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1 Heart Foundation Research Centre, Griffith University, Southport, QLD 4217, Australia 2 Department of Paediatrics and the Cardiovascular Research Centre, University of Virginia Health Sciences Centre, Charlottesville, VA 22908, USA 3 Department of Biochemistry and Molecular Biology, University of Texas Health Science Centre at Houston, Medical School, Houston, TX 77030, USA
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Abstract |
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(Received 24 August 2006;
accepted after revision 9 November 2006; first published online 10 November 2006)
Corresponding author J. P. Headrick: Heart Foundation Research Centre, Griffith University, Southport, QLD 4217, Australia. Email: j.headrick{at}griffith.edu.au
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Introduction |
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The specific aim of the present study was to test the hypothesis that ischaemic contracture development is not normally influenced by endogenous adenosine, but that pre-ischaemic AR activation is essential in triggering this form of pharmacological protection. To test the hypothesis, we examined the effects of endogenous versus exogenous adenosine on contracture development in hearts from wild-type and genetically modified mice overexpressing (Matherne et al. 1997; Headrick et al. 1998) or lacking (Reichelt et al. 2005) cardiac A1ARs. We additionally assessed relationships between contracture inhibition and postischaemic outcome.
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Methods |
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Investigations conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH publication no. 85-23, revised 1996). Male wild-type C57/Bl6 mice (2–4 months of age, n = 232), transgenic mice (C57/Bl6 background) overexpressing cardiac A1ARs (Matherne et al. 1997; n = 9) and A1AR gene knockout (KO) mice (Reichelt et al. 2005; n = 18) were anaesthetized with 50 mg kg–1 of sodium pentobarbitone administered intraperitoneally. A thoracotomy was performed and hearts rapidly excised into ice-cold Krebs bicarbonate buffer. The aorta was then cannulated and hearts perfused in a Langendorff mode at a pressure of 80 mmHg, as outlined by us in detail previously (Peart & Headrick, 2000; Headrick et al. 2001a,b; Peart et al. 2003). Hearts were perfused with a modified Krebs bicarbonate buffer containing (mM): NaCl, 119; NaHCO3, 22; KCl, 4.7; KH2PO4, 1.2; CaCl2, 2.5; MgCl2, 1.2; EDTA, 0.5; and with either 11 mM glucose or 11 mM glucose plus 2 mM pyruvate as exogenous substrates. Addition of pyruvate delays development of contracture during ischaemia (Flood et al. 2003). The perfusion fluid was saturated with 95% O2 and 5% CO2 at 37°C (yielding a pH of 7.4 and a partial pressure of O2 > 550 mmHg at the aortic cannula), and was continuously filtered via a 0.45 µm in-line filter. The left ventricle was vented with a polyethylene drain to prevent fluid accumulation, and an intraventricular balloon introduced for assessment of contractile function, as previously described (Headrick et al. 2001a). Coronary flow was monitored via an ultrasonic flow-probe in the aortic perfusion line connected to a T106 flowmeter (Transonic Systems Inc., Ithaca, NY, USA). Functional data were recorded at 1 kHz on a four-channel MacLab data acquisition system (ADInstruments, Castle Hill, NSW, Australia).
Ischaemia–reperfusion protocol
After instrumentation, all hearts were introduced into a water-jacketed chamber superfused with warmed buffer at 37°C, ensuring stable temperature throughout the protocols. Following a 15 min stabilization period at intrinsic heart rate, hearts were switched to electrical pacing at 420 beats min–1 and stabilized for a further 15 min. Hearts were excluded from analysis at this time if they met one of the following criteria: (i) left ventricular systolic pressure < 100 mmHg; (ii) coronary flow 
5 ml min–1 (i.e. 
40 ml min–1 g–1); (iii) fluctuating (unstable) contractile function; or (iv) significant arrhythmias (Headrick et al. 2001a). Baseline functional measurements were made before subjecting hearts to 20 min global normothermic ischaemia. In some cases, where relationships between contracture development and postischaemic outcome were assessed, hearts were subsequently reperfused for 45 min (see below). In all hearts, electrical pacing was stopped on induction of ischaemia, and in reperfused hearts it was resumed after 2 min of reperfusion (Headrick et al. 2001a).
