Adenosine improves recovery of postischemic myocardial function via an adenosine Al receptor mechanism ROBERT D. LASLEY AND ROBERT M. MENTZER, JR. Department of Surgery, University of Wisconsin Clinical Sciences Center, Madison, Wisconsin 53792 Lasley, Robert D., and Robert M. Mentzer, Jr. Adenosine improves recovery of postischemic myocardial function via an adenosine A, receptor mechanism. Am. J. Physiol. 263 (Heart Circ. Physiol. 32): H1460-H1465, 1992.-The effects of adenosine in the nonischemic heart have been shown to be mediated via its binding to extracellular adenosine A, and A, receptors located predominantly on myocytes and endothelial cells, respectively. We tested the hypothesis that the beneficial effect of adenosine on postischemic myocardial function is mediated via an adenosine Al receptor mechanism. Isolated rat hearts perfused at constant pressure (85 cmH&,O) were subjected to 30 min of global no-flow ischemia (37°C) and 45 min of reperfusion. Hearts treated with adenosine (100 FM) and the adenosine A 1 receptor agonist N’;-cyclohexyladenosine (CHA; 0.25 PM) recovered 72 & 4 and 70 t 4% of preischemic left ventricular developed pressures (LVDP), respectively, after 45 min of reperfusion compared with untreated hearts (54 * 3% of preischemic LVDP). Adenosine and CHA hearts exhibited greater myocardial ATP contents than control hearts after 10 min of ischemia, but there were no differences in tissue ATP levels after 30 min of ischemia. In contrast, hearts treated with the adenosine Al, receptor agonist phenylaminoadenosine (0.25 PM) failed to demonstrate improved postischemic function (52 t 5%). The addition of the Al-selective antagonist &cyclopentyl- 1,3-dipropylxanthine blocked the cardioprotective effect of adenosine (57 & 4%). These results suggest that adenosine enhances postischemic myocardial function via an A, receptor mechanism. global ischemia; myocardial protection; cyclohexyladenosine AFTER GLOBAL or regionalmyocardialischemia is characterized by depressed contractility and a slow resynthesis of myocardial ATP levels, both of which may take several days to recover (10, 29). The nucleoside adenosine, a product of ATP catabolism, accumulates in the ischemic myocardium but is rapidly metabolized to inosine and hypoxanthine. During reperfusion, adenosine is washed out of the tissue, rendering it unavailable for reincorporation into the myocardial adenine nucleotide pool via the purine salvage pathway (23). The preservation of endogenous adenosine during myocardial ischemia (9, 13, 16) and the administration of exogenous adenosine have been shown to enhance the recovery of postischemic function (6, 11, 31). These observations have led to the hypothesis that treatment of the ischemic heart with adenosine enhances postischemic function via its stimulation of myocardial ATP resynthesis. Two other mechanisms that have been proposed for the cardioprotective effect of adenosine are increased coronary blood flow (26) and the inhibition of neutrophil oxygen free radical production and adherence to the coronary endothelium (3, 7, 22). Recently, the cardiac actions of adenosine have been shown to be mediated via interaction of adenosine with specific membrane-bound receptors (4). Synthetic adenosine analogues have been used both in vitro and in vivo to characterize the cardiovascular effects of adenosine. REPERFUSION





