© 1997 American Heart Association, Inc.
Articles |
Ischemic Preconditioning Prevents the Impairment of Hypoxic Coronary Vasodilatation Caused by Ischemia/Reperfusion
Role of Adenosine A1/A3 and Bradykinin B2 Receptor Activation
From the Department of Pharmacology, Cornell University Medical College, New York, NY.
Correspondence to Roberto Levi, MD, Department of Pharmacology, Cornell University Medical College, 1300 York Ave, New York, NY 10021. E-mail rlevi{at}mail.med.cornell.edu
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Abstract |
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Abstract We previously reported that hypoxic coronary vasodilatation (HCVD) is initiated by endothelial NO and sustained by adenosine. Prolonged ischemia/reperfusion impairs endothelium-dependent coronary vasodilatation, whereas transient ischemia (ie, preconditioning) protects the myocardium from subsequent ischemic events. Accordingly, we assessed whether prolonged ischemia/reperfusion impairs HCVD and whether preconditioning prevents this dysfunction. HCVD, elicited in isolated guinea pig hearts by a 1-minute exposure to 100% N2, consisted of an
70% increase in
coronary flow associated with enhanced nitrite/nitrate and
adenosine overflow (+40% and 5-fold, respectively). After
30-minute global ischemia and 20-minute reperfusion, HCVD was
decreased by 60%, and the increases in nitrite/nitrate and
adenosine overflow were abolished. Preconditioning (ie, three
cycles of 5-minute global ischemia+5-minute reperfusion)
prevented the impairment of HCVD and fully restored the increase in
nitrite/nitrate overflow, but not that of adenosine. The
protective effect of preconditioning was mimicked by perfusion with the
adenosine A1 receptor agonist
N6-cyclopentyladenosine and prevented by
the A1 receptor antagonist N-0861. In addition,
the A3 receptor agonist
N6-(3-iodobenzyl)adenosine-5'-N-methyl-carboxamide
had a similar protective effect. The bradykinin B2 receptor
antagonist HOE 140 abolished the protective effect of
preconditioning, whereas the NO synthase inhibitor
N
-methyl-L-arginine and the
cycloxygenase inhibitor
indomethacin did not. Our data indicate that
preconditioning restores HCVD by a process that is triggered by
activation of adenosine A1/A3 and
bradykinin B2 receptors. The action of bradykinin is
independent of NO and prostacyclin production. Once restored by
preconditioning, HCVD is mediated by NO but no longer sustained by
adenosine.
Key Words: adenosine • bradykinin • hypoxic coronary vasodilation • ischemic preconditioning • nitric oxide
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Coronary arteries are known to dilate in hypoxic conditions.1 Previous observations in our laboratory determined that endothelium-derived NO is a major mediator of HCVD, that adenosine sustains this NO-initiated effect, and that other factors are of lesser consequence.2
In contrast to brief hypoxic episodes, sustained myocardial ischemia/reperfusion results in a prolonged decrease in coronary vasodilator responsiveness,3 4 5 6 and this is associated with an impairment of endothelium-dependent vasodilatation.7 8 9 10 Accordingly, prolonged ischemia/reperfusion could diminish HCVD.
Ischemic preconditioning has long been recognized to protect the heart from ischemia/reperfusion injury11 and to reduce the incidence of reperfusion arrhythmias.12 Whether the protective effect of preconditioning also extends to the coronary circulation has not been established. In fact, with the exception of few studies,13 14 15 virtually all preconditioning protocols have focused on the limitation of infarct size, reperfusion arrhythmias, and myocardial stunning16 17 as end points. Thus, it would seem important to assess whether ischemia/reperfusion impairs HCVD and, if so, whether ischemic preconditioning can prevent this impairment.
Currently, the mechanism of preconditioning and its protective effects are not fully understood. A large body of evidence suggests that activation and blockade of adenosine A1 receptors (and most recently A3 receptors) mimic and abolish, respectively, the reduction in infarct size afforded by ischemic preconditioning.18 19 20 21 22 23 Alternatively, NO and bradykinin may play a role, since either NO synthase inhibitors or bradykinin B2 receptor antagonists prevent the protective effect of preconditioning.24 25 26 27
Recently, increasing attention has been devoted to distinguishing two phases in ischemic preconditioning: a triggering phase and a mediation phase.25 28 29 Yet, compared with the large body of work on preconditioning, little emphasis has been placed on detecting the release of potential mediators, such as adenosine and NO, from preconditioned hearts, despite few important exceptions.30 31 32 33
Even more recently, emphasis has been placed on defining the mediation (or maintenance) phase as a receptor-reoccupation phase, which occurs during the long ischemic period (ie, reoccupation theory).28 29 Accordingly, this approach should also be taken into consideration with regard to HCVD and its protection by ischemic preconditioning.
