© 2001 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Role of adenosine in ischemic preconditioning in rats depends critically on the duration of the stimulus and involves both A1 and A3 receptors
Experimental Cardiology, Thoraxcenter, Cardiovascular Research Institute Coeur, Erasmus University Rotterdam, Rotterdam, The Netherlands
duncker{at}tch.fgg.eur.nl
* Corresponding author. Tel.: +31-10-408-8029; fax: +31-10-408-9494
Received 8 February 2001; accepted 12 April 2001
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Abstract |
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Objectives: There is currently general agreement that adenosine is not involved in ischemic preconditioning (IP) in rat hearts. We hypothesized that the failure to show a role for adenosine is due to the use of brief preconditioning stimuli, and therefore investigated whether adenosine is involved when longer stimuli are employed and which receptor subtypes are involved. Methods and results: Infarct size (IS) was determined in anesthetized rats after 180 min of reperfusion (REP) following a 60-min coronary artery occlusion (CAO). IS was 69±2% (n=15) of the risk area in control rats and 45±2% (n=19; P<0.05) following IP by a single 15-min CAO. The non-selective adenosine receptor antagonist SPT, which itself had no effect on IS (74±1%), blunted the protection by IP (IS=57±2%, P<0.05) in a dose of 2x5 mg/kg i.v., and abolished the protection (IS=70±1%) at 2x25 mg/kg i.v. Following IP by three cycles of 3-min CAO and 3-min REP, IS was 24±6% (P<0.05), which was not affected by SPT in doses of 2x10 and 2x25 mg/kg i.v. The A3 antagonist MRS-1191 (3.3 mg/kg, i.p.), which itself did not affect IS (70±2%), blunted the protection by IP with a 15-min CAO (IS=54±2%, P<0.05). When 2x5 mg/kg SPT (a dose selective for A1-receptors, as it did not affect the protection by the A3 selective agonist IB-MECA, 51±3%) and MRS 1191 were combined the protection by IP was abolished (IS=67±2%). Conclusions: Involvement of adenosine in IP in rats depends critically on the duration of the stimulus. Thus, whereas adenosine was not involved when stimuli of 3-min duration were employed, activation of both A1 and A3 receptors contributed when a stimulus of 15 min was used.
KEYWORDS Adenosine; Infarction; Ischemia; Preconditioning; Receptors
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1 Introduction |
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TopAbstract1 Introduction2 Methods3 Results4 Discussion5 Conclusions and therapeutic...References |
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The cardioprotective role of adenosine has been firmly established in all species in which this has been investigated. Adenosine has also been shown to be one of the mediators involved in the protection afforded by ischemic preconditioning (IP). However, based on numerous studies including those in which the selective adenosine A1 receptor antagonist PD 115,199 and the non-selective antagonist SPT failed to block IP [1–3], Ganote and Armstrong [4] conclude in a recent issue of this journal that there is now general agreement that adenosine does not play a role in the myocardial infarct size (IS) limitation by IP in rats. In these studies [1–3] the duration of the (multiple) IP stimuli was 3–5 min. Interestingly, Schulz et al. [5] have shown that intracoronary adenosine deaminase was ineffective in attenuating IS limitation by a 3-min coronary artery occlusion (CAO), but abolished the cardioprotection by a 10-min CAO in the pig heart. We therefore hypothesized that adenosine could play a role in IP in rats when preconditioning stimuli of longer duration are used. Consequently, we investigated the role of adenosine in IP by a 15-min CAO, a stimulus which we have previously shown to protect the rat heart [6,7], and repeated the protocol of three cycles of 3-min CAO and 3-min REP used by Li and Kloner [2], to exclude that differences in results were caused by differences in breed, sex and experimental procedures. Our results not only confirmed the findings by Li and Kloner [2] but also demonstrated that a high dose of SPT completely blocked the cardioprotection by a single 15-min CAO stimulus. Because SPT is a non-selective adenosine receptor antagonist, we subsequently investigated which of the adenosine receptor subtypes are involved in IP. This is of interest, because evidence is accumulating that not only selective A1 but also selective A3 agonists confer cardioprotection in a variety of animal models. For instance, the selective A3 agonists APNEA and IB-MECA limit myocardial injury to a similar degree as IP in isolated rabbit cardiomyocytes [8], and in isolated [9] and in vivo [10] rabbit hearts. Since the affinity of adenosine for the A3 receptor is 10–100 less than for the A1 receptor, it has been questioned whether A3 receptor activation is involved in the protection afforded by IP [11]. Studies on the role of A3 receptors in IP in vivo have been hampered by lack of selective A3 receptor antagonists [4]. However, MRS-1191 has recently been described as a highly selective A3 receptor antagonist [4,11]. Consequently, we studied the contributions of A1 and A3 receptor subtypes to the protection by IP in the in vivo rat heart.
