-adrenergic receptors
couple with protein kinase C (PKC),18 19 20 21 which seems to
play a pivotal role in preconditioning in several animal
species13 14 17 22 23 24 and in human atrial
trabeculae.25
To establish the role played by -adrenergic receptors in
preconditioning in humans, we assessed the effect of
phentolamine, a nonselective -adrenergic receptor
antagonist,26 in patients undergoing repeated
coronary occlusions in the setting of elective angioplasty of
an isolated stenosis on the left anterior descending
coronary artery. Because collateral recruitment can occur
during coronary angioplasty27 28 29 and can be
affected by phentolamine,30 31 32 changes in blood
flow velocity in the contralateral coronary artery during
balloon occlusions, an accepted index of collateral
recruitment,33 34 35 were also measured by using an
intracoronary Doppler guide wire.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Patients
We studied 18 consecutive patients (16 men and 2 women; age, 43 to 77 years; mean age, 55 years) who underwent successful uncomplicated elective coronary angioplasty for an isolated obstructive lesion (internal diameter reduction comprised 50% to 90% on the basis of the use of the quantitative cardiovascular software program ACA, Philips, DCI)36 in the proximal two thirds of the left anterior descending coronary artery. Patients with stenoses of >90% were not included in the study to avoid "preinflation ischemia" due to obstruction from the guide wire across the lesion, which would prolong the ischemic time of the first inflation compared with the second.37 All patients fulfill the entry criteria of (1) history of chronic stable angina pectoris lasting
3 months, (2) no history of previous
myocardial infarction, (3) no angiographic evidence of coronary
collateral vessels (grade 0, according to Rentrop's
classification),27 and (4) right dominant coronary
circulation. No patient had evidence of left ventricular
hypertrophy on the echocardiogram or conduction defects on
the ECG that could have interfered with the interpretation of
ST-segment changes. All patients had normal hepatic and renal function
and fasting blood glucose levels. All patients gave written informed
consent for participation in the study, which was approved by the
Institutional Ethics Committee.
Study Protocol
In this single-blind study, which was performed within 5 days of
the diagnostic coronary angiography, patients were
randomly allocated to one of two groups. One group consisted of nine
patients (eight men and one woman; age range, 47 to 77 years; mean age,
58 years) who received an intravenous infusion of
phentolamine (phentolamine mesylate 50 mg/5 mL
dissolved in 50 mL 0.9% NaCl; Ciba-Geigy SA). The infusion was started
15 minutes before coronary angioplasty and was stopped at the
end of the second inflation. The infusion rate of phentolamine
was titrated individually according to the hemodynamic
response observed; the drug was considered to be effective when a
stable drop of 10 mm Hg in systolic
arterial pressure or an increase of 10 bpm in heart rate
was observed. Doses ranged from 0.4 to 0.7 mg/min. The other
group consisted of nine patients (eight men and one woman; age range,
43 to 60 years, mean age, 53 years) who received an
intravenous infusion of placebo (0.9% NaCl) started 15
minutes before coronary angioplasty and stopped at the end of
the second inflation. ß-Blocking agents were withdrawn 5 days before
the study. All patients were receiving oral aspirin (100 mg OD),
diltiazem (60 mg TID), and isosorbide dinitrate (40 mg BID) for 48
hours before coronary angioplasty. All patients received the
morning dose of treatment before coronary angioplasty, which
was performed within the next 4 hours. No patient received sublingual
or intravenous nitrates in the last 24 hours before the
study or throughout the study. Patients were not premedicated with
diazepam or other sedatives.
An 8F and a 5F femoral sheath were inserted in the right and left
femoral arteries, respectively. A 5F right Judkins femoral catheter was
advanced through the left femoral sheath into the ostium of the right
coronary artery for guidance of a 0.014-in Doppler-tipped
guide wire (FloWire, Cardiometrics, Inc). Coronary angioplasty
of the stenosed artery was performed by a standard technique using the
right femoral approach, as previously described.10
Briefly, after placement of the guiding catheter through the right
femoral sheath and performance of baseline angiography, the
guide wire was placed across the lesion in the distal segment of the
stenosed artery. The balloon catheter was then placed within the
stenosis, and the balloon was inflated for 2 minutes. After
balloon deflation and withdrawal proximal to the lesion, with the guide
wire still across the lesion, a recovery period of 5 minutes was
allowed to reestablish baseline hemodynamic and ECG
conditions. A second balloon inflation for 2 minutes was then
performed. In each individual patient, balloon pressure during the
first and second inflations was identical. After the first two
inflations, coronary angioplasty was completed on the basis of
the specific needs of individual patients.