Therefore, the aim of the present study was to test the hypotheses that (1) ischemia/reperfusion impairs HCVD, (2) preconditioning prevents the impairment of HCVD caused by ischemia/reperfusion, and (3) NO, bradykinin, and adenosine trigger and/or mediate the preconditioning-induced restoration of HCVD.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Isolated Heart Perfusion
Male Hartley guinea pigs weighing 250 to 300 g were killed by cervical dislocation under light anesthesia with CO2 vapor. After midline thoracotomy, the heart was rapidly excised and perfused in a retrograde fashion at a constant pressure of 45 cm H2O in a Langendorff apparatus with Ringer's solution at 37°C saturated with 100% O2.2 The composition of the Ringer's solution was (mmol/L) NaCl 154.0, KCl 5.61, NaHCO3 5.95, CaCl2 2.16, and dextrose 5.55. Coronary flow was determined by measuring the volume of coronary effluent collected during several consecutive 30-second periods. Collected coronary perfusate was stored at -70°C for analysis of adenosine content. Isometric ventricular contractions were recorded with a force-displacement transducer connected via a thread to the apex of the left ventricle.
Induction of HCVD
HCVD was induced by perfusing the hearts for a 1-minute period
with Ringer's solution equilibrated with 100% nitrogen.2
The time course of the increase in coronary flow was monitored
by collecting the effluent for several consecutive 30-second periods
before, during, and after the 1-minute hypoxic perfusion. HCVD was
first elicited at the end of the 30-minute stabilization period, before
the beginning of the respective experimental protocols. HCVD was then
repeated three more times, at 20-minute intervals, beginning 20 minutes
after the end of each experimental protocol. After each HCVD cycle,
hearts were allowed to reequilibrate for a 20-minute period. In some
experiments, the initial HCVD was not performed, in order to exclude
possible preconditioning effects of hypoxia itself.
Experimental Protocols
Hearts were first perfused with oxygenated Ringer's
solution for 30 minutes until the sinoatrial rate, contraction, and
coronary flow reached a steady state. HCVD was then induced as
described above. Hearts in all groups were subsequently subjected to a
30-minute global ischemia followed by a 60-minute reperfusion.
HCVD was tested again, after 20, 40, and 60 minutes, during the
reperfusion period (Fig 1
). In the
control group, hearts underwent only the above-mentioned procedure (see
Fig 1, protocol A). In the preconditioned group, hearts were subjected
to three periods of 5-minute global ischemia, each separated by
5 minutes of reperfusion, before undergoing the 30-minute global
ischemia+60-minute reperfusion (see Fig 1, protocol B). In the
agonist-treated groups, ischemic preconditioning was mimicked
by exposing the hearts either to the selective adenosine
A1 receptor agonist CPA34 or the
adenosine A3 receptor agonist
IB-MECA.35 These agents were infused through the aortic
cannula at a 1:20 dilution in order to achieve the final concentration
(see "Results" for specific drug concentrations) for three
periods of 5 minutes, each separated by 5-minute washout periods with
Ringer's solution, before the onset of the prolonged ischemia
(see Fig 1, protocol C). In the
antagonist/inhibitor-treated groups, the
selective adenosine A1 receptor
antagonist N-0861,36 the selective bradykinin
B2 receptor antagonist HOE 140,37
or the specific NO synthase inhibitor NMA38
was separately infused through the aortic cannula, beginning 5 minutes
before the induction of ischemic preconditioning (see Fig 1, protocol D). To allow for a complete washout of the drug, the infusion
was suspended 2.5 minutes before the induction of the prolonged
ischemia/reperfusion. In the post-preconditioning
antagonist–treated groups, the selective adenosine
A1 receptor antagonist N-0861 and the selective
bradykinin B2 receptor antagonist HOE 140 were
separately infused through the aortic cannula beginning 2.5 minutes
after the ischemic-preconditioning procedure (see Fig 1, protocol E).
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Adenosine Assay
Adenosine was assayed by reverse-phase HPLC, as
previously described.2 Adenosine overflow was
calculated by combining the concentration of adenosine with its
metabolic product, inosine.
