Cardiovascular Research

Cardiovascular Research 2000 45(1):134-140; doi:10.1016/S0008-6363(99)00312-0
© 2000 by European Society of Cardiology

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Copyright © 2000, European Society of Cardiology

Adenosine and preconditioning in the rat heart

Charles E. Ganote and Stephen C. Armstrong^*

Veterans Affairs Medical Center and Department of Pathology, James H. Quillen College of Medicine, P.O. Box 70568, East Tennessee State University, Tennessee, TN 37614, USA

^* Corresponding author. Tel.: +1-423-439-6210; fax: +1-423-439-4195

KEYWORDS Adenosine; Arrhythmia (mechanisms); Conractile function; Ischemia; Preconditioning; Reperfusion

	1 Introduction

Top 1 Introduction 2 Functional recovery versus... 3 Adenosine protection 4 Effects of more... 5 Conflicting studies 6 Isolated cardiomyocyte studies 7 Species-dependent A3-receptor... 8 A3-receptor role in... 9 Conclusion References

 
The report by Cave et al. [21] was a landmark paper which demonstrated that functional recovery protection by ischemic preconditioning (IPC) is not mediated by adenosine in the globally ischemic rat heart. This report raised several issues in the field of preconditioning. (1) It was enigmatic in that recent studies had demonstrated a predominant role of adenosine-receptors in preconditioning in the rabbit and dog so that the inability of adenosine to precondition in the rat implied that species differences might exist in the receptor pathways that lead to initiation of preconditioning. (2) Since rat cardiomyocyte metabolism preferentially relies upon exogenous glucose to support glycolysis, whereas the rabbit, dog, pig and man are more dependent upon endogenous glycogen, this report opened the possibility that species-dependent metabolic differences could also be involved in the mechanisms of IPC. (3) Since adenosine did not appear to precondition the rat, emphasis was placed on multiple G-protein coupled receptors that can induce preconditioning, e.g., ₁-adrenergic-receptors in the rat [1], and on focused research on postreceptor, downstream events in the search for the ultimate mediators of protection. (4) Finally, the manuscript focused debate on the relationships between the mechanisms of preconditioning as assessed by functional recovery (stunning), reductions in arrythmias or ischemic cell death (infarction).

	2 Functional recovery versus cell death as end-points

Top 1 Introduction 2 Functional recovery versus... 3 Adenosine protection 4 Effects of more... 5 Conflicting studies 6 Isolated cardiomyocyte studies 7 Species-dependent A3-receptor... 8 A3-receptor role in... 9 Conclusion References

 
Aortic flow during reperfusion is a sensitive end-point commonly used to assess postischemic functional recovery. Postischemic functional recovery is influenced by multiple parameters including: (1) degree of stunning during ischemia; (2) rate of anaerobic glycolysis; (3) ability to recover oxidative respiration, intracellular pH and ionic equilibrium; and (4) degree of diastolic contracture and vascular integrity at onset of reperfusion. Increased diastolic pressures subsequent to ischemic contracture reduce subendocardial perfusion such that zones of no-reflow may occur upon reperfusion. These subendocardial zones of no-reflow are a perfused heart artifact due to increased vascular resistance subsequent to global ischemia and contracture. Without reflow contracture cannot be reversed and continued ischemia results in irreversible cardiomyocyte injury. In perfused hearts zonal no-reflow precedes irreversible cardiomyocyte injury. In perfused hearts irreversible injury is not confined to the endocardial zone, and develops only after prolonged ischemia (45 min coronary artery occlusion [2] or 60–90 min sustained substrate-free anoxic perfusion [3] in the rat). Reperfusion following irreversible injury in both perfused hearts and hearts in situ results in abrupt oxygen induced enzyme release and contraction band necrosis. In perfused hearts mediators that improve subendocardial reflow may improve functional recovery and prevent continuing ischemia leading to cell death without being directly related to events that mediate infarct size reduction in the in situ animal heart. The dichotomy of the two end-points of cell death and function is emphasized by reports that IPC in rabbits protects from cell death and necrosis, but does not improve functional recovery [4,5].