Modifications of the purine ring at the N-6 position yield adenosine analogues such as R-N”-(Z-phenylisopropyl)adenosine (PIA) and W-cyclohexyladenosine (CHA) that show selectivity for the adenosine A, receptor. Substitutions in the ribose ring [Y-(N-ethylcarboxamido)adenosine] or at the C-Z position in the purine ring [phenylaminoadenosine (PAA)] produce adenosine analogues that are selective for the adenosine A2 receptor. The antiadrenergic and negative chronotropic/dromotropic effects of adenosine are believed to be mediated by adenosine A1 receptors located primarily on the cardiac myocytes (13). The effects of adenosine on coronary blood flow are thought to be mediated by interaction with adenosine A2 receptors located predominantly on endothelial cells (24). Using the Langendorff isolated rat heart preparation and selective adenosine receptor agonists, we tested the hypothesis that adenosine enhances postischemic recovery of function via interaction with adenosine A1 receptors. METHODS All experiments were conducted on adult male Wistar rats weighing 300-400 g. Rats were heparinized (500 U ip) and anesthetized with pentobarbital sodium (65 mg/kg ip). The heart was rapidly excised and immediately placed into ice-cold KrebsHenseleit buffer to produce cardiac arrest. After cannulation of the aorta, hearts were perfused at a constant perfusion pressure of 85 cmH,O with Krebs-Henseleit buffer consisting of (in mM) 118 NaCl, 4.7 KCl, 1.2 MgSO,, 1.2 KHZP04, 1.30 CaC1,, 25.0 NaHCO,,, 11.0 glucose, and 0.05 EDTA. The perfusate was maintained at 37°C in a constant-temperature reservoir and was bubbled with 95% O,-5% CO, resulting in pH 7.35-7.45, Pco., 35-40 mmHg, and PO, 560-620 mmHg. Myocardial temperature was maintained at 37°C by submersing the heart into a water-jacketed chamber filled with Krebs-Henseleit buffer. To equalize energy demands among the groups, the hearts were paced at 300 beats/min (4 ms, 4 V) via electrodes placed on the right ventricle during the equilibration period and for the first 4 min of ischemia, at which time negligible contractile activity was observed. Pacing was resumed during the reperfusion period. At 15 and 25 min of equilibration, pacing was briefly discontinued to measure spontaneous heart rate. After 20 min of equilibration, hearts were perfused with normal Krebs-Henseleit buffer or buffer supplemented with one of the following agents (n 2 7 per group): 100 PM adenosine, 0.25 PM CHA, or 0.25 PM PAA. After an additional 10 min of perfusion the hearts were subjected to 30 min of global, normothermic (37°C) ischemia and then reperfused for 45 min with control Krebs-Henseleit buffer. Hearts were freeze-clamped in liquid nitrogen at the end of equilibration, at 10 and 30 min of ischemia, and at 45 min of reperfusion for the determination of tissue metabolite contents. Measurement of uentricular function. Ventricular function was assessed by measuring left ventricular developed pressure (LVDP) with a fluid-filled latex balloon, connected via a polyethylene catheter to a pressure transducer (Gould model P23XL, Cleveland, OH). The balloon was inserted into the left