Nitrite/Nitrate Assay
NO was monitored by assaying the formation of NOx
with a NO chemiluminescence analyzer (Sievers, model 270B)
after reduction of NOx to NO by acidic
vanadium.39
Drugs
The selective adenosine A1 receptor
antagonist N-0861 and the selective bradykinin
B2 receptor antagonist HOE 140 were gifts of
Whitby Research, Inc, and Hoechst AG, respectively. The specific NO
synthase inhibitor NMA was synthesized by Dr O.W. Griffith,
Medical College of Wisconsin, Milwaukee. The selective
adenosine A1 receptor agonist CPA and the
adenosine A3 receptor agonist IB-MECA were
purchased from Research Biochemicals Intl. Adenosine
hemisulfate and indomethacin were purchased from Sigma
Chemical Co.
Statistics
Values are expressed as mean±SEM. Comparison of more than
two groups was performed by ANOVA combined with Fisher's test. A value
of P<.05 was considered statistically significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Effect of Ischemic Preconditioning on the Impairment of HCVD Caused by Ischemia/Reperfusion
When spontaneously beating isolated guinea pig hearts were perfused at constant pressure for 1 minute with Ringer's solution bubbled with 100% nitrogen, a rapid and marked increase in coronary flow ensued (HCVD, Fig 2
). Coronary flow increased to a
maximum of 
70% by the end of the hypoxic period and rapidly
returned to prehypoxic levels 40 seconds after perfusion with fully
oxygenated Ringer's solution was reinstated. HCVD remained
constant in magnitude and duration during at least four consecutive
hypoxic periods separated by 20-minute intervals at 100% oxygen (Fig 2).
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In hearts subjected to 30-minute global ischemia followed by
reperfusion, the magnitude of HCVD decreased by 60% at 20, 40, and
60 minutes of reperfusion (1.4±0.5 mL/min [postischemic
HCVD, n=5] versus 3.4±0.3 mL/min [preischemic HCVD,
n=5], P<.05, Fig 2
). This impairment in HCVD was almost
completely prevented when ischemia/reperfusion was preceded by
ischemic preconditioning (ie, three subsequent 5-minute periods
of global ischemia, each separated by 5-minute reperfusion
intervals; Fig 2).
Effect of Activation of Adenosine A1
and A3 Receptors on the Impairment of HCVD Caused by
Ischemia/Reperfusion
In subsequent experiments, ischemic preconditioning was
mimicked by infusing the hearts with the selective adenosine
A1 receptor agonist CPA (100 nmol/L) for three
consecutive 5-minute periods, separated by 5-minute intervals of
perfusion with plain Ringer's solution. Adenosine
A1 receptor activation with CPA almost completely prevented
the impairment in HCVD caused by ischemia/reperfusion. Indeed,
HCVD in hearts perfused with CPA before ischemia/reperfusion
did not differ from HCVD in the control and preconditioned groups (Fig 3A). Furthermore, when hearts were
infused with the selective adenosine A1 receptor
antagonist N-0861 (5 µmol/L), beginning 5
minutes before ischemic preconditioning, the protective effect
of preconditioning was abolished (Fig 3A).
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We next mimicked ischemic preconditioning by infusing the
hearts with the adenosine A3 receptor agonist
IB-MECA (1 µmol/L) for three consecutive 5-minute
periods, separated by 5-minute intervals of perfusion with plain
Ringer's solution. As shown in Fig 3B, activation of adenosine
A3 receptors mimicked the protective effect of
ischemic preconditioning. In this action, IB-MECA was slightly,
although not significantly, more effective than the A1
receptor agonist CPA.
Effects of Bradykinin B2 Receptor Blockade and NO
Synthase Inhibition on the Impairment of HCVD Caused by
Ischemia/Reperfusion
When hearts were perfused with the selective bradykinin
B2 receptor antagonist HOE 140 (100
nmol/L), beginning 5 minutes before ischemic
preconditioning, the protective effect of preconditioning was abolished
(Fig 4). Indeed, in hearts treated with
HOE 140 before preconditioning, HCVD after ischemia/reperfusion
was as low as in nonpreconditioned hearts (Fig 4).
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Because these findings suggested an involvement of bradykinin in the
protective effect of preconditioning, we next questioned whether
bradykinin triggers preconditioning via NO release. Accordingly, hearts
were perfused with the specific NO synthase inhibitor NMA
(100 µmol/L), beginning 5 minutes before ischemic
preconditioning. As shown in Fig 4, in hearts perfused with NMA, the
protective effect of preconditioning was slightly, but not
significantly, reduced. This suggested that bradykinin triggers
preconditioning via mediators other than NO.