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2 Methods |
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Experiments were performed in ad libitum fed male Wistar rats (
300 g) in accordance with the Guide for the Care and Use of Laboratory Animals (NIH publication 86-23, revised 1985) and with approval of the Animal Care Committee of the University.
2.1 Drugs
The following agents were used: the non-selective adenosine receptor antagonist 8-p-sulfophenyltheophylline (SPT); the selective A1 agonist 2-chloro-N6-cyclopentyladenosine (CCPA); the selective A3 receptor agonist N-(3-iodobenzyl)adenosine-5'-N-methyluronamide (IB-MECA); the selective A3 receptor antagonist 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4,-[±]-dihydro-pyridine-3,5-decarboxylase (MRS-191); the histamine H1 antagonist mepyramine (Mep), and N,N-dimethylacetamide (DMAC) in which MRS-1191 was dissolved. All other agents were dissolved in physiological saline.
2.2 Surgical and experimental procedures
Pentobarbital-anesthetized (60 mg/kg) rats were intubated for positive pressure ventilation (Harvard rodent ventilator) with room air [6,7]. Through the carotid artery a PE-50 catheter was positioned in the thoracic aorta for measurement of arterial blood pressure and heart rate. In the inferior caval vein a PE-50 catheter was placed for infusion of Haemaccel (Behringwerke) to compensate for blood loss during surgery. After thoracotomy, via the left third intercostal space, the pericardium was opened and a silk 6-0 suture was looped under the left anterior descending coronary artery for later CAO. A catheter was positioned in the abdominal cavity to allow intraperitoneal (i.p.) administration of pentobarbital for maintenance of anesthesia. Rectal temperature was continuously measured and maintained at 36.5–37.5°C [6,7]. To prevent local heat loss from the thorax, the thoracotomy site was covered with aluminum foil. After completion of surgery, a 30-min stabilisation period was allowed before experimental protocols were carried out.
Rats that fibrillated were allowed to complete the protocol, provided that conversion to normal sinus rhythm occurred spontaneously within 1 min, or that defibrillation by gently thumping on the thorax or with a 9 V battery was successful within 2 min after onset of fibrillation. Occlusion and reperfusion were visually verified [6,7].
2.3 Experimental groups
Fig. 1 depicts the experimental groups in which IS was determined after 180-min REP following a 60-min CAO. Area at risk (AR) and infarct area (IA) were determined using Trypan blue and nitro-blue-tetrazolium staining (Sigma) [6,7]. IS was expressed as IA/AR.
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2.3.1 Protocol I: does adenosine contribute to ischemic preconditioning in the rat heart?
One group underwent a 25-min sham period prior to the 60-min CAO followed by 180-min of REP (Control). To determine whether adenosine contributed to IP when stimuli of longer duration are used, we preconditioned three groups with a 15-min CAO followed by 10-min of REP. These groups received either no treatment (PC15), or were pretreated with intravenous (i.v.) SPT in doses of 2x5 mg/kg (PC15+10SPT) or 2x25 mg/kg (PC15+50SPT), respectively. To study the effects of SPT on IS per se, one group was pretreated with 2x25 mg/kg SPT i.v. prior to the 60-min CAO (Control+50SPT). To exclude the possibility that confounding factors such as breed (Sprague–Dawley [2] versus Wistar), sex (females [2] versus males) or experimental procedures (90-min CAO [2] versus 60-min CAO) contributed to differences between our observations and those by Li and Kloner [2], we also determined in two groups whether three cycles of 3-min CAO followed by 3-min REP (PC3), protected the myocardium against infarction produced by a 60-min CAO and whether 2x10 mg/kg SPT (PC3+20SPT), the dose of SPT used by Li and Kloner [2], or the high dose of 2x25 mg/kg SPT (PC3+50SPT) affected this cardioprotection.
2.3.2 Protocol II: is A3 receptor stimulation cardioprotective and does SPT in the doses used possess A3-receptor antagonistic properties in the rat heart?
