(Circulation. 1995;92:2259-2265.)
© 1995 American Heart Association, Inc.
Articles |
1B-Adrenoceptors, Pertussis ToxinSensitive G Proteins, and Protein Kinase C
From the Department of Pharmacology and Therapeutics (K.H., S.N.), McGill University and the Department of Medicine (S.N.), Montreal Heart Institute and the University of Montreal, Montreal, Canada.
Correspondence to Stanley Nattel, MD, Research Center, Montreal Heart Institute, 5000 Belanger St East, Montreal, Quebec H1T 1C8, Canada.
| Abstract |
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Methods and Results Reduction of isometric tension development
was used as an index of the effects of ischemia in isolated,
Langendorff-perfused rat hearts. Two 5-minute periods of
ischemia followed by 10 minutes of reperfusion attenuated the
reduction of developed tension caused by 30 minutes of ischemia
and 15 minutes of reperfusion. Pretreatment with pertussis toxin (PTX),
depletion of norepinephrine stores with reserpine, or
blockade of
1-adrenoceptors with prazosin prevented the
effects of ischemic preconditioning. Whereas
1B-receptor blockade with chloroethylclonidine blocked
ischemic preconditioning,
1A-receptor blockade
with 5-methylurapadil had no effect. The
-adrenergic agonist
phenylephrine mimicked the effects of ischemic
preconditioning in a concentration-dependent manner, and
pretreatment with PTX prevented the action of maximally effective
concentrations of phenylephrine. The protein kinase C
activator phorbol 12-myristate 13-acetate mimicked
and the protein kinase C inhibitors
1-(5-isoquinolinesulfonyl)-2-methylpiperazine and bisindolylmaleimide
prevented ischemic preconditioning.
Conclusions Ischemic preconditioning in isolated,
perfused rat hearts is caused by stimulation of
1B-adrenoceptors by endogenous
catecholamines through the activation of protein kinase C
via a PTX-sensitive G protein. The PTX-sensitive inhibitory
protein Gi, which can be activated by
adenosine, muscarinic agonists, and
1-adrenoceptor agonists, may play a central role in
ischemic preconditioning mediated by protein kinase C across a
broad range of species.
Key Words: signal transduction receptors adrenergic alpha arrhythmia catecholamines ischemia myocardial infarction
| Introduction |
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Extensive studies have been performed to elucidate the mechanism by which transient ischemia protects the heart. In rabbits,13 dogs,14 and pigs,15 activation of A1 receptors by an endogenous agonist (probably adenosine) appears to play a critical role in mediating the protective effects of preconditioning. IKATP has been implicated in preconditioning in dogs,14 16 17 and a PTX-sensitive G protein is involved in preconditioning in rabbits.18 Because adenosine activates the PTX-sensitive inhibitory G protein Gi19 and Gi can facilitate the activation of IKATP,20 Gi is a strong candidate to play an important role in mediating the protective effects of preconditioning caused by adenosine receptor activation. Compatible with this concept is the observation that muscarinic cholinergic agonists, which also activate Gi,19 mimic preconditioning in rabbits18 and dogs.21
Neither adenosine22 nor IKATP23 appears to mediate the effects of ischemic preconditioning in the rat heart. The present study was designed to address the mechanisms by which ischemic preconditioning attenuates the consequences of subsequent prolonged ischemia in the rat heart. The results indicate a central role for PTX-sensitive G proteins in the cardioprotective effects of preconditioning in the rat and raise the possibility that PTX-sensitive G proteins may constitute a common pathway mediating the protective effects of ischemic preconditioning across various species.
| Methods |
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Experimental Design
Sets of rats were studied in parallel,
with one
nonpreconditioned heart and one preconditioned heart
studied on each experimental day. Experimental interventions were
applied to both hearts to compare recovery of developed tension in both
preconditioned and nonpreconditioned hearts exposed to
the same intervention. The general experimental protocols employed are
illustrated in Fig 1
and described in detail below.
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Preconditioning was performed with two 5-minute periods of no-flow
ischemia, followed by 10 minutes of reperfusion for each period
of no-flow ischemia. Changes in left
ventricular developed tension were used as an index of
ventricular dysfunction caused by myocardial
ischemia. Preconditioning (with ischemia or with drugs
dissolved in the Krebs buffer) was applied for 5 minutes on two
occasions separated by a 10-minute interval. Ten minutes after the
second preconditioning period, hearts were subjected to 30 minutes of
sustained ischemia, followed by 15 minutes of reperfusion.