0 1992 the American



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ventricle via the left atrium and was inflated to yield an enddiastolic pressureof 5 mmHg. Once the left ventricular balloon volume was set during the preischemicperfusion, it was maintained constant during ischemia and reperfusion. Differentiation of the LVDP signal yielded the first derivative of left ventricular pressure (LV dP/dt). During the period of global ischemia the time to completion of ischemic contracture was recordedasthe time point at which diastolic pressurereacheda maximum value. Coronary flow rate was determined via timed collections of effluent overflow from the heart bath. The postischemic recovery of LVDP, +dP/dt, and coronary flow were expressedasa percent of the preischemiavalues.All experimental data wererecordedon a Gould modelRS 3400chart recorder. Materials. Adenosine was obtained from Boehringer Mannheim (Indianapolis, IN). The adenosinereceptor agonistsCHA and PAA, and the adenosineA, receptor antagonist &cyclopentyl-1,3-dipropylxanthine (DPCPX) were obtained from ResearchBiochemicals (Natick, MA). Adenosine, CHA, and PAA weredissolveddirectly in the Krebs-Henseleitbuffer. A 10 mM stock solution of DPCPX was made in dimethyl sulfoxide and wasthen diluted in the buffer. Tissueprocessing.Samplesof frozen tissue (- 100 mg) were rapidly weighed, immediately transferred to homogenizing tubes containing 3.0 ml of ice-cold 0.6 N perchloric acid, and homogenizedwith a model K41 tissue homogenizer (Tri-R Instruments, Rockville, NY) at full speedin an ice:water:ethanol mixture (-6°C) to produce a homogeneousslurry. The suspension wascentrifuged at 2°C for 10 min at 10,000 g, after which 2.0 ml of the supernatant fraction were neutralized with 4.0 ml of 0.5 M tri-n-octylamine in Freon. The mixture wasvigorously agitated for 1 min and centrifuged at 2°C for 5 min at 3,000g, and the aqueouslayer was removed and stored at -80°C until metabolite analysis. Separate portions of frozen tissue were dried for 24 h at 100°C to determine tissue dry weight. Assay of adenine nucleotides,nucleosides,and lactate. Processedtissue sampleswere analyzed for ATP, ADP, and AMP by strong anion exchangehigh-performance liquid chromatography (HPLC) as previously described (17). Tissue levels of adenosine,inosine, and hypoxanthine were determined by reverse-phaseHPLC as previously described (27). Peaks were determinedby absorbanceat 254 nm and identified by comparison of retention times with known external standards. Peak quantification was determined by peak height. Myocardial lactate contents were determined by standard enzymatic spectrophotometric methods as describedby Bergmeyer (5). Myocardial adenine nucleotide, nucleoside,and lactate contents were expressedas micromolesper gram dry weight of tissue. Statistical analysis.Resultsare expressedasmeans+ SE. The data were analyzed by a one-way analysisof variance with statistical significance between the control and treatment groups determined by Dunnett’s test. A P value of ~0.05 was considered statistically significant.



Table 1. Hemodynamic data before and after 10 min of treatment with uderwsine and udenosine agonists

Pretreatment Control Pre-ADO Pre-CHA Pre-PAA After


LVDP, mmHg


CF, ml,min-‘.g-’

100+2 102+2 lOl+l

1,753+52 1,821+47 1,739+65

10.4kO.6 ll.OIkO.5 10.6zkO.3




HR beats/min 282+7 275+7 2751t9 28423


treatment 11.7kO.5 Control 102+3 1,74Ort58 272rf;5 ADO 99+3 1,721+52 22.5+0.8*t 110+10*t 22.3+1.1*t CHA 103+4 1,825*52 76+12*t PAA 102+2 1,829+43 21.4+1.5*t 280+6 Values are means + SE; n 2 6 per group. LVDP, left ventricular developed pressure; dP/dt, first derivative of LV pressure vs. time: CF, coronary flow; HR, spontaneous heart rate when pacing was temporarily discontinued; ADO, adenosine; CHA, W-cyclohexyladenosine; PAA, phenylaminoadenosine. * P < 0.05 vs. control; t P < 0.05 vs. pretreatment.

A2 activities of these adenosine receptor agonists. CHA significantly reduced spontaneous heart rate, comparable to the response seen with adenosine, whereas treatment with PAA had no effect on spontaneous heart rate. The effects of adenosine Ai receptor activation are ev-

ident during the ischemic period. Adenosine and CHA significantly prolonged the time to maximal ischemic contracture development to 20.6 + 0.7 and 21.6 zk 0.5 min, respectively, compared with untreated hearts (17.8 & 0.5 min) and PAA-treated hearts (18.8 + 0.6 min). In addition, CHA also reduced the magnitude of contracture development (54 + 2 vs. 82 + 4 mmHg) after 30 min of ischemia. The recovery of LVDP (expressed as a percent of preischemic values) in the four groups during reperfusion is shown in Fig. 1. Hearts treated with adenosine and the adenosine Ai receptor agonist CHA showed significantly greater recovery of LVDP than untreated hearts throughout reperfusion. After 45 min of reperfusion, adenosine and CHA-treated

hearts recovered 73 + 4 and 70 + 4% of

preischemic LVDP, respectively, compared with 54 + 3% recovery in untreated hearts. Hearts treated with the adenosine A2 receptor agonist PAA recovered similarly to untreated control hearts (52 + 5%). When volume was