In two groups the effect of A3 receptor stimulation on IS was studied by administration of IB-MECA in doses of 33 µg/kg (IB-MECA33) or 100 µg/kg (IB-MECA100), prior to the 60-min CAO and compared to the Control group from Protocol I to which two animals were added (Fig. 1). Since IB-MECA releases histamine from mast cells in rats [10], another group was pretreated with 5 mg/kg Mep prior to IB-MECA and the 60-min CAO (IB-MECA100+Mep), and compared to a group that received only 5 mg/kg Mep prior to the 60-min CAO (Control+Mep). To investigate whether SPT possesses A3 receptor antagonistic properties, we pretreated rats with 2x5 mg/kg SPT prior to administration of 33 µg/kg IB-MECA (IB-MECA33+10SPT) or 100 µg/kg IB-MECA with Mep (IB-MECA100+Mep+10SPT) and studied the effect of 2x25 mg/kg SPT on the cardioprotection by 100 mg/kg IB-MECA in the presence of Mep (IB-MECA100+Mep+50SPT).
2.3.3 Protocol III: are A3 receptors involved in ischemic preconditioning in the rat heart?
Two groups received the 15-min CAO IP stimulus and 3.3 mg/kg MRS-1191 (i.p.) either without (PC15+MRS) or with 2x5 mg/kg SPT (PC15+MRS+10SPT). The results of these two groups were compared to the Control, PC15 and PC15+10SPT groups from Protocol I, to which a number of new animals were added (see Fig. 1). To exclude an effect of MRS-1191 or its solvent DMAC on IS per se, one group received 3.3 mg/kg MRS-1191 i.p. (Control+MRS) and another group received the solvent DMAC (Control+DMAC) prior to the 60-min CAO.
MRS-1191 has been reported to be a highly selective A3 antagonist, but in vivo experience with this compound is limited. Therefore, to exclude that A1 antagonistic properties contributed to the actions of MRS-1191, we studied the bradycardic responses to the selective A1 agonist CCPA after treatment with MRS-1191 (n=6) or its solvent DMAC (n=5). Two consecutive doses (50 and 100 µg/kg, i.v.) of CCPA were administered. The second dose was given when heart rate had reached a stable level after administration of the first dose.
2.4 Data analysis and presentation
IS was analyzed by one-way ANOVA followed by Dunnett's test. Hemodynamic variables were compared by two-way ANOVA for repeated measures followed by the paired or unpaired t test. Statistical significance was accepted when P<0.05. Data are presented as mean±S.E.M.
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3 Results |
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3.1 Mortality
Eleven rats were excluded because of sustained ventricular fibrillation or pump failure (two in Control, one in PC15, one in PC15+10SPT, one in PC3+20SPT, one in PC3+50SPT, two in IB-MECA33 and three in Control+DMAC.
3.2 Infarct size
3.2.1 Area at risk
There were no differences (P=0.61) in AR (34±1%) between any of the experimental groups.
3.2.2 Effect of duration of preconditioning stimuli on the involvement of adenosine
Fig. 2 shows that IP by a 15-min CAO limited IS to 49±3% vs. 70±2% in Control. SPT in a dose of 2x5 mg/kg attenuated the cardioprotection, while a 5-times higher dose, which by itself had no effect on IS, abolished the protection. Fig. 2 also shows that IP by 3-min CAOs limited IS to 24±6% and that SPT, not only in a dose of 2x10 mg/kg (confirming the observations by Li and Kloner [2]), but also in the high dose of 2x25 mg/kg, did not attenuate the cardioprotection (18±3%).
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, P<0.05 PC15+10SPT and PC15+50SPT vs. PC15; 
, P<0.05 PC15+50SPT vs. PC15+10SPT.3.2.3 Selectivity of SPT and IB-MECA for A1 and A3 receptor subtypes
Pretreatment with IB-MECA limited IS to 59±1% and 51±3% at doses of 33 and 100 µg/kg, respectively, (both P<0.05, Fig. 3). Mep blunted the IB-MECA-induced hypotension by 35%, but had no effect on IS limitation, indicating that histamine release did not contribute to the cardioprotection by IB-MECA. IB-MECA, in either dose, had no effect on heart rate (Table 1), which indicates that IB-MECA, in the doses used, was selective for the A3 receptor. The low dose of SPT had no effect on the cardioprotection by either dose of IB-MECA, indicating that the low dose of SPT had no A3 antagonistic effects. In contrast, the high dose of SPT blunted the cardioprotection by IB-MECA100 (62±2%, P<0.05), suggesting that SPT possesses A3 antagonistic properties at this dose. For this reason, we employed the A1 selective low dose of SPT in combination with MRS-1191 to study the role of A1 and A3 subtypes in IP in protocol III.
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3.2.4 Adenosine subtypes involved in ischemic preconditioning
Cardioprotection by IP was reduced by approximately half, when animals were pretreated with either 3.3 mg/kg MRS-1191 or the low dose of SPT (Fig. 4). Combining SPT and MRS-1191 completely abolished the cardioprotection by IP.
