© 2001 by European Society of Cardiology
Copyright © 2001, European Society of Cardiology
Adenosine inhibits norepinephrine release in the postischemic rat heart: the mechanism of neuronal stunning
aMedizinische Klinik II, Universitätsklinikum Lübeck, Ratzeburger Allee 160, 23538 Lubeck, Germany
bDeutsches Herzzentrum München, Munich, Germany
* Corresponding author. Tel.: +49-451-500-2420; fax: +49-451-500-6437 gert.richardt{at}medinf.mu-luebeck.de
Received 7 September 2000; accepted 20 November 2000
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Abstract |
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 Top Abstract 1 Introduction2 Methods3 Results4 DiscussionAcknowledgmentsReferences |
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Objective: Numerous studies support the concept of impaired postischemic sympathetic neurotransmission in the heart. We hypothesized that postischemic neuronal dysfunction (neuronal stunning) is caused by a transient suppression of exocytotic norepinephrine (NE) release from sympathetic nerve terminals. Furthermore, we assessed the role of presynaptic adenosine-receptors and
2-adrenoceptors in neuronal stunning. Methods and results: Exocytotic NE release was induced by two electrical field stimulations (S1 and S2) in isolated perfused rat hearts. S1 was performed under baseline conditions and S2 either during or following intervention. Results are expressed as mean S2/S1 ratios±S.E.M. Stepwise increase of global ischemic periods (10, 20, and 30 min) induced a progressive suppression of NE release in the postischemic hearts, which was reversible during reperfusion. Both the degree and duration of NE suppression was dependent on the extent of the preceding ischemic period. Following 10-min ischemia complete recovery of NE release was achieved after 5-min reperfusion (1.07±0.12), whereas 5-min reperfusion did not restore NE release after 30 min (0.36±0.07) of ischemia. The adenosine-receptor antagonists 8-phenyltheophylline (8-PT; non-selective) and 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; adenosine A1-receptor subtype selective) significantly increased NE release after 30-min ischemia and 5-min reperfusion (0.78±0.06 and 0.64±0.07), while in the same experimental protocol blockade of 2-adrenoceptors by yohimbine failed to restore the postischemic release (0.24±0.06). In non-ischemic hearts the adenosine analogue R(–)N6-(2-phenylisopropyl)adenosine (R-PIA) resulted in a marked suppression of NE release (0.61±0.07). The inhibitory effect of R-PIA and 2-chloro-N6-cyclopentyladenosine (CCPA; adenosine A1-receptor subtype selective agonist) persisted 5 min after cessation of R-PIA (0.62±0.05) and CCPA (0.58±0.04). Activation of 2-adrenoceptors by 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine (UK 14,304) also caused a reduction of NE release (0.50±0.02), but the release increased to control levels 5 min after cessation of UK 14,304 (0.90±0.06). Conclusions: The results establish the phenomenon of neuronal stunning in terms of a postischemic suppression of exocytotic NE release and provide evidence that neuronal stunning is mediated by endogenous adenosine through activation of presynaptic adenosine A1-receptors.
KEYWORDS Adenosine; Adrenergic (ant)agonists; Ischemia; Reperfusion; Neurotransmitters
This article is referred to in the Editorial by J. Pernow (pages 693–694) in this issue.
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1 Introduction |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionAcknowledgmentsReferences |
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Short periods of myocardial ischemia cause a reversible dysfunction of myocardial contraction extending into the reperfusion period (myocardial stunning) [1]. In addition to a transient impairment of contractile function, there is evidence that the functional integrity of other cardiac structures, such as coronary endothelium and sympathetic nerves, is also impaired after short myocardial ischemia [2–4]. Ischemic and postischemic neuronal dysfunction has been documented in different experimental models. A reduced myocardial segment shortening to neural sympathetic stimulation has been shown during ischemia and reperfusion, whereas responsiveness to systemic norepinephrine (NE) was not altered [5,6]. Moreover, attenuated coronary vasoconstrictor responses to sympathetic nerve stimulation have been demonstrated in the reperfused myocardium of the dog, whereas the peak increase in coronary vascular resistance to infused NE was unchanged [7], indicating the prejunctional location of postischemic attenuation of sympathetic neurotransmission [8]. So far, however, the exact mechanism of neuronal stunning is unknown. Within the heart, sympathetic nerve terminals are surrounded by other metabolically active tissues that release metabolites such as adenosine in response to ischemia. Epicardial superfusion of adenosine is capable of reducing efferent sympathetic and vagal neurotransmission in the canine heart [9]. Our group has documented that endogenous adenosine inhibits exocytotic release of NE in the ischemic rat heart by activation of presynaptic adenosine-receptors [10]. We therefore sought to test two hypotheses: (i) ischemia induces neuronal stunning in terms of a postischemic suppression of exocytotic NE release from sympathetic nerve terminals; and (ii) adenosine is the endogenous inhibitor which is responsible for postischemic attenuation of NE release by stimulation of prejunctional adenosine-receptors.