Experimental groups
Two series of experiments were performed: in hearts perfused with glucose as sole exogenous substrate and in hearts perfused with glucose plus pyruvate (displaying delayed intrinsic contracture development). In the glucose group, contracture development was monitored in untreated wild-type hearts (n = 14), and in hearts treated with 50 µM adenosine (n = 10), 10 µM 2-chloroadenosine (2-CAD; non-selective AR agonist; n = 9), 50 nM N6-cyclohexyladenosine (CHA) (A1AR specific agonist; n = 10), 150 nM 2-chloro-N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (Cl-IB-MECA) (A3AR specific agonist; n = 10), 20 nM 2[4-(2-carboxyethyl) phenethylamino]-5'-N-methylcarboxamidoadenosine (CGS21680) (A2AAR specific agonist; n = 9), 5 µM erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA) (adenosine deaminase inhibitor; n = 9), 50 µM 8-sulphophenyltheophylline (8-SPT) (non-specific antagonist; n = 10), 150 nM DPCPX (A1AR specific antagonist; n = 9), 50 µM adenosine plus 50 µM 8-SPT (n = 10), or 50 µM adenosine plus 150 nM DPCPX (n = 10). Agonist and antagonist infusions were commenced 10 min prior to ischaemia. To examine temporal requirements of AR activation, we also compared the abilities of 3 (n = 8), 10 (n = 10) or 15 min periods (n = 9) of adenosine pretreatment (50 µM) to limit contracture development. Preliminary experiments confirmed functional AR activation within the first minute of infusion, as evidenced by coronary vasodilatation (A2AAR agonism) and A1AR-mediated bradycardia (data not shown).
A 50 µM exogenous adenosine concentration was chosen for most of the study, based on prior concentration–response data for this model (Headrick et al. 2001b) demonstrating that this exogenous concentration is required to ensure maximal activation of different AR subtypes in this model. This vascular concentration markedly exceeds interstitial levels (which the cardiac ARs are exposed to) achieved during infusion owing to rapid and extensive cellular transport and catabolism of infused adenosine (Kroll et al. 1992; Lasley et al. 1998). We also undertook basic concentration–response analysis in which we assessed and compared the abilities of 0.5 µM (n = 7), 10 µM (n = 8) and 50 µM adenosine (n = 10) to inhibit contracture development in glucose-perfused hearts.
Hearts supplied with glucose plus pyruvate as substrates exhibit an intrinsically prolonged time for ischaemic contracture to develop (Flood et al. 2003), permitting assessment of the roles of AR agonism under conditions of slowed/prolonged contracture development. Responses were monitored in wild-type hearts which were either untreated (n = 10) or treated with 50 µM adenosine (n = 9), 10 µM 2-chloroadenosine (n = 7), 50 µM 8-SPT (n = 9) or 150 nM DPCPX (n = 8).
To further examine the role of endogenous adenosine, we also studied contracture development in hearts from A1AR-deficient mice (Reichelt et al. 2005) that were either untreated (n = 10) or subjected to AR agonism (non-selective) with 10 µM 2-chloroadenosine (n = 8). This analogue was chosen as a more stable agonist (reducing the impact of potential differences in altered adenosine handling/metabolism in wild-type versus gene-modified hearts). Contracture was also studied in hearts overexpressing cardiomyocyte A1ARs (Matherne et al. 1997; n = 9).
In the final experiments, relationships between postischaemic outcomes and contracture development were examined in glucose plus pyruvate perfused hearts subjected to 20 min ischaemia and 45 min reperfusion from the following groups: untreated hearts (n
= 8); hearts treated with 50 µM adenosine (n
= 9); hearts treated with 150 nM Cl-IB-MECA (n
= 8); hearts overexpressing A1ARs (n
= 9); hearts in which A1ARs were absent (n
= 8); and hearts treated with 5 mM of the Ca2+ desensitizer 2,3-butanedione monoxime (BDM) during ischaemia only (n
= 7). This agent (at 
5 mM) inhibits Ca2+-activated cross-bridges without altering Ca2+ transients or ATP levels. We therefore assessed its actions both to test for Ca2+-dependent contracture and to identify the impact of a reduction in ischaemic contracture on postischaemic outcome. In this latter experiment, contractile function was monitored during BDM infusion and ischaemia was immediately induced upon detecting a 5 mmHg fall in systolic force (as the agent exerts a negative inotropic action). The agent was not infused during reperfusion. In addition to monitoring contractile function, coronary venous effluent was collected over the duration of reperfusion in untreated and BDM-treated hearts, and analysed for lactate dehydrogenase (LDH) content (a marker of cell death), as previously described (Headrick et al. 2001a; Peart et al. 2003; Reichelt et al. 2005).
Myocardial energy metabolites
Out of interest, we also assessed the effects of exogenously applied adenosine treatment on myocardial ATP and phosphocreatine (PCr) levels prior to and at the end of the ischaemic insult. Briefly, hearts were untreated or received 50 µM adenosine, and were snap frozen in liquid N2 either immediately prior to ischaemia (n = 8 and 7 for untreated and adenosine treated, respectively) or at the end of 20 min of ischaemia (n = 7 and 8 for untreated and adenosine treated, respectively). Frozen tissue was stored at –80°C until powdered and extracted in perchloric acid, and neutralized extracts analysed for ATP and PCr content via reverse-phase HPLC, as outlined in detail previously (Headrick et al. 1998, 2001b). Tissue metabolite content is expressed as micromoles per gram wet weight.