The hemodynamic characteristics of the four groups before global ischemia are shown in Table 1. All four groups exhibited similar LVDP, +dP/dt, coronary flow, and spontaneous heart rate values at 20 min of equilibration, before the initiation of treatment with the various agents. Treatment for 10 min with adenosine increased

coronary flow twofold but had no effect on LVDP and dP/dt. CHA, the adenosine Ai receptor agonist, and PAA, the adenosine AZ receptor agonist, both produced increases in coronary flow similar to adenosine but had no effect on LVDP

and +dP/dt.

PAA on spontaneous

The effects of CHA and

heart rate demonstrate

the Ai and

Fig. 1. Recovery of postischemic left ventricular developed pressure (LVDP) expressed as percent of preischemic LVDP. Values are means + SE; n 2 6 in each group. ADO, adenosine; CHA, Wcyclohexyladenosine; PAA, phenylaminoadenosine. * P < 0.05 compared with untreated control hearts.

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withdrawn from the balloon at the end of reperfusion, to return end-diastolic pressure to the preischemic value of 5 mmHg, recovery of preischemic LVDP was 36 + 3% in untreated hearts and 62 + 3% in adenosine- and CHAtreated hearts (P < 0.05 vs. untreated). Similar effects were obtained for recovery of LV +dP/dt (Fig. 2). Hearts treated with adenosine and CHA exhibited the most rapid and greatest recovery of LV +dP/dt during reperfusion, whereas hearts treated with PAA recovered similarly to untreated control hearts. Because the ventricular balloon volume was kept constant during ischemia and reperfusion, left ventricular end-diastolic pressure (LVEDP) served as an index of diastolic function. All groups experienced reperfusion contracture, but, as illustrated in Fig. 3, adenosine and CHA treatment attenuated the postischemic increase in LVEDP. Treatment with PAA had no beneficial effect on reperfusion diastolic pressure. The effects of the various treatment regimens on the recovery of coronary flow during reperfusion are shown in Fig. 4. The recovery of coronary flow in the adenosine, CHA, and PAA groups was expressed as a percent of preischemic flow before initiation of treatment with these agents. After 10 min of reperfusion, coronary flow in CHA-treated hearts was 21% greater than preischemic values. This improved recovery of coronary flow in the CHA-treated hearts was maintained for the first 30 min of reperfusion, although all groups experienced significantly reduced coronary flow after 45 min of reperfusion compared with their respective preischemic flow rates (72 * 3,80 + 4,88 f 3, and 72 f 6% for untreated, adenosine, CHA, and PAA groups, respectively). The effects of adenosine and CHA on myocardial adenine nucleotide contents before, during, and after ischemia are shown in Table 2. There were no differences among the groups before ischemia, but after 10 min of ischemia hearts treated with adenosine and CHA had higher ATP contents than untreated control hearts. After 30 min of ischemia the only difference in adenine nucleotide content was the higher AMP content in CHAtreated hearts. At the end of 45 min of reperfusion, hearts treated with adenosine showed a significant increase in ATP content compared with untreated hearts, but all groups exhibited significantly reduced ATP levels compared with their respective preischemic values.


I ,o

Fig. 3. Left ventricular end-diastolic pressure (LVEDP) at end of ischemia and during reperfusion. LVEDP during equilibration period was set at 5 mmHg, and then balloon volume was kept constant. Values are means rl: SE, n 2 6 in each group. * P < 0.05 compared with untreated control hearts.

Fig. 4. Recovery of postischemic coronary flow (CF) expressed as percent of preischemic CF. For ADO, CHA, and PAA hearts this was expressed as percent of pretreatment CF (i.e., CF at 20 min of equilibration). E, end of equilibration; I, ischemia. Values are expressed as means + SE; n 2 6 in each group. * P < 0.05 compared with untreated control hearts.