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2 Methods |
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The investigation conforms with 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).
2.1 Isolated perfused heart
Male Wistar rats (243±8 g) (Charles River, Sulzfeld, Germany) were anesthetized with thiopental-sodium (100–200 mg/kg, i.p., Trapanal®). A medial laparotomy was carried out and 0.1 ml heparin-sodium (500 U, Liquemin®) was injected into the inferior vena cava. The thorax was opened and the heart was rapidly removed, weighed (0.90±0.02 g), and placed in cold perfusion buffer. Isolated hearts were perfused via the ascending aorta at a constant flow of 8 ml/min per g heart weight with a modified Krebs–Henseleit solution (KHS; composition in mmol/l: Na+ 142, K+ 4.0, Ca2+ 1.85, Mg2+ 1.1, Cl– 135, H2PO4– 0.22, HCO3– 16.7, glucose 11, EDTA 0.027) [11,12]. The KHS was saturated with 95% O2/5% CO2. The gas flow was adjusted to achieve a pH of 7.4±0.04 and the temperature was maintained at 37°C at the point of entry into the ascending aorta. During the experiment, each heart was placed within a glass chamber which was also kept at a temperature of 37°C. All experiments were performed in the presence of desipramine (DMI; 100 nmol/l) to inhibit neuronal uptake of NE and prevent non-exocytotic NE release [12–14].
2.2 Exocytotic NE release
Two 13x8-mm concavely shaped metal paddles were placed in opposite positions on each heart, touching the heart in such a manner that the interventricular septum was located between both paddles [15]. NE release was induced by two electrical field stimulations (1 min, 5 V, 6 Hz, 2-ms pulse length; S1: prior to experimental intervention, S2: either during or following intervention). The effect of each experimental intervention on NE release (S2) was intraindividually compared with the release during baseline condition (S1). Stimulation-induced NE release as described has been characterized previously to be exocytotic [15].
2.3 Experimental procedure (Fig. 1)
After the aorta was cannulated, each heart was perfused for 25 min without intervention (equilibration period). Global ischemia was evoked by interruption of perfusate flow (10-, 20- or 30-min stop flow ischemia). Thereafter, reperfusion was established at the initial flow rate. S1 was performed in the 21st min of perfusion, i.e. 5 min prior to ischemia; S2 was performed either in the 1st, 5th or 30th min of reperfusion. To determine ischemia-induced NE release per se, separate stop-flow experiments were performed without a second stimulation (S2). Washout of ischemia-evoked NE release was assessed within the first 3 min of reperfusion.
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The effects of receptor antagonists on postischemic NE release were examined in the experimental setting of 30-min ischemia and 5-min reperfusion. Antagonists were given either during reperfusion or from the 11th min of perfusion till the end of the experiment. In non-ischemic hearts, receptor agonists were added to the KHS from the 26th until completion of the 55th min. S1 was carried out 5 min prior to this pharmacological intervention. The effects of adenosine-receptor/
2-adrenoceptor activation on transmitter release (S2) were examined either in the last minute of agonist infusion or in the 5th min after the end of infusion.
2.4 NE determination
Samples for determination of endogenous NE were collected from the effluent immediately before, during, and for 2 min following each electrical stimulation. Samples were cooled on ice, stabilized by the addition of Na2EDTA to a final concentration of 10 mmol/l, and stored at –60°C until assayed. NE was measured by using a high performance liquid chromatography (HPLC) method [12]. Briefly, after a two-step extraction, separation was performed with a reversed phase C18 column. Electrochemical detection was used for quantitative analysis. Recovery was 98%, the limit of detection 0.1 pmol per g heart weight, and the coefficient of variation was 5.9%. The chemicals used did not interfere with the extraction, separation or detection of NE.