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To establish that the actions of MRS-1191 were indeed caused by A3 antagonism, we studied the bradycardic response to the selective A1 agonist CCPA in the absence and presence of MRS-1191. In the animals pretreated with DMAC, heart rate was lowered by 183±22 and 261±21 bpm by the 50 and 100 µg/kg dose of CCPA, respectively (Fig. 5). After pretreatment with 3.3 mg/kg MRS-1191, the CCPA-induced heart rate reductions (191±23 and 275±11 bpm, respectively) were not different from those in the presence of DMAC, indicating that at the dose used, MRS-1191 had no A1 antagonistic properties. In contrast, 3.3 mg/kg MRS-1191 produced a high degree of A3 blockade as it attenuated the hypotension induced by 100 µg/kg IB-MECA by 70% (from 40±4 to 12±3 mmHg, n=7, P<0.05).
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3.2.5 Heart rate and arterial blood pressure during 60-min CAO and 180-min REP
In all groups of Protocol I arterial blood pressure had decreased at the end of the 60-min CAO and did not recover during reperfusion (Table 1). Heart rate remained virtually unchanged, although it decreased slightly (10–15%) in some, but not all, groups treated with SPT.
In the animals pretreated with IB-MECA, mean arterial pressure was lower than in the other groups of animals at the start of the 60-min CAO, which is most likely the reason for the smaller decrease in mean arterial pressure in these animals during the 60-min CAO, while heart rate remained virtually unchanged. In these animals, heart rate decreased slightly (5–10%) during 180-min REP. Mepyramine produced a 10% decrease in heart rate and blood pressure, but had no effect on blood pressure and heart rate response to the 60-min CAO and 180-min REP in any group.
Animals pretreated with MRS-1191 behaved similarly as the other groups of animals during the 60-min CAO and 180-min REP procedure. In these animals heart rate increased 10–15% after administration of MRS-1191, which was mostly likely due to its solvent.
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4 Discussion |
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Major findings in the present study in the rat heart were that (i) the non-selective adenosine receptor antagonist SPT had no effect on cardioprotection produced by three cycles of 3-min CAO and 3-min REP, confirming observations by Li and Kloner [2], but attenuated (low dose) and abolished (high dose) the protection afforded by a single 15-min CAO and 10-min REP; (ii) the selective A3 receptor agonist IB-MECA limited infarct size dose-dependently, which was not affected by pretreatment with the low dose, but was blunted by the high dose of SPT and (iii) the selective A3 receptor antagonist MRS-1191 attenuated IP and together with the low dose of SPT abolished the protection by IP with a 15-min CAO.
4.1 Involvement of adenosine in IP in the rat heart
Since the original observation by Liu et al. [12] in an in vivo rabbit model, that the adenosine receptor blockers SPT and PD115,199 were able to abolish cardioprotection afforded by ischemic preconditioning, the role of adenosine in ischemic preconditioning has been confirmed in other species such as dogs [13] and swine [14,15]. However, the evaluation of the contribution of adenosine to IS limitation by IP has led to negative results in the rat, although several studies have shown that pretreatment with exogenous adenosine can be cardioprotective in this species [4]. Capitalizing on observations by Schulz et al. [5] we hypothesized that the failure to establish the role of adenosine in the aforementioned studies in rats [4] could be due to the fact that the duration of the IP stimulus may have been too short. In the present study we not only confirmed the findings by Li and Kloner [2] that protection afforded by three cycles of 3-min CAO and 3-min REP was not amenable to adenosine receptor blockade with SPT in a dose of 2x10 mg/kg [2], but also in the high dose of 2x25 mg/kg which antagonized both A1 and A3 receptors. However, when a preconditioning stimulus of longer duration was used (15-min CAO), the protection was blunted by a dose of SPT that was half (2x5 mg/kg) and abolished by a dose that was 2.5 times (2x25 mg/kg) that used by these investigators. These observations imply that adenosine receptor activation is involved in the protection by IP, provided that the duration of the preconditioning stimulus is sufficiently long.
Headrick [16] reported that in interstitial fluid collected between 1 and 6 min of a 6-min period of global normothermic ischemia in isolated hearts, myocardial interstitial adenosine concentrations increased from 0.25 to 6.8 µM in rats and only from 0.33 to 2.0 µM in rabbits. The Ki value of adenosine for the A1 receptor is 10–100 nM in rats and 28 nM in rabbits [4,11]. These findings of higher interstitial adenosine levels together with a similar affinity for A1 receptors in rat and rabbit hearts are difficult to reconcile with a contribution of adenosine to IP by brief stimuli in the rabbit, but not the rat heart [4]. Since Headrick [16] used a 6-min CAO, the different results obtained in rats and rabbits can only be explained by an early increase in adenosine in the rabbits, whereas in rats, similar to pigs [5], interstitial adenosine levels do not increase sufficiently during the initial 3 min of occlusion.