	3 Adenosine protection

Top 1 Introduction 2 Functional recovery versus... 3 Adenosine protection 4 Effects of more... 5 Conflicting studies 6 Isolated cardiomyocyte studies 7 Species-dependent A3-receptor... 8 A3-receptor role in... 9 Conclusion References

 
Adenosine A₁-receptors are widely distributed and have a diversity of functions [6] which include, in the rat, the cardioprotective effects of: stimulation of glucose transport, acceleration of glycolysis, increased lactate production, and enhanced ATP production with lengthing of time to ischemic contracture [7–12]. In a working, low flow ischemia model, pretreatment with adenosine increased the degree of functional recovery due to decreased glycolysis and lactate accumulation during ischemia [13]. These metabolic responses are consistent with antiadrenergic responses to adenosine [14,15]. In a perfused rat heart model, adenosine infusion immediately prior to aortic cross-clamping caused slowing of ischemic contracture and reductions in glycolytic rate, ATP depletion, lactate accumulation, acidosis and accumulation of calcium, with resultant improved functional recovery [16]. The delay of glycolysis by adenosine was attenuated with prolonged ischemia, such that the effects of adenosine during early ischemia may not be evident during severe, sustained ischemia and irreversible injury. Divergent results exist concerning the role of adenosine on glycolysis, however protection by postischemic function recovery clearly correlates with reduced acidosis and ATP depletion. In contrast, IPC in rat hearts shows either no [17] or an inverse [18,19] correlation between ATP depletion/ischemic contracture and protection assessed either as infarct size reduction or functional recovery. IPC of rat hearts attenuated glycogenolysis, stimulated glucose utilization and reduced lactate and acidosis during subsequent ischemia [20]. Thus, enhancement of functional recovery following IPC and adenosine-receptor activation are possibly due to a reduction in acidosis or diastolic contracture or improved endocardial reflow.

In contrast to adenosine pretreatment protocols, Cave et al. found that 10–100 µM adenosine, infused for 5 min followed by a 5 min washout was not protective [21]. Protection against infarction in intact rats by IPC was not blocked by the A₁-receptor antagonist, 8-sulfophenyl theophylline (SPT) [22]. Although infused intravascular adenosine is known to equilibrate to five- to tenfold lower interstitial adenosine levels, brief infusions may not allow equilibrium to be reached, so that the actual interstitial adenosine level achieved by Cave et al. is uncertain. As a control, 10 µM SPT was found to block the negative chronotropic effect of a bolus adenosine injection, providing evidence of A₁-receptor antagonism. However, a bolus injection would not result in equilibration across the endothelial vascular barrier, so that only low interstitial adenosine levels were likely achieved, that allowed SPT blockade of A₁-receptor mediated negative chronotropism (Fig, 1). Although SPT did not block the protection induced by IPC the validity of the assumption that adenosine-receptors were actually blocked by SPT is not substantiated by critical analysis of the experimental protocols. Interstitial adenosine determined by microdialysis during 6 min ischemia ranges from 0.25 to 6.8 µM in the rat and 0.33 to 1.98 µM in the rabbit. [23]. Microdialysis may well overestimate baseline interstitial adenosine in that normoxic values exceeding 100–200 nM would result in high occupancy of both rat A₁-receptors with a K_i of 1–20 nM and rabbit receptors with a K_d of 28 nM (Fig. 1). A microdialysis probe measures 300 µm in diameter and compresses adjacent myocardium [24] and potentially could create a zone of partial ischemia surrounding the probe, accounting for high control adenosine levels. Estimates of elevated adenosine levels within ischemic myocardium, however, are possibly influenced by a narrow zone of compressed tissue. Interstitial adenosine levels in rats and rabbits agree with estimates in the dog heart during regional ischemia which peak near 3 µM after 20 min ischemia in virgin hearts and 1.5–2 µM in preconditioned hearts [25]. The K_i of SPT for A₁ in rats is about 2.6 µM; A₂, 15.3 µM and A₃, 10 µM and in rabbits A₁, 0.43 µM and A₃, 37.8 µM [26]. Thus with an assumed interstitial concentration of 10 µM adenosine and receptor binding affinities for adenosine in rats of A₁, 10 nM; and A₃, >1 µM and in rabbits A₁, 28 mM; A₃, 746 nM [27], 10 µM SPT would block adenosine binding to rabbit but not rat A₁-receptors. Doses of SPT exceeding 100 µM would be required to block rat A₁-receptors at the 10 µM concentrations of adenosine estimated to occur during the induction of IPC (Fig. 1).

View larger version (27K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 Graphs depicting percent occupancy of the adenosine A1-receptor versus concentration of adenosine calculated assuming a dissociation constant of adenosine (Kd) of 10 nM in the rat [65] and 28 nM in the rabbit [26]. The curve depicted by the dashed line represents percent receptor occupancy of the receptor in the absence of adenosine antagonists and is obtained by setting the receptor number (Bmax) to a value of 100 according to the formula The solid lines represent calculated percent adenosine A1-receptor occupancy in the presence of the indicated concentrations of the antagonists 8-sulfophenyl theophylline (SPT) assuming a Kd for the adenosine A1-receptor in the rat of 2.6 µM (value given by supplier, RBI Research Biochemicals International 1997–1998 Catalogue) and the rabbit of 430 nM [26]; 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, PD-116,948) with a Kd of 0.69 nM (RBI catalogue); BW1433 with a Kd of 3 nM [26], according to the formula: with Bmax set to 100. The vertical dashed lines at 10 µM adenosine in the rat and 4 µM adenosine in the rabbit indicate interstitial adenosine concentrations determined by microdialysis after 6 min ischemia [27].