Statistical analyses
Baseline functional data, time to onset of contracture (TOC; the time for diastolic pressure to reach 20 mmHg), peak contracture (PC; the maximal level of contracture achieved during ischaemia) and postischaemic functional recoveries were compared via one-way ANOVA. Where significant intergroup differences were detected, a Newman–Keuls post hoc test was employed for specific comparisons. Efflux of LDH in untreated and BDM-treated hearts was assessed via Students unpaired t test. Significance was accepted at P < 0.05. All data are presented as means ± S.E.M.
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Results |
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Normoxic contractile function was similar in all groups (Table 1) and not significantly altered by any of the adenosine agonists (despite an insignificant trend to higher pressure development with adenosine). Adenosine, 2-chloroadenosine and EHNA all significantly increased coronary flow. Upon initiation of ischaemia, ventricular pressure development rapidly dissipated, with no detectable systolic force development beyond 2 min. Subsequently, end-diastolic pressure increased (contracture), reaching a peak value (PC) of 80 mmHg after 10 min in untreated glucose-perfused hearts (Fig. 1). The time for pressure to reach 20 mmHg, defined here as time to onset of contracture or TOC (Headrick et al. 2001a,b; Peart et al. 2003; Reichelt et al. 2005), was 4.5 min (Figs 1–3). Perfusion with glucose plus pyruvate delayed and reduced contracture, with TOC prolonged to 8.5 min and PC reduced to 52 mmHg (Fig. 4).
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Effects of adenosine on contracture did not result from changes in ATP or PCr content at the onset of ischaemia (Fig. 5). Neither metabolite was modified by adenosine pretreatment in normoxic tissue. However, ATP (but not PCr) content at the end of ischaemia was moderately but significantly enhanced by adenosine treatment. Adenosinergic impairment of ischaemic contracture is thus associated with preservation of myocardial ATP (Fig. 5).
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To identify effects of endogenous adenosine, we tested the abilities of AR antagonists to modify contracture development (Figs 3 and 4). Neither 8-SPT nor DPCPX modified TOC or PC in the absence of exogenous AR agonists. A similar concentration of DPCPX was previously shown to limit responses to maximally effective levels of AR agonists (Peart & Headrick, 2000) and, as already noted, the antagonists did inhibit responses to exogenous adenosine (Fig. 3). We also assessed contracture development in hearts lacking A1ARs and which were insensitive to AR agonism in terms of contracture inhibition (Fig. 4). Neither rate nor extent of contracture development differed in A1AR KO versus wild-type hearts (Fig. 4).
Importance of AR agonist pretreatment
A possible explanation for lack of effect of endogenously generated adenosine (versus protection with exogenous agonists) is that significant periods of pre-ischaemic AR activation may be necessary to invoke this form of protection. We compared effects of 3, 10 and 15 min periods of pre-ischaemic AR agonism. Data in Fig. 6 reveal that while a 3 min period of adenosine pretreatment fails to modify contracture, longer 10 and 15 min periods of pretreatment result in comparable inhibition of contracture.
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Ischaemic contracture may exaggerate tissue injury and impair postischaemic outcome. We examined the impact of contracture inhibition with BDM on postischaemic outcome, and relationships between contracture and postischaemic outcomes in hearts subjected to adenosinergic interventions (Fig. 7A). Infusion of BDM prior to ischaemia (thus present during the ischaemic episode and washed out during reperfusion) significantly inhibited contracture and resulted in a substantial improvement in postischaemic contractile recovery (Fig. 7). Additionally, BDM reduced postischaemic efflux of LDH (a marker of necrosis) by 40%, from 21 ± 2 to 13 ± 2 i.u. g–1 (P < 0.05).
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Discussion |
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Inhibition of AR-dependent contracture
Largely through the work of Lasley and colleagues it has become clear that A1AR agonism can impair contracture development via Gi-dependent signalling (Lasley et al. 1990; Lasley & Mentzer, 1993b) and modulation of glucose metabolism (Lasley & Mentzer, 1993a). Here we unequivocally confirm that adenosinergic contracture inhibition is entirely A1AR mediated: contracture is insensitive to A2AAR or A3AR agonism (Fig. 3) and only modified by agents targeting A1ARs (an effect mimicked by A1AR overexpression; Figs 3 and 4); selective antagonism of A1ARs blocks the effect of applied adenosine (Fig. 3); and genetic deletion of A1ARs abrogates adenosinergic inhibition of contracture (Fig. 4). Although we cannot directly test the role of A2BARs (owing to lack of selective agonists), findings for A1AR KO and antagonism collectively exclude contributions from this subtype.