Assessment of Myocardial Ischemia
Standard surface 12-lead and intracoronary ECGs
derived from the angioplasty guide wire were continuously monitored and
simultaneously recorded (Mingograf 7, Siemens) at a
paper speed of 25 mm/s throughout the study. The ECGs were
analyzed by a cardiologist who had no knowledge of the study
protocol. At baseline (with just the guide wire across the lesion) and
at the end of the first two inflations, ST-segment shift was measured
80 milliseconds after the J point. The severity of myocardial
ischemia was expressed as (1) the summation of the absolute
values of the ST-segment elevation or ST-segment depression from
baseline, on surface ECG, from all 12 leads; and (2) the absolute
values of the ST-segment elevation or ST-segment depression from
baseline on intracoronary ECG. ST-segment shifts were expressed
in millimeters (1 mm=0.1 mV).
Assessment of Cardiac Pain
At the beginning of each coronary angioplasty procedure,
patients were informed that they might develop chest pain. At the end
of the first two balloon inflations, the intensity of cardiac pain was
assessed by using a visual-analog scale.38 Patients were
asked to put a mark on a 100-mm scale marked from no symptoms (0) to
severe symptoms (100).
Assessment of Coronary Blood Flow Velocity
After heparinization (10 000 U IV) and placement of the
angioplasty guiding catheter into the ostium of the left main
coronary artery and before administration of
phentolamine or placebo infusion, a 0.014-in Doppler-tipped
intracoronary guide wire (FloWire and FloMap, Cardiometrics,
Inc) was advanced through the 5F right Judkins catheter into the medium
tract of the right coronary artery and positioned until an
optimal and stable Doppler signal, not in the proximity of a side
branch, was obtained. Blood flow velocity was calculated from the
Doppler frequency shift of a reflected 15-MHz signal by fast
Fourier transformation and displayed in a spectral format, as
previously described.39 40 Flow velocity signals were
continuously displayed throughout the study. Average peak velocity
(cm/s) was derived automatically by the integrated signal-analyzing
computer. Satisfactory velocity data were obtained for all 18
patients.
Average peak velocity in the contralateral artery was measured at baseline, before the first (15 minutes after phentolamine or placebo infusion) and the second balloon inflations and at the end of the first two inflations. Collateral recruitment was expressed as the changes in average peak velocity in the contralateral coronary artery during the first and second balloon inflations.
Statistical Analysis
Two-factor repeated-measures ANOVA with repeated measures on one
factor was used to compare ischemic ECG and average peak
velocity changes during balloon inflations in the two groups of
patients. When significant differences were detected, pairwise
comparisons were made using the Scheffé F test. Comparisons of
the remaining continuous or discrete variables between the two
groups were performed using an unpaired Student's t or a
2 test, respectively. Visual-analog scales were
analyzed using the Wilcoxon signed rank test or the
Mann-Whitney U test as appropriate. Correlations between
changes in average peak velocity from the first to the second inflation
and changes in ST-segment shift or pain severity were assessed by
univariate linear regression analysis. Data are
expressed as mean±1 SD; values of P<.05 were considered
significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Clinical, anatomic, and hemodynamic features in the two groups of patients are summarized in Table 1
. According to the study protocol,
systolic arterial pressure significantly decreased
(from 140±15 to 123±13 mm Hg, P<.05) and heart rate
increased (from 76±6 to 82±6 bpm, P<.05) after the
intravenous infusion of phentolamine but did not
show any further change at the end of the first and the second
inflations. Conversely, no significant changes in systolic
arterial pressure or heart rate were detected after
intravenous infusion of placebo. As a result, there was no
significant difference between the two groups of patients in the
rate-pressure product at baseline, 15 minutes after
phentolamine or placebo infusion (immediately before the first
balloon inflation), before the second balloon inflation, and at the end
of the first two inflations (Table 1).