Tissue nucleoside and purine levels in the control, adenosine, and CHA hearts are shown in Table 3. Before ischemia, adenosine-treated hearts exhibited greater adenosine and inosine levels, as expected. After 10 min of ischemia, hearts treated with CHA had significantly lower adenosine, inosine, and hypoxanthine levels compared with control hearts. At the end of the 30-min ischemic period adenosine-treated hearts had a greater tissue content of adenosine, and CHA-treated hearts had higher tissue levels of adenosine and inosine. Tissue lactate contents in hearts treated with adenosine and CHA before and during ischemia are illustrated in Fig. 5. Before ischemia there were no differences in tissue lactate levels among the control, adenosine, and CHA hearts (5.1 rt 1.3,4.6 + 0.8, and 4.0 f 0.9 hmol/g dry wt, respectively). After 10 min of ischemia tissue lactate levels in control, adenosine, and CHA hearts were similar, but tissue lactate levels in CHA-treated hearts continued to increase during the remainder of the ischemic period (P c 0.05 vs. control, < 0.05 vs. 10 min ischemia). Because adenosine and CHA increased coronary flow and decreased heart rate, neither agent acted selectively on adenosine Al receptors. Therefore a series of experiments was performed, using the same protocol, in which hearts (n = 6) were treated with adenosine (100 PM) + the selective adenosine Al receptor antagonist DPCPX (5 P

Fig. 2. Recovery of postischemic first derivative of left ventricular pressure (LV dP/dt) expressed as percent of preischemic LV dP/dt. Values are means & SE; n z 6 in each group. *P < 0.05 compared with untreated control hearts.

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Table 2. Myocardial


tissue adenine nucleotide AMP








and reperfusion


are means










0.27t0.02 0.28kO.02

6.41k0.46 5.8OkO.86

26.08t2.02 24.22t3.70

2.44t0.33 2.26k0.38

9.35t0.91 9.72t0.74

12.25tl.44* 13.84t1.09"

30-min. Control Treatment ADO CHA



Equilibration Control Treatment ADO CHA












10.79t1.21 17.40t0.71*

2.33t0.26 2.16k0.23

2.27k0.44 1.66k0.36

2.36k0.32 2.94kO.47

3.44t0.25 8.56t1.01" 2.95kO.44 7.54k1.11 * P < 0.05 vs. control.

t SE expressed

as pmol/g

dry wt; n > 6 per group.


end of equilibration.

Table 3. Myocardial tissue nucleoside and purine contents during ischemia and reperfusion ADO





Equilibration Control Treatment ADO CHA Control Treatment ADO CHA ND,





0.64t0.04* 0.024t0.005

0.21*0.02* 0.026kO.005

0.16t0.01 ND

1.51t0.07 0.98t0.15'

1.60t0.15 1.03~0.10*

0.75t0.16 0.53t0.04*

30-min &hernia 3.28zk0.29





3.63t0.33 5.09t0.19*

1.19kO.09 1.54t0.16

0.28t0.05 0.34t0.07

0.90t0.19 0.92kO.18

0.45kO.07 0.36t0.06

Values are means t SE expressed as pmol/g not detectable. * P < 0.05 vs. control.

F z





dry wt; n L: 6 per group.




03 "


k+ 4 L 4 W3




El z L-’

50 --






4.22t0.38* 4.33&0.28*





+ z








0 25


t/ 0


;ytvlE OF ISCtitlk


Fig. 5. Tissue lactate content during no-flow global ischemia. Values are means t SE, in pmol/g dry wt; n > 6 in each group. * P < 0.05 compared with value at 10 with untreated control hearts; + P < 0.05 compared mm.