To determine whether an increased prostacyclin production mediates the triggering effect of bradykinin, hearts were perfused with indomethacin (10 µmol/L), either alone or in combination with NMA (100 µmol/L), beginning 5 minutes before ischemic preconditioning. Increases in coronary flow rate, a measure of HCVD, were 3.16±1.21 and 3.93±0.44 mL/min in indomethacin-treated and indomethacin+NMA–treated hearts, respectively, and 3.13±0.2 and 3.03±0.33 mL/min in control and preconditioned hearts, respectively (n=3 for each group). This suggested that neither NO nor prostacyclin plays a role in the triggering of preconditioning.
Reoccupation Theory
To determine whether receptor reoccupation is necessary for the
mediation-maintenance phase of ischemic
preconditioning, we administered either adenosine
A1 or bradykinin B2 receptor
antagonists after the ischemic preconditioning
procedure but before the prolonged ischemic period. We found
that A1 and B2 receptor antagonists
both failed to prevent the protective effect of preconditioning in this
protocol (Fig 5). Thus, neither
adenosine A1 nor bradykinin B2 receptor
reoccupation appears to be necessary in the "mediation
maintenance" of ischemic preconditioning.
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Impairment of HCVD Caused by Ischemia/Reperfusion: Release
of NO
NO is a major mediator of HCVD and a putative mediator of the
cardioprotective effect of preconditioning. Thus, we assessed whether
the impairment of HCVD caused by ischemia/reperfusion is
associated with a decreased production of NO. As shown in Fig 6, HCVD was accompanied by an increase in
NO release. This increase was completely abolished after
ischemia/reperfusion, yet fully restored when
ischemia/reperfusion was preceded by ischemic
preconditioning (Fig 6).
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Impairment of HCVD Caused by Ischemia/Reperfusion: Release
of Adenosine
Adenosine is known to mediate the sustained phase of HCVD
and is a putative mediator of the cardioprotective effect of
preconditioning. Thus, we assessed whether the impairment of HCVD
caused by ischemia/reperfusion is associated with a decreased
production of adenosine. As shown in Fig 7, HCVD was accompanied by an increase in
adenosine release. This increase was completely abolished after
ischemia/reperfusion, but in contrast to NO, it was not
restored by ischemic preconditioning (Fig 7).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The ability of the heart to withstand hypoxic events relies, among other mechanisms, on the capacity of the coronary vessels to dilate and thus to increase arterial flow.1 2 40 41 We demonstrate in the present study that although coronary vasodilatation in response to hypoxia is severely impaired after ischemia/reperfusion, it is fully preserved by ischemic preconditioning.
Two subsequent phases are now recognized in the mechanism of ischemic preconditioning: a triggering phase and a mediation phase.25 29 Using HCVD as the end-point response, we established that CPA and IB-MECA can mimic ischemic preconditioning. This suggests that activation of adenosine A1 and A3 receptors triggers ischemic preconditioning. In addition, we found that selective blockade of adenosine A1 receptors with compound N-0861 prevented the induction of preconditioning. Selective blockade of bradykinin B2 receptors with compound HOE 140 also abolished the protective effects of preconditioning. Collectively, these findings imply that endogenous ligands produced during ischemic preconditioning, namely adenosine21 and bradykinin,26 initiate the adaptive process involved in the preservation of HCVD after ischemia/reperfusion.
Notably, inhibition of NO synthase with NMA did not affect the restoration of HCVD afforded by ischemic preconditioning. This finding appears to concur with the lack of NO contribution reported by some investigators,42 43 44 but not with the involvement claimed by others,24 who chose restoration of contractility or protection from reperfusion arrhythmias as end points. Inhibition of cyclooxygenase with indomethacin also failed to affect the restoration of HCVD afforded by ischemic preconditioning. This finding agrees with the lack of prostanoid involvement noted by some investigators45 but not with the involvement claimed by others,46 who adopted infarct size reduction and arrhythmia limitation as protective end points. Thus, the triggering of preconditioning by bradykinin in our model appears not to be mediated by NO and prostacyclin, both of which are otherwise known to mediate the endothelium-dependent effects of bradykinin.47 Instead, bradykinin could function by directly activating protein kinase C,26 29 as shown in other models.48 49 Protein kinase C activation had been previously proposed by some investigators as a transductional mechanism of ischemic preconditioning mediated by adenosine A1 receptors,50 51 ultimately leading to ATP-dependent K+ channel opening.20 21 52 53 54 55 Others, however, have found that protein kinase C activation, and/or translocation, is unrelated to the protective effect of preconditioning.56 57 58 59 60
With the exception of few studies, little has previously been done to directly assess changes in adenosine30 31 32 33 and NO release in relation to ischemic preconditioning. Nevertheless, alterations in the generation of NO that had been implied in earlier ischemia/reperfusion models61 62 were recently directly measured in isolated hearts.63 64 These studies have yielded opposing conclusions as to the protective or deleterious role of NO.