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Coronary Angioplasty
Coronary angioplasty was successfully performed in all 18
patients (residual stenosis <50%) (Table 1
). The mean balloon
pressure was similar in phentolamine- and placebo-treated
patients (4.3±0.7 versus 4±1.2 atm, respectively; P=NS).
The recovery period between the two balloon inflations was similar in
phentolamine- and placebo-treated patients (6.9±1.9 versus
6.8±1.6 minutes, respectively; P=NS).
Coronary Blood Flow Velocity
The values of average peak velocity in the contralateral artery at
baseline, before the first (15 minutes after phentolamine or
placebo infusion) and the second balloon inflations, and at the end of
the first two inflations are reported in Table 2.
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There was no significant difference between phentolamine- and
placebo-treated patients in average peak velocity at baseline (23±4
versus 23±5 cm/s, respectively; P=NS), before the first
balloon inflation (15 minutes after phentolamine or placebo
infusion) (22±4 versus 23±5 cm/s, respectively; P=NS), and
before the second balloon inflation (23±4 versus 23±3 cm/s,
respectively; P=NS). Within each group, the values of
average peak velocity at the three time points were also similar
(P=NS) (Table 2).
In both phentolamine- and placebo-treated patients, average
peak velocity in the right coronary artery significantly
increased from baseline to the end of the first inflation (from 22±4
to 28±6 cm/s, P<.01, and from 23±5 to 28±6 cm/s,
P<.01, respectively) but did not show a further increase
during the second inflation (28±4 and 29±4 cm/s, respectively;
P=NS versus the first inflation) (Fig 1). Of note, there was no significant
difference between the two groups of patients in average peak velocity
at the end of the first (P=NS) and the second inflation
(P=NS) (Table 2). Average peak velocity increased by >20%
at the end of the first inflation compared with baseline in five (55%)
phentolamine-treated patients and five (55%) placebo-treated
patients (P=NS). Similarly, average peak velocity increased
by >20% at the end of the second inflation compared with baseline in
five (55%) phentolamine-treated patients and six (67%)
placebo-treated patients (P=NS). In contrast, a further
increase in average peak velocity from the first to the second
inflation by >10% was detected in two (22%)
phentolamine-treated patients and two (22%) placebo-treated
patients only (P=NS).
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Myocardial Ischemia
The ST-segment shift values at the end of the first two
inflations, as changes from baseline, are reported in Table 2. In
phentolamine-treated patients, the mean ST-segment shift at the
end of the second balloon inflation was similar to that at the end of
the first inflation on both the surface ECG (16±10 versus 13±11
mm, P=NS) and the intracoronary ECG (13±9 versus
12±8 mm, P=NS). Conversely, in placebo-treated
patients, the mean ST-segment shift at the end of the second balloon
inflation was significantly less than that at the end of the first
inflation on both the surface ECG (9±4 versus 13±4 mm,
P<.01) and the intracoronary ECG (6±4 versus
13±7 mm, P<.01) (Fig 2). The drug-inflation interaction for
ST-segment changes on the surface and intracoronary ECGs was
highly significant (P=.0025 and P=.003,
respectively). Of note, there was no significant difference between the
two groups of patients in the degree of ST-segment shift at the end of
the first inflation on either surface (P=NS) or
intracoronary (P=NS) ECG (Table 2). Finally, in both
phentolamine- and placebo-treated patients, changes in average
peak velocity from the first to the second inflation did not correlate
with those in ST-segment shift on surface (r=.176,
P=NS, and r=.081, P=NS, respectively)
or intracoronary (r=.054, P=NS, and
r=.187, P=NS, respectively) ECG.