Tension generation was measured under control conditions and at the end
of each reperfusion period. When blockers of
1-receptors
and PKC were used, they were added to the perfusate for the
10-minute intervals preceding each ischemic period (asterisks
in Fig 1
).
Measurement of Tension Development
The heart was preloaded
with an initial resting tension of 1.0
g. Cardiac contractile force was estimated by monitoring isometric
tension with the use of a hook attached to the apex of the heart and a
force-displacement transducer (model FT 03, Grass Instruments). The
signal from the force transducer was measured with a Grass 7P1
preamplifier, which was coupled to a 7DA driver amplifier.
Drugs and Solutions
Phenylephrine, prazosin, propranolol,
reserpine, and PTX were purchased from Sigma Chemical Co. The
1A-selective antagonist 5-MU and the
1B-specific antagonist CEC were purchased
from Research Biochemicals, Inc. The PKC activator PMA,
also referred to as 12-O tetradecanoyl phorbol 13 acetate or TPA, and
the protein kinase inhibitor H-7 were purchased from ICN
Biochemicals. The highly selective PKC inhibitor
bisindolylmaleimide hydrochloride24 and the nonPKC
stimulating phorbol ester 4
-PDD were purchased from
Calbiochem-Novabiochem International. PMA was prepared as a 0.8 mmol/L
stock solution in DMSO and added in small quantities to the Krebs
buffer to achieve the desired concentration. Prazosin was dissolved in
absolute ethanol to produce a 2-mmol/L stock solution. Stock solutions
of the other compounds were prepared in distilled water and added in
small quantities to produce the final concentrations needed.
PMA was studied at a concentration of 0.1 µmol/L, which has been shown to potently enhance PKC activity in the perfused beating rat heart.25 H-7 was studied at a concentration of 6 µmol/L, which causes significant inhibition of PKC.26 Bisindolylmaleimide was studied at a concentration of 30 nmol/L, over twice the Ki for PKC (14 nmol/L).24 PTX was administered as a dose of 25 µg/kg IP 48 hours before study, according to a previously described regimen.18 Reserpine was administered as a 0.5 mg/kg IP dose 24 hours before study to deplete endogenous norepinephrine stores.27
Statistical Analysis
Group data are expressed as
mean±SEM. ANOVA with a range test
(the least significant difference test) was used for comparison between
group means. Fisher's exact test was applied to contingency data. A
two-tailed P value of
.05 was taken to indicate
statistical significance.
| Results |
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23% reduction in tension. The second ischemic period (5'
I2 in Fig 2
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A second effect of preconditioning that was
noted was a reduction in
the prevalence of ventricular tachycardia and
ventricular fibrillation. Among hearts not subjected to
preconditioning ischemia, over 80% experienced
ventricular tachycardia or ventricular
fibrillation during 30 minutes of ischemia followed by 15
minutes of reperfusion. As shown in Fig 3
, less than
20% of hearts subjected to preconditioning ischemia developed
ventricular tachycardia or fibrillation
(P<.001 compared with control).
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Effects of Pretreatment With PTX
To evaluate the potential
role of PTX-sensitive G proteins,
the protocols shown in Fig 1
were applied to hearts pretreated
with
PTX. A single 5-minute period of ischemia followed by 10
minutes of reperfusion was associated with a 34±4% reduction in
tension relative to preischemic values. A subsequent period
of 5 minutes of ischemia followed by 10 minutes of reperfusion
produced a very similar reduction in tension (35±4%,
P=NS). In these preconditioned hearts pretreated with PTX,
30 minutes of ischemia followed by 15 minutes of reperfusion
caused a 46±2% reduction in developed tension.
Nonpreconditioned hearts pretreated with PTX and
exposed to 30 minutes of ischemia followed by 15 minutes of
reperfusion showed a very similar reduction (48±2%) in developed
tension. Fig 3
shows that in PTX-pretreated hearts there was no
significant difference in the incidence of ventricular
tachyarrhythmias in preconditioned compared with
nonpreconditioned hearts. These results indicate that
pretreatment with PTX abolishes the protective effect of
preconditioning ischemia against reductions in developed
tension and the induction of ventricular
arrhythmias caused by subsequent ischemic episodes.