Mechanistically, contracture is considered to involve Ca2+-independent stable actin–myosin cross-bridge formation as myocardial [ATP] falls below a critical submillimolar threshold (Altschuld et al. 1985; Allshire et al. 1987; Kihara et al. 1989; Nichols & Lederer, 1990; Ventura-Clapier & Veksler, 1994; Eberli et al. 2000). Glycolytically derived ATP may be uniquely important in delaying this process (Bricknell et al. 1981; Lipasti et al. 1984; Owen et al. 1990; Kingsley et al. 1991; Cross et al. 1994). However, there is evidence of Ca2+-dependent contracture (Hendrikx et al. 1994; Hartmann & Decking, 1999; Sato et al. 1999; Swartz et al. 1999; Hotta et al. 2004), consistent with ischaemic changes in [Ca2+] (Kihara et al. 1989; Camacho et al. 1994; Dekker et al. 1996; Ladilov et al. 2003), and effects of Mg-ATP and Mg-ADP on Ca2+-dependent cross-bridge generation (Ebus et al. 2001; Papp et al. 2002). From the perspective of adenosinergic protection, adenosine and A1ARs inhibit acidosis and Ca2+ overload (Fralix et al. 1993) and preserve cytosolic [ATP] and the free energy of ATP hydrolysis during ischaemia (Fralix et al. 1993; Headrick et al. 1998). These effects will limit both Ca2+- and energy-dependent cross-bridge formation. Our data confirm that exogenous adenosine preserves ischaemic ATP without modifying normoxic ATP or PCr levels (Fig. 5). Other A1AR actions, such as inhibition of catecholamine release (Richardt et al. 1987), could play some role, although the glucose sensitivity of the action of adenosine (Lasley & Mentzer, 1993a) argues for a substrate-/energy-dependent mechanism.
Interestingly, we were able to separate effects of adenosine on rate or rapidity versus extent of contracture in pyruvate-supplemented hearts (Fig. 4). This probably indicates differing mechanisms underlying these two aspects of contracture, in that onset is thought to coincide with failure of glycolytic flux/ATP generation and accumulation of cytosolic [Ca2+] (Bricknell et al. 1981; Lipasti et al. 1984; Owen et al. 1990; Cross et al. 1994; Kingsley et al. 1991), while subsequent development of contracture is governed by the quantity of ATP then available to myosin ATPase (Bricknell et al. 1981; Allshire et al. 1987; Bowers et al. 1992; Cross et al. 1994).
No role for endogenous adenosine in modulating contracture
Although exogenous adenosine may exert A1AR-dependent ‘pharmacological’ inhibition of contracture, this need not reflect the protective function of endogenous adenosine. We have previously shown that recovery from ischaemia correlates with A1AR expression/functionality, increasing with enhanced A1AR expression (Matherne et al. 1997; Headrick et al. 1998) and declining when A1ARs are ablated (Reichelt et al. 2005). We show here that contracture inhibition occurs with as little as 0.5 µM exogenous adenosine (Fig. 2), a concentration that, owing to rapid catabolism and transport, will increase interstitial adenosine to a much lower level. Since interstitial adenosine accumulates above 0.5 µM in the ischaemic heart (Peart & Headrick, 2000), sufficient endogenous agonist must exist to activate protective A1ARs. Nonetheless, our results reveal (paradoxically) that A1AR-dependent contracture inhibition is only evoked by exogenous adenosine or artificially enhanced AR activation and not by locally generated adenosine. Genetic deletion of the A1AR, and both non-selective and A1AR-selective antagonism, all fail to modify the development of intrinsic contracture (Figs 3 and 4).
It can be challenging to identify physiological roles of endogenous autacoids (including adenosine), the levels and activity of which are typically controlled in a negative feedback manner. Receptor antagonism can effectively ‘open’ regulatory loops, exaggerating or amplifying the initiating stimulus. However, while this has been documented for AR responses (Heller et al. 1991; Headrick et al. 1993), it does not explain the lack of effect of AR antagonism here; protection in response to even higher levels of AR activation (i.e. exogenous adenosine) is sensitive to receptor antagonism (Fig. 3). Thus, lesser degrees of AR activation via endogenous adenosine should be more sensitive to antagonism. More conclusively, A1AR deletion also fails to modify contracture development (Fig. 4). We conclude that artificially enhanced levels of A1AR activity delay ischaemic contracture, whereas the response is not evoked by endogenous adenosine.