4.2 Adenosine subtype receptor activation and cardioprotection
SPT is a non-selective adenosine receptor antagonist which is only five-fold more potent for A1 receptors than for A3 receptors [11]. Consequently, the SPT-induced dose-dependent attenuation of the cardioprotection by IP may therefore have been the result of adenosine A1 as well as A3 antagonism. The cardioprotection by the selective A3 agonist IB-MECA, demonstrates the presence of cardioprotective A3 receptors in the rat heart, similar to the rabbit heart [9,10]. However, SPT in a dose of 2x5 mg/kg did not modify the cardioprotection by IB-MECA in a dose of 33 and 100 µg/kg, which indicates that this low dose of SPT was selective for A1 receptors. Therefore, the attenuation of cardioprotection by IP with the low dose of SPT can be attributed to A1 blockade. In contrast, the high dose of SPT blunted the protection by IB-MECA, indicating that SPT possesses A3 antagonistic properties at this dose. These findings suggest that the abolition of protection by IP with the high dose of SPT may have been caused by combined A1 and A3 blockade. Alternatively, the abolition of the protection by IP by the high dose of SPT may also have been the result of a higher degree of A1 blockade. Consequently, additional studies using the selective A3 antagonist MRS-1191 were pivotal. We observed that at a dose of 3.3 mg/kg MRS-1191 produced a high degree of A3 blockade without any A1 blockade, confirming its reported 28-fold selectivity for A3 over A1 receptors in the rat heart [11]. Single treatment with either MRS-1191 or the A1 selective low dose of SPT attenuated IS limitation by the 15-min CAO by approximately 50%, while the combination of these two agents completely abolished the cardioprotection by IP. These findings indicate that adenosine A1 and A3 receptors both contribute to cardioprotection by the 15-min CAO preconditioning stimulus.
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5 Conclusions and therapeutic implications |
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TopAbstract1 Introduction2 Methods3 Results4 Discussion5 Conclusions and therapeutic...References |
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The present study demonstrates for the first time that adenosine is involved in ischemic preconditioning in rat hearts in vivo but only when the duration of the stimulus is sufficiently long. The study also shows that not only A1 but also A3 receptors contribute to ischemic preconditioning in vivo. It is not yet clear whether A3 receptors also contribute to IP in species other than the rat, in which interstitial adenosine levels may rise to higher levels than in other species, during IP stimuli of >5-min [16]. Since endogenous adenosine has a 10–100 fold higher affinity for A1 receptors over A3 receptors [11], it is possible that in other species the A3 receptor may not contribute to the same extent. Interestingly, the protection by hypoxic preconditioning against hypoxia-induced damage in isolated rabbit cardiomyocytes could only be partially blocked by the adenosine A1 selective antagonist DPCPX, and required a combination of DPCPX with either the adenosine A1/A3 antagonist BWA1433 or with SPT, for complete blockade, suggesting that also in the rabbit heart both adenosine A1 and A3 receptors might contribute to ischemic preconditioning in vivo [17].
Stimulation of A3 receptors on mast cells produces histamine release in rats but not in rabbits or humans [10,11]. Consequently, in the latter species A3 receptor stimulation does not result in hemodynamic alterations [10], contrasting with the bradycardia and hypotension that results from A1 and A2 receptor stimulation, which suggests that A3 receptor agonists are of potential interest for clinical application as cardioprotective agents. However, caution is warranted as Lee and Emala [18] reported that pretreating the kidney with IB-MECA added to the loss of renal function produced by renal ischemia. Although the authors used a ten-fold higher dose of IB-MECA than in the present study, the observation that A3 receptor blockade with MRS-1191 enhanced the protection by IP in the kidney suggests that also A3 receptor stimulation by endogenous adenosine levels during brief renal ischemia exerts a deleterious effect in the kidney. Consequently, systemic treatment of myocardial ischemia with A3 receptor agonists would appear premature.
Time for primary review 28 days.
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Acknowledgements |
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This study was supported by Netherlands Heart Foundation Grants D96.024 (M.A. van den Doel), NHS 95.103, NHS 99.143, and the Established Investigator Stipend 2000D038 (D.J. Duncker).
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