2.5 Pharmacological agents
Desipramine hydrochloride (DMI), 8-phenyltheophylline (8-PT), 3,7-dimethyl-1-propargylxanthine (DMPX), R(–)N6-(2-phenylisopropyl)adenosine (R-PIA), and yohimbine hydrochloride were obtained from Sigma (Deisenhofen, Germany); 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), 2-chloro-N6-cyclopentyladenosine (CCPA), 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS 1191), and 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine (UK 14,304) were from Research Biochemicals International (Natick, MA, USA). 2-p-(2-Carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride (CGS-21680), and 1-[2-chloro-6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-1-deoxy-N-methyl-β-D-ribofuranuroamide (2-Cl-IB-MECA) were obtained from Tocris (Ballwin, MO, USA).
2.6 Statistical analysis
The results are expressed as mean±S.E.M. of the absolute values (S1, S2) in results and as mean±S.E.M. of the intraindividual S2/S1 ratios in figures. Statistical calculation was done by one-way analysis of variance (ANOVA) and use of Bonferroni's multiple comparison test for post hoc analysis when three or more experimental groups were compared. Unpaired and paired Student's t-tests were performed when two groups were compared or for innergroup comparisons (S2 vs. S1). A P-value <0.05 was considered statistically significant.
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3 Results |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionAcknowledgmentsReferences |
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Under baseline conditions the NE concentrations in the effluent were below the detection limit. None of the drugs which were used induced a detectable NE release prior to S1 and S2. Exocytotic NE release was calculated as cumulative overflow during and 2 min following each stimulation period.
Normoxic control experiments with two electrical field stimulations in the same heart performed 35 min apart showed a comparable amount of NE release (S1: 244±18 pmol/g, S2: 226±17 pmol/g, n = 8) (Fig. 2).
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Washout of ischemia-evoked NE release following 10-min ischemia remained below the detection limit of 0.1 pmol/g. Following 20- and 30-min ischemia NE release was 45±11 pmol/g (n = 26) and 51±8 pmol/g (n = 25), respectively. In the experiments with S2 performed in the 1st min of reperfusion after 20- and 30-min ischemia (Section 3.1), NE release was calculated as total NE overflow minus ischemia-induced NE release. NE amounts in the 5th and 30th min of reperfusion were not corrected, because ischemia-induced NE release decreased below the detection limit within 3 min of reperfusion.
3.1 NE release in the reperfused myocardium (Fig. 2)
In the 1st min of reperfusion after 10 min of ischemia, the NE release was markedly lower than that released during the baseline conditions (S1: 180±26 pmol/g, S2: 123±20 pmol/g, n = 6, P<0.01). A complete recovery of NE release was observed in the 5th min of reperfusion (S1: 137±25 pmol/g, S2: 141±28 pmol/g, n = 5). Ischemic periods of 20 and 30 min revealed a more pronounced suppression of NE release in the 1st min of reperfusion (20-min ischemia S1: 346±59 pmol/g, S2: 59±11 pmol/g, n = 4, P<0.05; 30-min ischemia S1: 275±21 pmol/g, S2: 48±9 pmol/g, n = 4, P<0.01), and this suppression was still observable through the 5th min of reperfusion (20-min ischemia S1: 91±12 pmol/g, S2: 65±21 pmol/g, n = 8, P<0.05; 30-min ischemia S1: 196±18 pmol/g, S2: 61±8 pmol/g, n = 15, P<0.01). With 20-min ischemia, complete functional recovery of sympathetic nerve terminals was achieved by prolongation of reperfusion to 30 min (S1: 111±13 pmol/g, S2: 111±11 pmol/g, n = 8). Following 30-min ischemia, a reperfusion period of 30 min also revealed a distinct increase in the S2/S1 ratio compared to the ratio after 5-min reperfusion period (Fig. 2), though the absolute amount of NE release in the 30th reperfusion minute continued to remain suppressed (S1: 269±19 pmol/g, S2: 199±17 pmol/g, n = 8, P<0.01).
3.2 Effects of adenosine-receptor/2-adrenoceptor antagonism on postischemic NE release (Figs. 3 and 4
)
Pharmacological blockade of presynaptic adenosine-receptors or 2-adrenoceptors was performed exclusively in the experimental setting of 30-min ischemia with subsequent 5-min reperfusion. Ischemia/reperfusion experiments without pharmacological intervention served as control group. If the non-selective adenosine-receptor antagonist 8-PT (10 µmol/l) was administered only during reperfusion, suppression of NE release continued (S1: 327±29 pmol/g, S2: 136±14 pmol/g, n = 8, NS vs. control). Conversely, an increase of NE release was found if 8-PT (10 µmol/l) was started prior to ischemia and continued until the end of the experiment (S1: 277±25 pmol/g, S2: 212±25 pmol/g, n = 11, P<0.01 vs. control) (Fig. 3). The 2-adrenoceptor antagonist yohimbine (1 µmol/l) infused during reperfusion did not increase the postischemic transmitter release (S1: 237±29 pmol/g, S2: 110±17 pmol/g, n = 8, NS vs. control). A comparable suppression of NE release was also observed if yohimbine was given from the 11th min of perfusion till the end of the experiment (S1: 486±67 pmol/g, S2: 94±9 pmol/g, n = 8, NS vs. control) (Fig. 3).