These results
strongly suggest that a PTX-sensitive G protein mediates
the protective effects of preconditioning ischemia in this
isolated rat heart model. PTX-sensitive G proteins are important in
mediating preconditioning in the rabbit heart, presumably in relation
to activation of Gi by stimulation of adenosine
A1-receptors.18 In the rat heart, however,
evidence has been presented against a role for
adenosine receptor stimulation in the protective effects of
ischemic preconditioning.22 We therefore turned
our attention to the potential role of endogenous
catecholamines in preconditioning the rat heart, because
-adrenergic stimulation can also lead to effects mediated by
inhibitory G proteins.19
Evidence for a Role of Stimulation of
1B-Adrenoceptors by Endogenous
Catecholamines in Ischemic
Preconditioning
Reserpine was used to deplete endogenous
norepinephrine stores, and the protocols shown in Fig 1
were applied. Thirty minutes of ischemia (without
preconditioning) followed by 15 minutes of reperfusion caused a 35±2%
reduction in developed tension in the hearts of rats pretreated with
reserpine 24 hours before study (n=6 hearts). Reserpine-pretreated
hearts subjected to the preconditioning protocol shown in Fig 1
had a
very similar reduction (37±2%; n=6; P=NS) in
developed
tension after a 30-minute period of ischemia. Furthermore, both
the first and second 5-minute periods of preconditioning
ischemia were followed by very similar reductions in developed
tension (21±3% and 22±3%, respectively), with values that
resemble
those produced by a single 5-minute ischemic episode in control
hearts (Fig 2
). These results indicate that pretreatment with
reserpine, which depletes endogenous
norepinephrine stores, prevents the protective effects of
preconditioning ischemia in this model.
The potential role of
1-adrenoceptor stimulation by
endogenous norepinephrine was evaluated by
studying the effects of prazosin (1 µmol/L) included in the
perfusate for 10 minutes before and during the 10-minute
reperfusion periods following each episode of preconditioning
ischemia in five hearts. In the presence of prazosin, the first
5-minute ischemic period followed by 10 minutes of reperfusion
resulted in a 16±5% reduction in developed tension. A second period
of 5 minutes of ischemia was followed by virtually the same
reduction (17±3%). A subsequent 30-minute period of ischemia
followed by 15 minutes of reperfusion reduced tension by 42±3%, a
value virtually identical to the result (40±1% reduction) obtained in
four nonpreconditioned hearts that received prazosin
for 10 minutes before the same duration of ischemia and
reperfusion. These results indicate that in the presence of prazosin,
brief periods of ischemia had no protective effect to attenuate
the reduction of tension produced by subsequent ischemic
periods. Taken together, the results of experiments with reserpine and
prazosin suggest that the endogenous release of
catecholamines mediates the effects of preconditioning by
stimulating
1-adrenergic receptors.
To explore further
the
1-adrenoceptor system involved,
we exposed hearts to the selective
1A-receptor
antagonist 5-MU or the irreversible
1B-receptor antagonist CEC.28
CEC (100 µmol/L) was administered in the superfusate for
10 minutes before the first ischemic period in both
preconditioned and nonpreconditioned hearts and other
procedures applied as shown in Fig 1
. 5-MU (0.1 µmol/L) was
administered in the superfusate at all times indicated by
asterisks in Fig 1
. Concentrations of these antagonists
were selected on the basis of previous work demonstrating high degrees
of selective receptor blockade at these concentrations.28
As shown in Fig 4
, the
1A-antagonist 5-MU had no apparent effect on
ischemic preconditioning, whereas the latter was completely
blocked by the
1B-antagonist CEC.
|
To evaluate further
the potential protective effect of
1-adrenergic stimulation, we studied the ability of
5-minute infusions of phenylephrine, a selective
-adrenergic agonist, to mimic the effects of preconditioning.
The protocol in Fig 1
was employed, but instead of
preconditioning with
two 5-minute periods of ischemia, phenylephrine was
infused for 5 minutes, followed by 10 minutes of perfusion with
phenylephrine-free solution, followed by an additional
5 minutes of phenylephrine, 10 minutes of perfusion with
phenylephrine-free solution, and then 30 minutes of
ischemia and 15 minutes of reperfusion in the absence of
phenylephrine. Fig 5
illustrates the effects
of preconditioning with phenylephrine on the reduction of
tension produced by 30 minutes of ischemia followed by 15
minutes of reperfusion. In each experiment, one
phenylephrine concentration was infused during both
preconditioning periods. Phenylephrine caused a
concentration-dependent attenuation in the reduction of tension
caused by 30 minutes of ischemia followed by 15 minutes of
reperfusion. The threshold dose for a statistically significant effect
was 1 µmol/L, and a maximum effect was observed at 100 µmol/L. To
determine whether the effects of phenylephrine were
mediated by a PTX-sensitive G protein, we pretreated rats with PTX 48
hours before study and then observed the effects of preconditioning
with a maximal concentration of phenylephrine (100
µmol/L) in the hearts of rats exposed to PTX. As shown in Fig
5
,
pretreatment with PTX prevented the protective effects of
phenylephrine. The reduction in tension caused by
ischemia after preconditioning with 100 µmol/L
phenylephrine was significantly greater in the hearts of
rats pretreated with PTX compared with rats not so pretreated
(P<.01) and was not significantly different in hearts
pretreated with PTX compared with nonpreconditioned
control hearts not exposed to phenylephrine. To exclude a
ß-adrenergically mediated effect of phenylephrine,
hearts were preconditioned with 100 µmol/L phenylephrine
in the presence of 1 µmol/L propranolol. As shown in Fig 5
,
100 µmol/L phenylephrine continued to produce a
substantial attenuation in the reduction of tension produced by
subsequent ischemia despite the presence of the
ß-blocker. These results indicate that the
-agonist
phenylephrine is able to mimic the effects of
ischemic preconditioning in the isolated rat heart and that
these preconditioning effects of phenylephrine are mediated
by
1B-receptors and dependent on the presence of a
PTX-sensitive G protein.