The chief question arising from these observations is why locally generated adenosine is unable to activate protection, whereas exogenous AR agonism is effective. One possibility relates to the temporal characteristics of AR-coupled protective signalling. Endogenous adenosine is predicted to maximally activate ARs after 10 min of ischaemia, based on interstitial accumulation in ischaemic hearts from mice (Peart & Headrick, 2000) and other species (Harrison et al. 1998; Mortimer et al. 2000). Compounding delayed accumulation (and thus AR agonism), protective kinase activation by adenosine is phasic in cardiac and non-cardiac myocytes, peaking at 5–10 min and then waning (Liu & Hofmann, 2003; Germack et al. 2004; Shen et al. 2005). Similarly, functional effects of mitochondrial KATP channels (protective channels targeted by ARs and associated kinase cascades) may require 5 min to evolve and plateau, based on flavoprotein fluorescence measures of mitochondrial redox state (Liu et al. 1998). Summation of temporal delays may retard expression of protection by 10 min or more, effectively negating any ability of endogenous adenosine to limit contracture within the initial minutes of ischaemia (Fig. 1). This is supported by our observation that prolonged (10–15 min) adenosine pretreatment is required to trigger contracture inhibition, whereas a brief 3 min period of pretreatment is ineffective (Fig. 6). This is not a trivial finding, since it not only provides an explanation for the inability of endogenous adenosine to immediately protect ischaemic myocardium but may also explain a requirement for prolonged ischaemic episodes to trigger adenosine-dependent preconditioning (Liem et al. 2001). Although the latter has been attributed to recruitment of less sensitive AR subtypes (e.g. A3ARs), it is equally plausible that this reflects temporal delays in mediation of AR-dependent cardioprotection.
An additional explanation for differing effects of exogenous versus endogenous adenosine involves their actions on ischaemic energy metabolism/ATP. Exogenous adenosine (Fralix et al. 1993) and A1AR overexpression (Headrick et al. 1998) both improve ischaemic energy state and ATP levels, an effect predicted to limit contracture development. Indeed, we confirm that adenosine does enhance ischaemic (but not pre-ischaemic) [ATP] (Fig. 5). In contrast, blockade of endogenous adenosine does not appear to modify ischaemic changes in energy state/ATP (Angello et al. 1991). This inability of endogenous adenosine to modify ischaemic energy metabolism may also reflect temporal delays in cardioprotection. Either way, the ability of exogenous but not endogenous adenosine to improve energy state is internally consistent with the ability of exogenous but not endogenous adenosine to inhibit contracture.
Impact of delayed contracture on postischaemic outcomes and cardioprotection
Whether rapidity or extent of contracture development is important in modifying postischaemic outcome remains unclear. Ischaemic contracture may exaggerate ATP depletion and Ca2+ overload (Allshire et al. 1987) and inhibit ATP regeneration on reperfusion (Lipasti et al. 1985). Prior studies indicate that the severity (Tani et al. 1996; Torrance et al. 2000) and longevity (Stern et al. 1985) of contracture impact on postischaemic recovery. Cross et al. (1994) documented marked improvements in postischaemic outcome when contracture was avoided, irrespective of ischaemic duration. Nonetheless, contracture and postischaemic outcome can be dissociated under specific conditions, including ischaemic preconditioning (Kolocassides et al. 1996). Our data show that adenosinergic improvements in postischaemic recovery can occur independently of changes in contracture, in that A1AR deletion, A3AR agonism and non-selective AR agonism in the absence of A1ARs all modify postischaemic recoveries without changing ischaemic contracture (Fig. 7). Furthermore, cardioprotection via endogenous adenosine is independent of changes in contracture development (Figs 3 and 4). Nonetheless, these distinctions do not preclude some dependence of postischaemic outcome on contracture; we find that when contracture is delayed, be it with exogenous agonists, enhanced adenosine levels or A1AR overexpression, postischaemic outcomes are uniformly improved (Fig. 7A). A more direct test of this relationship was made with ischaemic BDM treatment, selectively limiting contractile effects of Ca2+ during but not following ischaemia. The effects of BDM (Fig. 7) support at least some Ca2+ dependence of contracture, consistent with earlier findings of Tani et al. (1996) in rats. Importantly, BDM also limited cell death and improved contractile recovery during reperfusion (Fig. 7). Thus, selective inhibition of contracture does influence postischaemic outcomes.
We observed a more consistent relationship between postischaemic outcome and onset versus peak levels of contracture (Fig. 7B). Since onset is dictated by cessation of glycolysis and ATP generation (Bricknell et al. 1981; Lipasti et al. 1984; Owen et al. 1990; Kingsley et al. 1991; Cross et al. 1994), this parameter directly reflects the ischaemic period over which hearts are critically de-energized, and so accumulate H+ and Na+. As outlined by Cross et al. (1994), when glycolysis is not maintained greater acidosis evolves, exaggerating injury during reperfusion through enhancement of Na+–H+ (and thus Na+–Ca2+) exchange. Thus, rapidity of contracture onset seems more relevant to injury than the actual extent of contracture, the latter being determined by the quantity of ATP available to myosin ATPase. This is in agreement with prior correlations between the period of contracture and degree of postischaemic recovery (Stern et al. 1985).