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Selective antagonism of adenosine A1-receptor subtype by DPCPX (1 µmol/l) prior to and during ischemia restored the NE release in the 5th min of reperfusion (S1: 347±50 pmol/g, S2: 218±32 pmol/g, n = 8, P<0.05 vs. control). Neither the adenosine A2-receptor subtype selective antagonist DMPX (10 µmol/l; S1: 282±24 pmol/g, S2: 107±11 pmol/g, n = 16, NS vs. control) nor the adenosine A3-receptor subtype selective antagonist MRS 1191 (1 µmol/l; S1: 353±46 pmol/g, S2: 123±18 pmol/g, n = 8, NS vs. control) affected NE release (Fig. 4).
3.3 Effects of adenosine-receptor/2-adrenoceptor activation on NE release in non-ischemic hearts (Figs. 5 and 6)
In a separate series of non-ischemic rat hearts, two electrical field stimulations performed 40 min apart revealed comparable amounts of NE release (S1: 217±15 pmol/g, S2: 203±16 pmol/g, n = 11, control).
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When normoxic hearts received the adenosine analogue R-PIA (1 µmol/l) from the 26th min to the 55th min of perfusion, the NE release was markedly suppressed in the last minute of perfusion (S1: 190±13 pmol/g, S2: 113±9 pmol/g, n = 5, P<0.05 vs. control), which persisted for 5 min after removal of R-PIA (S1: 234±30 pmol/g, S2: 143±23 pmol/g, n = 8, P<0.01 vs. control) (Fig. 5). Activation of presynaptic
2-adrenoceptors by a 30-min infusion of UK 14,304 (1 µmol/l) also caused a reduction of NE release (S1: 249±18 pmol/g, S2: 123±9 pmol/g, n = 8, P<0.01 vs. control), though the release increased to control levels 5 min after cessation of UK 14,304 (S1: 376±27 pmol/g, S2: 324±18 pmol/g, n = 12, NS vs. control) (Fig. 5). The adenosine A1-receptor subtype selective agonist CCPA suppressed transmitter release 5 min after stoppage of CCPA (1 µmol/l; S1: 261±24 pmol/g, S2: 145±10 pmol/g, n = 12, P<0.01 vs. control). Conversely, neither the adenosine A2-receptor subtype selective agonist CGS-21680 (1 µmol/l; S1: 306±46 pmol/g, S2: 287±45 pmol/g, n = 6) nor the adenosine A3-receptor subtype selective agonist 2-Cl-IB-MECA (1 µmol/l; S1: 452±28 pmol/g, S2: 370±25 pmol/g, n = 10) had a discernible effect on NE release in the same experimental protocol (Fig. 6).
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4 Discussion |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionAcknowledgmentsReferences |
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The principal findings in the present study are as follows. (i) Brief periods of global ischemia cause a transient postischemic suppression of endogenous NE release from sympathetic nerve terminals. (ii) Blockade of presynaptic adenosine A1-receptors prevents the attenuation of NE release following ischemia. (iii) Adenosine A1-receptor agonists are able to produce a sustained reduction of NE release under non-ischemic conditions. Taken together, these findings indicate a reversible postischemic impairment of sympathetic nerve terminals. The underlying mechanism of this neuronal stunning is the activation of presynaptic adenosine A1-receptors through endogenous ischemia-formed adenosine.
The present study clearly demonstrated that stepwise increase of global ischemic periods (10, 20, and 30 min) induced a progressive suppression of NE release in the postischemic hearts. Both the degree and duration of that suppression was dependent on the extent of the preceding ischemic period. The ability of adenosine-receptor blockers to restore transmitter release in the reperfusion period indicates that endogenous adenosine is the mediator of impaired release. It is known, that adenosine levels rapidly increase during ischemia and instantaneously fall to normal during reperfusion [16,17]. Therefore, it is tempting to conclude that endogenous adenosine triggers a suppression of NE release during ischemia which persists during reperfusion even after washout of adenosine. Such an assumption was further substantiated by the finding that adenosine-receptor blockers were unable to prevent the attenuation of NE release, if they were exclusively given during reperfusion.