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Role of PKC in Ischemic Preconditioning in the
Rat
The activation of PKC is a potential mechanism of action of
PTX-sensitive G proteins.19 To examine the possible role
of this second messenger system in transducing the protective effects
of
-adrenergic preconditioning, we used stimulators and blockers
of PKC (Fig 6
). When the phorbol ester PMA was
administered at a concentration of 0.1 µmol/L during two 5-minute
drug preconditioning periods, a subsequent 30-minute ischemic
period followed by 15 minutes of reperfusion resulted in an
approximately 24% reduction in developed tension. This value was
substantially less than the reduction of tension produced by
ischemia in nonpreconditioned hearts and not
significantly different from that observed after ischemic
preconditioning. In contrast, when the same procedure was repeated with
an equimolar concentration (0.1 µmol/L) of a phorbol ester devoid of
PKC-stimulating activity, 4
-PDD, the impairment in tension
development was the same as in nonpreconditioned
control hearts.
|
In an additional set of hearts, the ischemic
preconditioning
protocol was applied with the protein kinase inhibitor H-7
(6 µmol/L) or the highly-selective PKC inhibitor
bisindolylmaleimide (30 nmol/L) administered for 10 minutes before
preconditioning and during the reperfusion periods after each
preconditioning ischemic interval. Ischemic
preconditioning was studied in five hearts for each drug, and five
nonpreconditioned hearts that received H-7 or
bisindolylmaleimide for 10 minutes before ischemia were studied
as controls. As shown in Fig 6B
, the reduction of tension after
the
prolonged ischemic period was identical for preconditioned and
nonpreconditioned hearts in the presence of H-7 or
bisindolylmaleimide. The results in Fig 6
suggest that PKC
stimulation
with phorbol ester mimics ischemic preconditioning, and
inhibition of PKC with H-7 or bisindolylmaleimide prevents the
protective effect of ischemic preconditioning.
| Discussion |
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1-adrenoceptors. Blockade of
1A-receptors
with 5-MU does not affect ischemic preconditioning, whereas
blockade of
1B-receptors with CEC prevents
ischemic preconditioning. Phenylephrine mimics the
effects of preconditioning in a concentration-related way, and this
action of phenylephrine is prevented by pretreatment with
PTX. The phorbol ester PMA mimics preconditioning at concentrations
that activate PKC,25 whereas the nonPKC
activating phorbol ester 4
-PDD does not mimic preconditioning, and
doses of H-726 and bisindolylmaleimide24 that
inhibit PKC block ischemic preconditioning. These results
suggest that ischemic preconditioning in the rat heart is due
to the stimulation of
1B-adrenoceptors by the release of
endogenous catecholamines, resulting in the
activation of a PTX-sensitive G protein that enhances PKC activity.
Comparison With Other Studies of Ischemic Preconditioning
in Rat Hearts
Previous studies have suggested that neither
adenosine22 nor IKATP23
participates in the protective effects of ischemic
preconditioning in rat hearts. In a recent publication, Banerjee et
al29 presented evidence for a role of
endogenous norepinephrine in preconditioning
rat hearts. They found that either norepinephrine or
phenylephrine (0.95 µmol/min, or about 56 µmol/L)
simulated ischemic preconditioning, and that reserpine,
phentolamine, and BE-2254 (a selective
1-adrenoceptor antagonist) block
ischemic preconditioning. These results are consistent
with our findings.