 

	4 Effects of more selective A1 antagonists

Top 1 Introduction 2 Functional recovery versus... 3 Adenosine protection 4 Effects of more... 5 Conflicting studies 6 Isolated cardiomyocyte studies 7 Species-dependent A3-receptor... 8 A3-receptor role in... 9 Conclusion References

 
The conclusion that adenosine does not precondition the rat was supported by the observation that a transient 5 min infusion of 50 µM adenosine followed by a 5 min washout depressed rather than improved postischemic recovery [28] and that the selective A₁ antagonists BW1433U [28] and 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) [29] do not block preconditioning effects on functional recovery. Since the binding affinity of DPCPX for rat A₁-receptors is 0.69 nM; A₂, 502 nM and A₃, 49 µM, so that the 5 µM concentration of DPCPX used was sufficient to block adenosine-receptors, even at interstitial adenosine concentrations of 10 µM (Fig. 1). These studies using DPCPX confirm that the effect of IPC on functional recovery in the rat are not blocked by adenosine A₁-selective-receptor antagonists. However, a possible dichotomy between adenosine and IPC protection was evidenced by a study in which IPC was induced in perfused rat hearts in the presence of three adenosine antagonists (10 µM BW1433, or 5 µM DPCPX and PD-116 948) [30]. BW1433 and PD-116 948 blocked glucose uptake, while DPCPX did not. Blockade of glucose accelerated ATP depletion accounted for the apparent ability of BW1433 and PD-116 948 to block ischemic induced recovery of function, although neither drug blocked IPC induced reduction of infarct size. DPCPX did not block hexose uptake, recovery of postischemic function or reduction in infarct size. The high concentrations of drugs used assured total adenosine-receptor blockade, suggesting that some of the protective effects of A₁-receptor activation on functional recovery in rats are indeed related to glucose metabolism, but protection in the presence of BW1433 or PD-116 948 excluded the requirement of adenosine-receptor activation or enhanced glucose metabolism for the reduction of infarct size protection by IPC.

	5 Conflicting studies

Top 1 Introduction 2 Functional recovery versus... 3 Adenosine protection 4 Effects of more... 5 Conflicting studies 6 Isolated cardiomyocyte studies 7 Species-dependent A3-receptor... 8 A3-receptor role in... 9 Conclusion References

 
Low concentrations of 8-SPT (0.5–1 µM) reduced the beneficial effects of hypoxic preconditioning on functional recovery but did not reverse the reduction of enzyme release [31]. The dose of SPT used was however, incorrectly based on the assumption of a binding affinity of SPT for the A₁-receptor of 0.2–0.5 µM (a value from cultured chick myocytes [32]), rather than the actual 2.6 µM binding affinity of SPT for adenosine A₁-receptors in the rat. Notably, higher (1–10 µM) concentrations of SPT increased coronary resistance. It was concluded that while adenosine-receptors may be needed to mediate the protective effects of hypoxic preconditioning on functional recovery, they may not play a primary role in reduction of cellular injury. The assumption that protection seen was solely related to preconditioning can, however, be questioned on the basis that the perfusion protocol utilized a 5 min hypoxic interval immediately superseded by global ischemia with no intervening normoxic period of perfusion. Thus, these hypoxic hearts were exposed to adenosine immediately prior to onset of ischemia, reproducing more an adenosine preincubation protection protocol than a preconditioning protocol. In these experiments low hypoxic interstitial adenosine concentrations can be assumed since perfusate flow would wash out metabolic end-products, and otherwise the low (0.5–1 µM) concentrations of SPT used should not have been effective in producing adenosine A₁-receptor blockade (Fig. 1).