Another line of evidence indicating that adenosine is the mediator of neuronal stunning, derived from our experiments with exogenous adenosine-receptor agonists which were given during non-ischemic conditions. In this experimental setting the adenosine-receptor agonist revealed a substantial suppression of NE release, which persisted 5 min after withdrawing the agonist from the perfusion buffer. Accordingly, persistent receptor activation beyond the time of washout of adenosine has been shown previously in isolated rat hearts [18]. Activation of adenosine-receptors also induces persistent effects in rat neuronal cultures, which are most likely dependent on activation of protein kinase C and opening of K+-(ATP) channels [19].
Ongoing suppression of NE release after washout of the agonist appears to be a unique property of prejunctional inhibition by adenosine, since stimulation of presynaptic 2-adrenoceptors by UK 14,304 did not cause a persistent suppression of NE release after withdrawal of the agent. Blockade of presynaptic 2-adrenoceptors failed to prevent postischemic neuronal dysfunction. This observation indicated a loss of the inhibitory response to prejunctional 2-adrenoceptor stimulation during ischemia and implied that 2-adrenoceptor activation was not involved in neuronal stunning. A comparable impairment of presynaptic modulation of NE release via 2-adrenoceptors has been previously reported in human atrial tissue during simulated ischemia [20].
It is established that the adenosine-receptor family can be divided into A1-, A2- and A3-receptors. Additional A1A, A1B and A2A, A2B subtypes do exist and it has been reported that A1A-, A1B-, A2A- and A3-receptor subtypes are present in neural tissue [21]. In order to characterize the adenosine-receptor subtype involved in the prejunctional control of NE release during neuronal stunning, the effects of different subtype selective adenosine-receptor antagonists were evaluated in a 30-min ischemia/5-min reperfusion protocol. In this experimental setting neuronal stunning was most prominent. The non-selective xanthine derivative 8-PT, as well as the very potent A1-receptor selective antagonist DPCPX were able to restore NE release to baseline. DPCPX is 
740-fold more selective for A1- than A2-receptors, and 62-fold more selective for A1- than A3-receptors [22,23]. Moreover, it is unlikely that adenosine-receptors other than A1-receptors mediate neuronal stunning because blockade of A2- and A3-receptors by specific antagonists did not re-establish NE release. Regarding non-ischemic experiments with agonist infusion, the concentration of R-PIA used was not adenosine A1-receptor subtype specific, and stimulation of A2- or A3-receptors could have occurred. For this reason, we tested selected receptor subtype specific adenosine analogues, which also confirmed that presynaptic inhibition of NE release is exclusively mediated by A1-receptor stimulation. Our results are in line with previous work from our group, documenting that only the presynaptic adenosine A1-receptor subtype is involved in the inhibition of NE release [24]. Because highly selective antagonists/agonists for A1A- and A1B-receptors do not exist, we can not define the specific subtype of the A1-receptor involved in neuronal stunning.
Our study is, however, not in conformity with a study on sympathetic coronary innervation, which suggests that more than one adenosine-receptor subtype is involved in neuronal stunning [25]. It is possible that the latter study used an experimental model (coronary vasoconstriction in response to sympathetic stimulation) which does not selectively assess presynaptic actions and thereby dealt with mixed receptor populations.
Though this was not the focus of our study, it is apparent that neuronal stunning has substantial clinical implications. Heterogeneity of autonomic innervation may predispose to malignant arrhythmias, and denervation may aggravate subendothelial ischemia as neuronal activation influences transmural flow. On the other hand, neuronal stunning may play a protective role in the postischemic heart by inhibiting excessive sympathetic drive to the heart.
In conclusion, brief periods of global ischemia result in a transient postischemic suppression of endogenous NE release from sympathetic nerve terminals. The results do further indicate that this neuronal stunning is caused by activation of presynaptic adenosine A1-receptors through endogenous adenosine, which is formed during ischemia.
Time for primary review 22 days.
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Acknowledgments |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionAcknowledgmentsReferences |
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This study was supported by a grant of the Deutsche Forschungsgemeinschaft (DFG: RI 423/4-1). We are grateful to Anke Constantz, Dorit Kemken, Cindy Krause and Ines Stölting for their technical assistance.
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