Conclusions
The present findings reveal that ischaemic contracture development is not normally influenced by endogenously generated adenosine. Contracture inhibition only occurs when AR activity is artificially augmented for a significant period prior to ischaemic insult, using agonist pretreatment, pre-ischaemic inhibition of adenosine catabolism or enhancement of cardiac A1AR density. Inability of endogenous adenosine to modify contracture may reflect the rapidity of the contracture process versus the finite time necessary for expression of AR-mediated cardioprotection. Our data unequivocally confirm A1AR dependence of contracture inhibition with exogenous adenosine. Finally, although contracture inhibition plays no role in cardioprotection mediated by endogenous adenosine, reductions in contracture development with exogenous adenosinergic stimuli are nonetheless likely to contribute to improved myocardial outcomes.
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References |
|---|
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Altschuld RA, Wenger WC, Lamka KG, Kindig OR, Capen CC, Mizuhira V, Vander Heide RS & Brierley GP (1985). Structural and functional properties of adult rat heart myocytes lysed with digitonin. J Biol Chem 260, 14325–14334.
Angello DA, Headrick JP, Coddington NM & Berne RM (1991). Adenosine antagonism decreases metabolic but not functional recovery from ischemia. Am J Physiol Heart Circ Physiol 260, H193–H200.
Bowers KC, Allshire AP & Cobbold PH (1992). Bioluminescent measurement in single cardiomyocytes of sudden cytosolic ATP depletion coincident with rigor. J Mol Cell Cardiol 24, 213–218.[Medline]
Bricknell OL, Dariess PS & Opie LH (1981). A relationship between adenosine triphosphate, glycolysis and ischaemic contracture in the isolated rat heart. J Mol Cell Cardiol 13, 941–945.[CrossRef][Medline]
Camacho SA, Brandes R, Figueredo VM & Weiner MW (1994). Ca2+ transient decline and myocardial relaxation are slowed during low flow ischemia in rat hearts. J Clin Invest 93, 951–957.[Medline]
Cross HR, Opie LH, Radda GK & Clarke K (1994). Is a high glycogen content beneficial or detrimental to the ischemic rat heart? A controversy resolved. Circ Res 78, 482–491.
Dekker LR, Fiolet JW, VanBavel E, Coronel R, Opthof T, Spaan JA & Janse MJ (1996). Intracellular Ca2+, intercellular electrical coupling, and mechanical activity in ischemic rabbit papillary muscle. Effects of preconditioning and metabolic blockade. Circ Res 79, 237–246.
Eberli FR, Stromer H, Ferrell MA, Varma N, Morgan JP, Neubauer S & Apstein CS (2000). Lack of direct role for calcium in ischemic diastolic dysfunction in isolated hearts. Circulation 102, 2643–2649.
Ebus JP, Papp Z, Zaremba R & Stienen GJ (2001). Effects of MgATP on ATP utilization and force under normal and simulated ischaemic conditions in rat cardiac trabeculae. Pflugers Arch 443, 102–111.[CrossRef][Medline]
Ely SW & Berne RM (1992). Protective effects of adenosine in myocardial ischemia. Circulation 85, 893–904.
Ely SW, Mentzer RM Jr, Lasley RD, Lee BK & Berne RM (1985). Functional and metabolic evidence of enhanced myocardial tolerance to ischemia and reperfusion with adenosine. J Thorac Cardiovasc Surg 90, 549–556.[Abstract]
Finegan BA, Lopaschuk GD, Gandhi M & Clanachan AS (1996). Inhibition of glycolysis and enhanced mechanical function of working rat hearts as a result of adenosine A1 receptor stimulation during reperfusion following ischaemia. Br J Pharmacol 118, 355–363.[Medline]
Flood A, Hack BD & Headrick JP (2003). Pyruvate-dependent preconditioning and cardioprotection in murine myocardium. Clin Exp Pharmacol Physiol 30, 145–152.[CrossRef][Medline]
Fralix TA, Murphy E, London RE & Steenbergen C (1993). Protective effects of adenosine in the perfused rat heart: changes in metabolism and intracellular ion homeostasis. Am J Physiol Cell Physiol 264, C986–C994.
Germack R, Griffin M & Dickenson JM (2004). Activation of protein kinase B by adenosine A1 and A3 receptors in newborn rat cardiomyocytes. J Mol Cell Cardiol 37, 989–999.[CrossRef][Medline]
Harrison GJ, Willis RJ & Headrick JP (1998). Extracellular adenosine levels and cellular energy metabolism in ischemically preconditioned rat heart. Cardiovasc Res 40, 74–87.
Hartmann M & Decking UKM (1999). Blocking Na+-H+ exchange by cariporide reduces Na+-overload in ischemia and is cardioprotective. J Mol Cell Cardiol 31, 1985–1995.[CrossRef][Medline]
Headrick JP, Ely SW, Matherne GP & Berne RM (1993). Myocardial adenosine, flow, and metabolism during adenosine antagonism and adrenergic stimulation. Am J Physiol Heart Circ Physiol 264, H61–H70.