In perfused rat and rabbit hearts, 50 µM of SPT blocked improved functional recovery and recovery of coronary flow following preconditioning by 6 min global ischemia or 5 mM cyanide minus substrate, followed by 10 min normal reperfusion prior to 30 min global ischemia [23]. Protection was also achieved by 0.5 µM N⁶-cyclohexyladenosine (CHA), inferring that infusion of an adenosine A₁ agonist does precondition rat and rabbit. However, this conclusion rested on the unproven assumptions that 50 µM SPT blocked rat A₁-receptors at the 10 µM levels of adenosine measured during ischemia, and that the protection from CHA was identical to that of preconditioning stimuli. This may not have be the case, since the time to ischemic contracture was increased and end-diastolic pressure at the time of reperfusion was reduced in CHA-treated hearts so that coronary flow at reperfusion correlated with recovery, effects consistent with A₁ mediated metabolic protection [10,33]. The adenosine-receptor agonist N⁶-cyclopentyladenosine provided protection from hydrogen peroxide induced contractile dysfunction, but only in the presence of exogenous glucose [34]. DPCPX blocked this A₁-receptor mediated component of postischemic functional recovery protection, but did not block IPC protection. In rats, brief ischemia increases interstitial adenosine to levels sufficient to saturate A₁-receptors, and to protect functional recovery [35], however, effective IPC protection against necrosis usually requires two to four cycles of transient ischemia. A single cycle of ischemia may therefore provide sufficient adenosine-receptor stimulation to improve recovery of endocardial flow and postischemic function but not enough activation for induction of IPC to reduce infarct size. The studies suggesting a role for adenosine-receptors in mediating IPC in the rat can therefore be considered inconclusive because the IPC protocols did not unequivocally distinguish adenosine mediated protection from IPC.

	6 Isolated cardiomyocyte studies

Top 1 Introduction 2 Functional recovery versus... 3 Adenosine protection 4 Effects of more... 5 Conflicting studies 6 Isolated cardiomyocyte studies 7 Species-dependent A3-receptor... 8 A3-receptor role in... 9 Conclusion References

 
In isolated rat cardiomyocytes, adenosine and the adenosine A₁ agonist CCPA afforded a small but significant delay in the onset of ischemic osmotic fragility, which was related to a decrease in the time to ischemic contracture (TIC). This protection required exogenous glucose [36]. Neither CCPA nor adenosine protected rat cardiomyocytes in vitro. In contrast, rabbit cardiomyocytes under the same in vitro conditions used in the rat studies were preconditioned by adenosine-receptor activation and protection occurred in the absence of a reduction of TIC [37]. Rabbit cardiomyocyte protection was maintained even in the presence of glycolytic inhibition with iodoacetic acid indicating that protection was independent of glycolysis [38]. Although the preconditioning protocol in the rat utilized preincubation with adenosine or the A₁ agonist CCPA, it was subsequently confirmed using rabbit cardiomyocytes that an intervening drug-free interval is not necessary to invoke preconditioning in vitro [37]. The ability of adenosine-receptor activation to mimic IPC and of adenosine antagonists to block IPC protection in intact hearts of the rabbit, but not the rat, has thus been confirmed in vitro.

	7 Species-dependent A3-receptor differences

Top 1 Introduction 2 Functional recovery versus... 3 Adenosine protection 4 Effects of more... 5 Conflicting studies 6 Isolated cardiomyocyte studies 7 Species-dependent A3-receptor... 8 A3-receptor role in... 9 Conclusion References

 
In contrast to cross-species similarities of the A₁-receptor, ligand affinities of the A₃-receptor show striking species variation. Relative affinities of the adenosine antagonist BW1433 for the A₃-receptor, range from 15–24 µM in the rat and rabbit to 0.05–0.02 in man and sheep. Relative affinities of DPCPX for the A₃-receptor range between 5 µM in the rat and rabbit to 50 µM in the sheep and 0.76 in man [39]. In man the receptor affinities of the antagonist BW1433 are: A₁, 15 nM; A₂, 769nM; A₃, 21 nM [40]. In rabbits the affinity of BW1433 for A₁ is 1–3 nM and for A₃-receptors 746 nM [27]. Thus BW1433 is nonselective for A₁/A₃ in some species, while in the rabbit and man it is a highly selective A₁ antagonist.

	8 A3-receptor role in preconditioning

Top 1 Introduction 2 Functional recovery versus... 3 Adenosine protection 4 Effects of more... 5 Conflicting studies 6 Isolated cardiomyocyte studies 7 Species-dependent A3-receptor... 8 A3-receptor role in... 9 Conclusion References