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Cardiac Pain
In phentolamine-treated patients, the severity of
cardiac pain at the end of the second inflation was similar to that at
the end of the first inflation (51±34 versus 54±32 mm,
P=NS). Conversely, in placebo-treated patients, the severity
of cardiac pain at the end of the second inflation was less than that
at the end of the first inflation (26±20 versus 49±22 mm,
P<.05) (Fig 2). Of note, there was no significant
difference between the two groups of patients in cardiac pain severity
(P=NS) at the end of the first inflation (Table 2). Finally,
in both phentolamine- and placebo-treated patients, changes in
average peak velocity from the first to the second inflation did not
correlate with those in cardiac pain severity (r=.135,
P=NS, and r=.113, P=NS,
respectively).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The results of this study show that the adaptation to ischemia during coronary angioplasty is prevented by pretreatment with phentolamine, a nonselective antagonist of
-adrenergic receptors, and is independent
of progressive collateral recruitment. In fact, we found that in
phentolamine-treated patients, the mean ST-segment shift and
the severity of cardiac pain at the end of the second balloon inflation
were similar to those at the end of the first inflation, whereas in
placebo-treated patients, they were significantly less. Although blood
flow velocity in the contralateral coronary artery showed a
significant increase during the first inflation in both groups of
patients, it did not show a further increase during the second
inflation; furthermore, it was not affected by phentolamine.
Taken together, these findings confirm that the adaptation to
ischemia during repeated balloon inflations is due to
ischemic preconditioning and indicate that -adrenergic
receptors play an important role in this phenomenon.
A limitation of this study is the use of a single-blind design.
However, the selection of objective ECG end points and the
analysis of the results blind to treatment should substantially
overcome the drawbacks of the single-blind design. Another limitation
is that we based the assessment of myocardial ischemia on the
ECG changes that do not represent direct evidence of
ischemia and on the anginal pain severity, which is rather
subjective. However, the surface 12-lead and the intracoronary
ECGs represent well-accepted methods for the evaluation
of myocardial ischemia during coronary
angioplasty.7 8 10 11 12 41 42 Moreover, Shattock et
al,43 who measured ST-segment changes in open-chest pigs
subjected to two cycles of 8-minute ischemia and 8-minute
reperfusion followed by 60-minute ischemia and 2-hour
reperfusion, found that ST-segment changes provide a reliable index of
preconditioning during the first few minutes of coronary
occlusion. Regarding the assessment of the anginal pain, the
visual-analog scale is a well-accepted method for the evaluation of
pain perception,38 which we used in several previous
studies.8 10 12 44 45 Finally, with the number of patients
being small, it may be argued that the failure of phentolamine
to prevent the adaptation to ischemia during repeated balloon
inflations could have been due to the power of the study, which was not
very high: 83% at an level of .05. However, ST-segment changes in
phentolamine-treated patients were smaller than those observed
in placebo-treated patients, with a highly significant drug-inflation
interaction, thus indicating that phentolamine, compared with
placebo, was able to prevent the reduction of ECG ischemic
changes after repeated balloon inflations.
Mechanisms of Adaptation to Ischemia During Coronary
Angioplasty
Because collateral recruitment can occur during coronary
angioplasty,27 28 29 we assessed changes in blood flow
velocity in the contralateral coronary artery during balloon
occlusion by using a Doppler guide wire. In the absence of
significant changes in arterial pressure or heart rate, as
was the case in our study at the end of both inflations, blood flow
velocity changes in the contralateral coronary artery have been
shown to be a reliable index of collateral perfusion and function
during coronary angioplasty and more accurate than
thermodilution, measurement of coronary occlusion pressure
through the balloon catheter, or angiographic visualization of
collateral vessels.33 34 35 We found that coronary
blood flow velocity significantly increased at the end of the first
inflation in both groups of patients, whereas it exhibited a modest
further increase during the second inflation in only 
20% of the
patients and did not correlate with the changes in ST-segment shift or
cardiac pain severity after two 2-minute balloon occlusions. Our
findings are in agreement with those of Kyriakidis et
al,35 who assessed collateral recruitment by using a
Doppler flow velocimeter positioned in the proximal
right coronary artery in patients undergoing four sequential
90-second balloon inflations for single left anterior descending
coronary artery stenosis. They found that only 30%
of their patients exhibited progressive collateral recruitment after
the first inflation. Cribier et al,46 who assessed
collateral recruitment by using ipsilateral and contralateral
injections of contrast medium and coronary wedge pressure in
patients with isolated stenosis of the left anterior descending
coronary artery undergoing five sequential balloon inflations,
found an increase of collateral angiographic grade and coronary
wedge pressure during the first coronary occlusion and a
further increase during the fourth coronary inflation in one
half of their patients. However, in our study, as in most angioplasty
studies aimed at assessing ischemic preconditioning, only the
first two (or three) inflations were taken into
account.7 8 10 11 12 Thus, in our study, the adaptation to
ischemia during coronary angioplasty was mainly
determined by ischemic myocardial preconditioning.