We had previously reported that NO mediates the early phase of HCVD and that adenosine sustains the vasodilatation initiated by NO.2 Accordingly, we sought to determine to what extent NO and adenosine contribute to residual HCVD after ischemia/reperfusion and to what extent they contribute to HCVD as restored by preconditioning. For this, we measured the overflow of nitrite/nitrate and adenosine into the coronary effluent, both in control conditions and after ischemia/reperfusion, preceded or not by preconditioning. We found that at the peak of HCVD the production of NO and adenosine was much increased from basal levels but unchanged from basal levels when HCVD was preceded by prolonged ischemia. This suggests that a deficit in the production of NO and adenosine is likely to play a role in the attenuation of HCVD after ischemia/reperfusion.
Preconditioning restored HCVD in hearts subjected to prolonged ischemia. This coincided with a complete recovery of NO production. In contrast, as expected, preconditioning did not fully restore adenosine release. Thus, in our experimental model, NO production appears to play an essential role in the mediation phase of ischemic preconditioning, even though it is not involved in the triggering phase. In contrast, adenosine appears to act as a trigger, but not as a mediator, of the protective effect of ischemic preconditioning. We recognize that our concept of "mediation" does not fully coincide with that of the "mediation maintenance" implicated in the reoccupation theory, as commonly defined.29 In fact, we set out to investigate a mediation process further downstream, ie, an effector-like phase, represented by the release of humoral factors, such as adenosine and NO.
Therefore, we performed additional experiments to explore the "mediation maintenance," in the most common usage of the term,29 in relation to our experimental model. We found that A1 and B2 receptor antagonists, administered after ischemic preconditioning, both failed to prevent its protective effect. Thus, neither adenosine A1 nor bradykinin B2 receptor reoccupation appears to be necessary in the "mediation maintenance" of ischemic preconditioning. These data are in keeping with the findings of Goto et al29 involving the role of bradykinin as a trigger but not mediator of ischemic preconditioning. On the other hand, our data do not appear to support the findings of Goto et al with regard to adenosine. In fact, our results suggest a trigger-but-not-mediator role also for adenosine, thus paralleling our data on the role of adenosine in the effector-like mediation and concurring with the recent findings of Yao et al.65
In conclusion, using HCVD as an end-point response, we found that ischemia/reperfusion markedly impairs HCVD and that ischemic preconditioning restores it. Whereas both NO and adenosine mediate HCVD in control conditions, only NO mediates HCVD once restored by preconditioning. Preservation of HCVD by preconditioning is triggered by activation of adenosine A1/A3 and bradykinin B2 receptors. Because neither NO nor prostacyclin appears to play a role in the triggering action of bradykinin, it is conceivable that in this setting bradykinin functions by directly activating protein kinase C.26 29 Inasmuch as a defect in HCVD limits the ability of the heart to withstand hypoxic events, this vascular derangement may contribute to enhance myocardial dysfunction associated with ischemia/reperfusion. Given the protective effect of preconditioning, our elucidation of the processes involved in the preservation of HCVD after ischemia/reperfusion may contribute to a better understanding of the mechanisms of ischemic preconditioning.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by National Institutes of Health grants HL-34215 and HL-46403. Hans-Christian Mochmann was supported in part by a predoctoral fellowship of the Biomedical Sciences Exchange Program between North America and Europe. We wish to thank our colleague Dr Steven S. Gross for his help with the nitrite/nitrate assay.
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Footnotes |
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Presented as preliminary data at the XVth World Congress of the International Society for Heart Research, Prague, Czech Republic, July 2-7, 1995, and published in abstract form (J Mol Cell Cardiol. 1995;27:A150).
Received October 7, 1996; accepted June 26, 1997.
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