 
Adenosine A₃-receptor agonists pharmacologically precondition human [41,42], and rabbit [43–45] hearts. In the intact rabbit heart the A₁-receptor may be the predominant mediator of IPC, but full protection may occur only in concert with concomitant activation of other receptors [46,47]. The A₃-receptor differs from the A₁ in lack of coupling to adenylate cyclase and its rapid phosphorylation and desensitization [48] and coupling to diacylglycerols [49]. In rats the A₃-receptor is largely confined to reproductive organs [50] or mast cells [51], whereas in the sheep and other species it has a broad tissue distribution [52]. The cardioprotective function of the A₃-receptor is supported by studies using the selective A₃-receptor agonists APNEA [45], IB-MECA [43], and CB-MECA (A₃ K_i, 1 nM; A₁ K_i, 105 nm) with an EC₅₀ of 3 nM [44], as well as selective antagonists [53,54]. Adenosine-receptor mediated protection in the rabbit cardiomyocyte in vitro requires A₃-receptors [40,55]. In isolated rabbit cardiomyocytes single administrations of A₁-selective concentrations of adenosine or adenosine agonists only partially protect, although sequential selective stimulations of the A₁-receptor afford cumulative increases in protection [37]. Full preconditioning requires either multiple sequential activations of the A₁-receptor or A₁-receptor activation accompanied by A₃ or another G-protein coupled receptor. While there is substantial evidence that multiple receptors may induce IPC, in the rabbit the A₁-receptor has been reported to be the most predominant receptor that initiates IPC [27]. However, this study did not establish the A₁-receptor as an exclusive mediator of IPC, nor entirely rule out a contributing role of the A₃-receptor. Cardioprotection followed intravascular infusion of 20 µM adenosine, a concentration assumed to increase interstitial concentrations to 2–3 µM and to be A₁-selective. However, the actual interstitial adenosine levels could have been higher if the fivefold intervascular to interstitial adenosine ratio estimates were assumed [56]. In any case, 2–3 µM adenosine is not entirely A₁ selective and calculations based on an A₃ dissociation constant value of 532 nM, indicate 80–85% occupancy of the A₃-receptor. Although perfusion of 50 nM of the selective A₁ agonist R-PIA (K_i: A₁, 1–2 nM; A₃, 1.2 µM) [40] for 10 min, without an intervening washout prior to sustained ischemia, will induce IPC in the intact rabbit heart [57], exclusion of a role for the A₃-receptor in IPC would require currently unavailable highly selective A₃ antagonists. In rabbit cardiomyocytes in vitro the A₃-receptor assumes an ancillary role in IPC, while in the intact heart, A₃- or other G-protein coupled receptors (bradykinin, ₁-adrenergic, angiotensin, etc.) likely contribute to IPC. In rats, a low tissue abundance of A₃-receptors coupled with adenosine's very low A₃ ligand affinity (IC₅₀; 30±4 µM in competition for ¹²⁵I-APNEA binding to the A₃-receptor as compared to an IC₅₀ of 63±19 nM for R-PIA [25]), may limit the ability of adenosine to precondition. The ₁-adrenergic [1,58] and/or opioid receptors [59] have been suggested as alternative candidates for the initiation of preconditioning in the rat.

	9 Conclusion

Top 1 Introduction 2 Functional recovery versus... 3 Adenosine protection 4 Effects of more... 5 Conflicting studies 6 Isolated cardiomyocyte studies 7 Species-dependent A3-receptor... 8 A3-receptor role in... 9 Conclusion References

 
The initial report utilizing SPT (suggesting that adenosine A₁-receptor is not required for IPC in rat hearts) have been confirmed in subsequent studies using highly selective A₁ antagonists, multiple cycle IPC protocols, and by inclusion of infarct size estimates as an end-point. The reports conflicting with the above view are inconclusive, because they do not clearly distinguish between adenosine mediated protection and IPC, or do not include infarct size as an end-point. The literature is confusing because of the multiplicity of experimental models and end-points used in the various studies. Despite intensive study, the inability of adenosine to mimic IPC in the rat seems to remain incompletely explained. The enigma is highlighted by recent studies suggesting a role for p38 mitogen activated protein kinase (MAPK) in mediating protection from ischemic injury in rats and rabbits [60–63]. The possibility that p38 MAPK related protection may be related to IPC was partly based on the initial observation that adenosine activates MAPKAPK2 in the rat heart [64]. If the p38 MAPK pathway (which is strongly activated in rats by adenosine-receptors) is responsible for preconditioning protection, it remains unclear why adenosine-receptor activation is then unable to mediate IPC in the rat. It seems at this time likely that the explanation may lie in variations of the number and type of G-protein linked receptors that are present and required to initiate protection in different species.

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Top 1 Introduction 2 Functional recovery versus... 3 Adenosine protection 4 Effects of more... 5 Conflicting studies 6 Isolated cardiomyocyte studies 7 Species-dependent A3-receptor... 8 A3-receptor role in... 9 Conclusion References

 

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