There are conflicting reports regarding the role of PTX-sensitive G proteins in ischemic preconditioning in the rat. Piacentini et al30 reported that pretreatment with PTX abolished the antiarrhythmic effect of ischemic preconditioning in Langendorff-perfused rat hearts, whereas Lawson et al31 did not observe an effect of pretreatment with PTX on the antiarrhythmic action of ischemic preconditioning in rats. Liu and Downey32 found that pretreatment with PTX did not significantly influence the effects of ischemic preconditioning on infarct size and arrhythmias in rats subjected to 30 minutes of ischemia followed by 120 minutes of reperfusion. The reasons for these discrepancies are unclear but may be related to the details of experimental models studied. We found that pretreatment with PTX prevented the actions of ischemic preconditioning on two separate indexes (ventricular tachyarrhythmias and recovery of developed tension) and that PTX also prevented the protective effects of preconditioning by phenylephrine in an additional series of studies.
Relation to Preconditioning Mechanisms in Other
Species
Ischemic preconditioning in the rat does not depend
on adenosine activation of
A1-receptors,22 in contrast to
ischemic preconditioning in rabbits,13
dogs,14 and pigs.15 Rather, the evidence
presented in the present study, as well as in previously
published work,29 points toward norepinephrine
as the endogenous mediator of ischemic
preconditioning in rat hearts. On the other hand, there are some
interesting similarities between the mechanisms described in the
present study and those mediating preconditioning in rabbits. As in
rabbits,18 ischemic preconditioning in rat hearts
in the present study was blocked by pretreatment with PTX.
Furthermore, a recent study indicates that pretreatment with reserpine
prevents ischemic preconditioning in rabbit
hearts,33 suggesting a role for endogenous
catecholamines in preconditioning in the rabbit. Thornton
et al34 showed that
1-receptor activation
caused by the release of endogenous
norepinephrine by tyramine can precondition the rabbit
heart. This effect was blocked by an adenosine receptor
antagonist, suggesting that the stimulation of
1-receptors may act in rabbits by enhancing
adenosine release or by modulating the actions of background
adenosine receptor stimulation. Further studies are warranted
to evaluate the potential role of endogenous
norepinephrine in ischemic preconditioning in other
species and to determine the potential interrelations between
norepinephrine and adenosine action, because
preventing the action of either seems to inhibit preconditioning in the
rabbit. Given the importance of ischemic preconditioning and
its similar behavior across a broad range of species, it would not be
surprising if underlying mechanisms shared common elements among
various species.
Signal Transduction and Mechanisms of Ischemic
Preconditioning
1-Adrenergic receptor stimulation has
been shown to
cause hydrolysis of phosphoinositides in adult rat
ventricular myocytes35 and to lead to
increased production of 1,4,5-inositol
triphosphate.36 These actions depend on the participation
of a PTX-sensitive G protein.36 In addition to producing
inositol triphosphate, the hydrolysis of phosphatidylinositol
4,5-biphosphate liberates DAG, which activates
PKC.37 Phorbol esters activate PKC by binding to a
cell surface receptor for DAG.38 The present study
provides substantial evidence for involvement of this system in
ischemic preconditioning in the rat heart. The role of
endogenous norepinephrine is suggested by the
inhibition of preconditioning produced by reserpine, and
1-receptor involvement is indicated by the blocking
action of the selective antagonist prazosin. Furthermore,
our studies with CEC and 5-MU indicate that the receptor subtype
involved is an
1B-receptor. The importance of
PTX-sensitive G proteins is indicated by the inhibiting effect of PTX
on both ischemic preconditioning and preconditioning produced
by phenylephrine. Involvement of PKC is suggested by the
ability of PMA to mimic, and of the protein kinase
inhibitors H-7 and bisindolylmaleimide to block,
ischemic preconditioning.
There is evidence that Gi levels and activity are reduced by acute myocardial ischemia.39 40 The activation of Gi before an ischemic insult, via either adenosine or norepinephrine released during a preceding brief ischemic period, could result in the initiation of cardioprotective mechanisms that would otherwise be suppressed by Gi inhibition during subsequent ischemia. Even in the rat, in which endogenous adenosine does not appear to mediate ischemic preconditioning, activation of Gi by cyclohexyladenosine (as well as carbamylcholine) protects the heart against subsequent ischemia.13 The mechanisms by which Gi activation and consequent PKC stimulation protect against ischemia require further elaboration, and much more work remains to be done to fully elucidate the signal transduction pathways and physiological mediators of endogenous cardioprotective mechanisms.
| Selected Abbreviations and Acronyms |
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| Acknowledgments |
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Received March 25, 1994; revision received April 17, 1995; accepted May 18, 1995.
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