Headrick JP, Gauthier NS, Berr SS, Morrison RR & Matherne GP (1998). Transgenic A1 adenosine receptor overexpression markedly improves myocardial energy state during ischemia-reperfusion. J Mol Cell Cardiol 30, 1059–1064.[CrossRef][Medline]
Headrick JP, Hack B & Ashton KJ (2003). Acute adenosinergic cardioprotection in the ischemic reperfused heart. Am J Physiol Heart Circ Physiol 285, H1797–H1819.
Headrick JP, Peart J, Hack B, Flood A & Matherne GP (2001a). Functional properties and responses to ischaemia-reperfusion in Langendorff perfused mouse heart. Exp Physiol 86, 703–716.
Headrick JP, Peart J, Hack B, Garnham B & Matherne GP (2001b). 5'-Adenosine monophosphate and adenosine metabolism, and adenosine responses in mouse, rat and guinea pig heart. Comp Biochem Physiol A Mol Integr Physiol 130, 615–631.[CrossRef][Medline]
Heller LJ, Dole WP & Mohrman DE (1991). Adenosine receptor blockade enhances isoproterenol-induced increases in cardiac interstitial adenosine. J Mol Cell Cardiol 23, 887–898.[CrossRef][Medline]
Hendrikx M, Mubagwa K, Verdonck F, Overloop K, Van Hecke P, Vanstapel F, Van Lommel A, Verbeken E, Lauweryns J & Flameng W (1994). New Na+-H+ exchange inhibitor HOE 694 improves postischemic function and high-energy phosphate re-synthesis and reduces Ca2+ overload in isolated perfused rabbit heart. Circulation 89, 2787–2798.
Hotta Y, Nishimaki H, Takeo T, Itoh G, Yajima M, Otsuka-Murakami H, Ishikawa N, Kawai N, Huang L, Yamada K, Yamamoto S, Matsui K & Ohashi N (2004). Differences in the effects of Na+-H+ exchange inhibitors on cardiac function and apoptosis in guinea-pig ischemia-reperfused hearts. Eur J Pharmacol 503, 109–122.[CrossRef][Medline]
Janier MF, Vanoverschelde JL & Bergmann SR (1993). Adenosine protects ischemic and reperfused myocardium by receptor mediated mechanisms. Am J Physiol Heart Circ Physiol 264, H163–H170.
Kihara Y, Grossman W & Morgan JP (1989). Direct measurement of changes in [Ca2+]i during hypoxia, ischemia, and reperfusion of the intact mammalian heart. Circ Res 65, 1029–1044.
Kingsley PB, Sako EY, Yang MQ, Zimmer SD, Ugurbil K, Foker JE & From AH (1991). Ischemic contracture begins when anaerobic glycolysis stops: a 31P-NMR study of isolated rat hearts. Am J Physiol Heart Circ Physiol 261, H469–H478.
Kolocassides KG, Seymour AM, Galinanes M & Hearse DJ (1996). Paradoxical effect of ischemic preconditioning on ischemic contracture? NMR studies of energy metabolism and intracellular pH in the rat heart. J Mol Cell Cardiol 28, 1045–1057.[CrossRef][Medline]
Kroll K, Deussen A & Sweet IR (1992). Comprehensive model of transport and metabolism of adenosine and S-adenosylhomocysteine in the guinea pig heart. Circ Res 71, 590–604.
Ladilov Y, Efe O, Schafer C, Rother B, Kasseckert S, Abdallah Y, Meuter K, Dieter Schluter K & Piper HM (2003). Reoxygenation-induced rigor-type contracture. J Mol Cell Cardiol 35, 1481–1490.[CrossRef][Medline]
Lasley RD, Hegge JO, Noble MA & Mentzer RM Jr (1998). Comparison of interstitial fluid and coronary venous adenosine levels in in vivo porcine myocardium. J Mol Cell Cardiol 30, 1137–1147.[CrossRef][Medline]
Lasley RD & Mentzer RM Jr (1993a). Pertussis toxin blocks adenosine A1 receptor mediated protection of the ischemic rat heart. J Mol Cell Cardiol 25, 815–821.[CrossRef][Medline]
Lasley RD & Mentzer RM Jr (1993b). Adenosine increases lactate release and delays onset of contracture during global low flow ischaemia. Cardiovasc Res 27, 96–101.
Lasley RD, Rhee JW, Van Wylen DG & Mentzer RM Jr (1990). Adenosine A1 receptor mediated protection of the globally ischemic isolated rat heart. J Mol Cell Cardiol 22, 39–47.[Medline]
Liem DA, van den Doel MA, de Zeeuw S, Verdouw PD & Duncker DJ (2001). Role of adenosine in ischemic preconditioning in rats depends critically on the duration of the stimulus and involves both A1 and A3 receptors. Cardiovasc Res 51, 701–708.