Role of -Adrenergic Receptors in Ischemic
Preconditioning
Phentolamine is a nonselective antagonist of
-adrenergic receptors, which are present at presynaptic
sympathetic nerve terminals, in endothelial cells, in
smooth muscle cells, and in
cardiomyocytes.31 47
The blockade by phentolamine of presynaptic
1- and 2-adrenergic receptors causes an
increase in catecholamine release31 47 and
might influence the severity of myocardial ischemia during
balloon occlusion in two different ways. First, an increase in
catecholamine release may increase myocardial oxygen
consumption, thus worsening the severity of myocardial ischemia
during coronary occlusion. However, if this were the case, we
should have obtained greater ECG changes and more severe pain in
phentolamine-treated patients also at the end of the first
inflation. Instead, the magnitude of ischemic ECG changes,
severity of pain, and systemic hemodynamic
parameters at the end of the first inflation were
similar in phentolamine- and placebo-treated patients. Second,
an increase in catecholamine release may enhance
preconditioning.15 16 17 However, if this were the case,
presynaptic -adrenergic receptor blockade by phentolamine
should have resulted in cardioprotection rather than prevention of
preconditioning. Thus, in agreement with experimental
observations,15 16 17 it would appear that the blockade of
presynaptic -adrenergic receptors located on perivascular
sympathetic nerves does not account for the results observed in our
study.
The infusion of phentolamine did not affect blood flow velocity in the contralateral coronary artery or change rate-pressure product. Furthermore, both blood flow velocity in the contralateral coronary artery and rate-pressure product were similar at the end of the first and second balloon inflations and were similar to those observed during placebo infusion. Therefore, the vascular effects of phentolamine do not account for the results of our study. Of note, heart rate and blood pressure did not change at the end of balloon inflations; this was probably due to the short duration of myocardial ischemia and the absence, on the average, of severe pain and is consistent with the results of several previous studies.7 8 10 11 12 35
Our findings suggest, therefore, that phentolamine prevented
preconditioning during repeated coronary occlusions through the
blockade of postsynaptic - adrenergic receptors located on the
surface of cardiomyocytes. Although the precise mechanism
of preconditioning remains elusive, several experimental studies have
demonstrated that a variety of G protein-coupled receptors, including
1-adrenergic, adenosine A1,
muscarinic, bradykinin, and endothelin-1 receptors, appear to play an
important role in ischemic preconditioning, probably via an
upregulation of PKC.13 14 This in turn leads to the
translocation of PKC from the cytoplasm to the sarcolemma, where it
phosphorylates a substrate protein (possibly the
KATP channel), which confers resistance to
ischemia.13 14 It has also been suggested that
1-adrenergic receptor activation may increase
5'-nucleotidase activity, thus increasing adenosine release,
which in turn contributes to cause myocardial
protection.21 24 Some studies,48 49 however,
have shown that the stimulation of 1-adrenergic
receptors alone is insufficient to mimic the cardioprotective effect of
ischemic preconditioning in the dog model, raising the
possibility that at least in some species, 1-adrenergic
receptors work in parallel with other agonists, such as
adenosine and bradykinin, that also stimulate PKC-coupled
receptors.50
We previously demonstrated that KATP
channels10 and A1 adenosine
receptors12 are involved in ischemic
preconditioning in humans during brief repeated coronary
occlusions. How -adrenergic receptors, A1
adenosine receptors, and KATP channels interact in
humans in determining preconditioning cannot be deduced from the
results of our studies. Whether -adrenergic agonist administration
during myocardial ischemia in the clinical setting might be
useful to improve preconditioning warrants further investigations.
Received February 11, 1997; revision received April 30, 1997; accepted May 13, 1997.
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