PM). During the treatment period spontaneous heart rate remained unchanged (266 t 4 vs. 277 t 4 beats/min), and coronary flow increased from 12.1 to 19.9 t 1.1 ml min-l l g-l (P < 0.05). After 20 and 45 min of reperfusion, hearts treated with adenosine + DPCPX recovered 31 t 7 and 57 t 4% of preischemic function, respectively, similar to control hearts (29 t 6 and 54 t 3%). l


The major findings of this study are the observations that treatment of the ischemic heart with the adenosine A1 receptor agonist CHA enhanced postischemic recovery of function in a manner similar to treatment with adenosine, and that the cardioprotective effect of adenosine was blocked by the adenosine A1 antagonist DPCPX. These results are consistent with the hypothesis that the


end of equilibration;






beneficial effect of adenosine on the globally ischemic heart is mediated via an adenosine Al receptor mechanism. The mechanism most frequently cited for adenosine’s cardioprotective effect is its role as a precursor for ATP resynthesis (l&12,14,31), because enhanced recovery of postischemic function was often associated with increased myocardial ATP levels. However, Reibel and Rovetto (23) reported that reperfusion of isolated working rat hearts with adenosine enhanced ATP resynthesis but had no effect on postischemic function. The absence of any beneficial effect on postischemic myocardial function when adenosine is administered during reperfusion has also been observed by Ambrosio et al. (1) and Mauser et al. (20). These findings suggest that whereas adenosine can be rapidly incorporated into the adenine nucleotide pool in the postischemic heart, stimulation of the purine salvage pathway does not necessarily lead to improved postischemic cardiac function. The results obtained in this study suggest that adenosine protects the ischemic myocardium via a mechanism independent of its effect as an ATP precursor. Results obtained with selective adenosine analogues suggest that adenosine exerts its beneficial effect via interaction with adenosine A1 receptors. Adenosine and CHA, both of which produced marked negative chronotropic effects consistent with activation of adenosine A1 receptors on the cardiac myocytes, enhanced postischemic recovery of function, whereas PAA, which exhibited no A1 receptor activity, had no beneficial effect on postischemic function. In addition, the cardioprotective effect of adenosine was blocked by the selective adenosine A1 antagonist

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DPCPX. Treatment with CHA enhanced the recovery of postischemic function without any effect on myocardial ATP levels after ischemia or reperfusion. Adenosine exerted its protective effect without altering myocardial ATP levels after 30 min of ischemia, although adenosinetreated hearts exhibited greater ATP contents after 45 min of reperfusion. Although adenosine and CHA had no beneficial effect on ATP levels after 30 min of ischemia, they did exert other metabolic effects during ischemia. After 10 min of ischemia, hearts treated with adenosine and CHA exhibited higher ATP contents than untreated hearts, an observation we have previously reported with adenosine (11) and the adenosine A, agonist PIA (17). Metabolic studies were not performed in the PAA-treated hearts because we observed no cardioprotective effect with this agonist, and we have reported that PAA at a higher concentration had no effect on myocardial adenine nucleotide metabolism (17). The higher ATP contents in the adenosine and CHA hearts after 10 min of ischemia could be due to reduced ATP utilization or accelerated ATP production via anaerobic glycolysis. The lower tissue levels of adenosin % inosine, and hypoxanthine in the CHAtreated hearts su.ggest that the higher ATP content is a result of decreased ATP breakdown. In the adenosinetreated group, if preischemic tissue adenosine levels are subtracted from adenosine levels at 10 min of ischemia (1.51 - 0.64 pmol/g dry wt), it appears that adenosine production (0.87 pmol/g dry wt) is similar to that in hearts treated with CHA. These data suggest that adenosine and CHA reduced energy utilization during ischemia, observations consistent with the action of adenosine in decreasing myocardial energy demand. Endogenous and exogenous adenosine have been shown to protect the ischemic heart by reducing spontaneous heart rate (16) and inducing rapid cardiac arrest (25)) respectively. In our study it is unlikely that the higher ATP levels after 10 min of ischemia and the enhanced recovery of function seen with adenosine and CHA treatment were due entirely to reduced energy demand because before ischemia all hearts exhibited similar developed pressures, and hearts were paced at 300 beats/ min before and during the first 4 min of ischemia. In addition, interventions that decrease myocardial energy demand, such as calcium channel blockers (8, 28) and propranolol (15), diminish both ATP utilization and lactate accumulation during ischemia. Adenosine and CHA preserved ATP during early ischemia but did not reduce lactate production. Another possible mechanism for the higher ATP levels after 10 min of ischemia in the adenosine and CHAtreated hearts could be accelerated ATP production via anaerobic glycolysis. Lactate production during global ischemia has been used as a marker of glycolysis because it is the end product of anaerobic glycolysis and accumulates in the tissue during no-flow ischemia (2, 21). Although lactate levels were not elevated after 10 min of ischemia with adenosine and CHA treatment, lactate content should have been decreased if higher ATP levels were due solely to decreased energy utilization. This suggests that adenosine and CHA may have stimulated ATP