Lipasti JA, Alanen KA, Eskola JU & Nevalainen TJ (1985). Ischaemic contracture in isolated rat heart: reversible or irreversible myocardial injury? Exp Pathol 28, 89–95.[Medline]
Lipasti JA, Nevalainen TJ, Alanen KA & Tolvanen MA (1984). Anaerobic glycolysis and the development of ischaemic contracture in isolated rat heart. Cardiovasc Res 18, 145–148.[Medline]
Liu Q & Hofmann PA (2003). Modulation of protein phosphatase 2a by adenosine A1 receptors in cardiomyocytes: role for p38 MAPK. Am J Physiol Heart Circ Physiol 285, H97–H103.
Liu Y, Sato T, O'Rourke B & Marban E (1998). Mitochondrial ATP-dependent potassium channels: novel effectors of cardioprotection? Circulation 97, 2463–2469.
Matherne GP, Linden J, Byford AM, Gauthier NS & Headrick JP (1997). Transgenic A1 adenosine receptor over-expression increases myocardial resistance to ischemia. Proc Nat Acad Sci U S A 94, 6541–6546.
Mortimer SL, Kodl CT, Reiling CR & Van Wylen DGL (2000). Preconditioning-induced attenuation of purine metabolite accumulation during ischemia: memory and multiple cycles. Basic Res Cardiol 95, 119–126.[CrossRef][Medline]
Mubagwa K & Flameng W (2001). Adenosine, adenosine receptors and myocardial protection: an updated overview. Cardiovasc Res 52, 25–39.
Nichols CG & Lederer WJ (1990). The role of ATP in energy-deprivation contractures in unloaded rat ventricular myocytes. Can J Physiol Pharmacol 68, 183–194.[Medline]
Owen P, Dennis S & Opie LH (1990). Glucose flux rate regulates onset of ischemic contracture in globally underperfused rat hearts. Circ Res 66, 344–354.
Papp Z, Szabo A, Barends JP & Stienen GJ (2002). The mechanism of the force enhancement by MgADP under simulated ischaemic conditions in rat cardiac myocytes. J Physiol 543, 177–189.
Peart J & Headrick JP (2000). Intrinsic A1 adenosine receptor activation during ischemia or reperfusion improves recovery in mouse hearts. Am J Physiol Heart Circ Physiol 279, H2166–H2175.
Peart J, Willems L & Headrick JP (2003). Receptor and non-receptor dependent mechanisms of cardioprotection with adenosine. Am J Physiol Heart Circ Physiol 284, H519–H527.
Reichelt ME, Willems L, Molina JG, Sun CX, Noble JC, Ashton KJ, Schnermann J, Blackburn MR & Headrick JP (2005). Genetic deletion of the A1 adenosine receptor limits myocardial ischemic tolerance. Circ Res 96, 363–367.
Richardt G, Waas W, Kranzhofer R, Mayer E & Schomig A (1987). Adenosine inhibits exocytotic release of endogenous noradrenaline in rat heart: a protective mechanism in early myocardial ischemia. Circ Res 61, 117–123.
Sato R, Yamazaki J & Nagao T (1999). Temporal differences in actions of calcium channel blockers on K+ accumulation, cardiac function, and high-energy phosphate levels in ischemic guinea pig hearts. J Pharmacol Exp Ther 289, 831–839.
Shen J, Halenda SP, Sturek M & Wilden PA (2005). Cell-signaling evidence for adenosine stimulation of coronary smooth muscle proliferation via the A1 adenosine receptor. Circ Res 97, 574–582.
Stern MD, Chien AM, Capogrossi MC, Pelto DJ & Lakatta EG (1985). Direct observation of the ‘oxygen paradox’ in single rat ventricular myocytes. Circ Res 56, 899–903.
Swartz DR, Zhang D & Yancey KW (1999). Cross bridge-dependent activation of contraction in cardiac myofibrils at low pH. Am J Physiol Heart Circ Physiol 276, H1460–H1467.
Tani M, Hasegawa H, Suganuma Y, Shinmura K, Kayashi Y & Nakamura Y (1996). Protection of ischemic myocardium by inhibition of contracture in isolated rat heart. Am J Physiol Heart Circ Physiol 271, H2515–H2519.
Torrance SM, Belanger MP, Wallen WJ & Wittnich C (2000). Metabolic and functional response of neonatal pig hearts to the development of ischemic contracture: is recovery possible? Pediatr Res 48, 191–199.[Medline]
Ventura-Clapier R & Veksler V (1994). Myocardial ischemic contracture. Metabolites affect rigor tension development and stiffness. Circ Res 74, 920–929.
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P < 0.05 versus adenosine-treated hearts in the absence of antagonist.