synthesis in addition to reducing ATP utilization. We have reported that in the isolated rat heart adenosine stimulates myocardial glucose uptake (19)) increases glycolytic flux via an adenosine Ai receptor mechanism (30), and increases lactate production during low-flow ischemia (18). After 30 min of ischemia tissue adenosine levels in both adenosine- and CHA-treated hearts were significantly elevated. Lactate levels were also elevated, although this increase was not statistically significant in the adenosine group. It is important to note that hearts treated with CHA exhibited the greatest lactate accumulation during ischemia, the lowest magnitude of contracture development, and the greatest recovery of function. These observations are consistent with the findings of Apstein et al. (2), who reported that reduced contracture development during global ischemia was associated with higher tissue lactate accumulation. This is in contrast to the reports of Neely and Grotyohann (21), who observed an inverse relationship between ischemic tissue lactate accumulation and recovery of ventricular function. Another mechanism by which adenosine and CHA could have exerted their cardioprotective effects is via increased coronary flow. Adenosine, when administered during reperfusion, has been shown to improve both regional coronary blood flow and cardiac function (3, 26) and to decrease infarct size (22). It is possible that the enhanced recovery of function seen with CHA could be due to its activation of AZ receptors because before ischemia CHA increased coronary flow to a similar extent as adenosine and PAA. However, this is unlikely because PAA, which did interact selectively with A2 receptors, had no effect on contracture development or on postischemic recovery of function or flow. In addition, adenosine enhanced recovery of function with no effect on reperfusion coronary flow, and selective A1 receptor blockade with DPCPX during adenosine infusion blocked the cardioprotective effect of adenosine. The increased coronary flow in CHA-treated hearts during reperfusion could be a result of the increased accumulation of adenosine during ischemia and reduced ischemic injury because CHA significantly reduced the magnitude of both ischemic and reperfusion contracture. In conclusion, the results of this study suggest that adenosine enhances postischemic recovery of cardiac function via a mechanism independent of its roles as a precursor for adenine nucleotide synthesis, regulator of coronary blood flow, or modulator of neutrophil-endothelium interactions. The results obtained with the adenosine AL agonist CHA and the adenosine Ai antagonist DPCPX suggest that adenosine protects the ischemic myocardium via an adenosine A1 receptor mechanism. This work was supported by National Heart, Lung, and Blood Institute (NHLBI) Grant HL-34579. R. M. Mentzer, Jr., is a recipient of NHLBI Research Career Development Award HL-01299. Address for reprint requests: R. D. Lasley, Dept. of Surgery, Univ. of Wisconsin, H4-358 Clinical Sciences Center, 600 Highland Ave., Madison, WI 53792. Received

15 August

1991; accepted

in final


29 May


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Adenosine improves recovery of postischemic myocardial function via an adenosine A1 receptor mechanism.

The effects of adenosine in the nonischemic heart have been shown to be mediated via its binding to extracellular adenosine A1 and A2 receptors locate...
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