cardiodepressant mediators are released after myocardial ischaemia: modulation by catecholamines and...

Cardiodepressant mediators are released after myocardial

ischaemia: modulation by catecholamines and adenosine

V . S T A N G L , C . H A R M S , T . F R A N K , K . S T A N G L , J . M U û , K . B U T T K E ,

G . B A U M A N N and S . B . F E L I X

Med. Klinik und Poliklinik I, ChariteÂ der Humboldt-UniversitaÈt, Berlin, Germany

ABSTRACT

The interaction of recently characterized cardiodepressant mediators with catecholamines and

adenosine after myocardial ischaemia was investigated using a model of sequential perfusion of two

isolated guinea-pig hearts. Sequential perfusion was initiated after 10, 20, and 30 min (group I, II, and

III) of global ischaemia in the first heart. At the onset of sequential perfusion LVdP/dtmax and min of

Heart II decreased by 46 and 44% in group I, by 28 and 34% in group II, and increased by 60 and 24%

in group III. Infusion of the b1-receptor antagonist metoprolol (2.8 lmol L±1) into Heart II did not

modulate contractile changes after 10 min of ischaemia in Heart I, prevented the attenuation of the

cardiodepressant effect after 20 min of ischaemia, and completely reversed the positive inotropic

effect after 30 min of ischaemia. The A1- and A2-receptor antagonists DPCPX (2 lmol L±1) and

DMPX (20 lmol L±1) enhanced the positive inotropic and lusitropic effects in Heart II (LVdP/dtmax

+154%, LVdP/dtmin +71%) during sequential perfusion after 30 min of ischaemia in Heart I. It is

concluded that the effects of cardiodepressant mediators released after myocardial ischaemia are

counteracted by a time-dependent release of catecholamines. Endogenous cardiac adenosine, in

turn, attenuates the modulatory effects of catecholamines.

Keywords adenosine, catecholamines, contractility, ischaemia, isolated guinea-pig heart,

reperfusion.

Received 12 August 1998, accepted 18 December 1998

Recently we have shown that after global ischaemia of

an isolated heart, cardiodepressant mediators are re-

leased during reperfusion which induce a pronounced

decrease in contractility and vasodilation in a sequen-

tially perfused second heart (double-heart model) (Felix

et al. 1997, Stangl et al. 1997). The observed negative

inotropic effect is rapid in onset, reversible, and not

caused by ionic changes, increased lactate levels, aci-

dosis or hypoxia. In addition, we excluded that the

cardiodepressant effect is mediated by free radicals,

nitric oxide, adenosine or arachidonic acid metabolites.

Initial chemical characterization indicates that the me-

diator(s) are stable, as storage of the coronary ef¯uent

at room temperature up to 24 h did not attenuate its

negative inotropic effect. Even after heating the coro-

nary ef¯uent up to 56 °C for 30 min and incubation

with proteases for 24 h at room temperature the effect

was still present, which supports the hypothesis that the

factor(s) are probably not proteins. Passage through a

0.5 kDa ®lter likewise failed to in¯uence the negative

inotropic effect, suggesting that the mediator(s) are

small molecules (Felix et al. 1997).

Interventions capable of preventing ventricular

dysfunction or accelerating functional recovery of the

myocardium following ischaemia are of clinical rele-

vance. In acute myocardial infarction, myocardial tissue

and plasma levels of catecholamines markedly increase

(Nadeau & Dechamplain 1979, Bertel et al. 1982). The

release of endogenous catecholamines induces an in-

crease in contractility of surviving myocardium, thus

counteracting myocardial contractile failure after acute

myocardial infarction. On the other hand, the increase

in myocardial catecholamine tissue levels is detrimental

because of the arrhythmogenic potential and increased

Correspondence: Dr Verena Stangl, Med. Klinik und Poliklinik I, ChariteÂ der Humboldt-UniversitaÈt, Schumannstr. 20/21, 10098 Berlin,

Germany.

Acta Physiol Scand 1999, 165, 387±393

Ó 1999 Scandinavian Physiological Society 387

myocardial oxygen requirement which accelerates pro-

gression of ischaemic cell damage (Corr & Gillis 1978,

Penny 1984, Rona 1985).

Several studies have shown that adenosine ± known

to be released after myocardial ischaemia ± antagonizes

the positive inotropic effects of catecholamines by in-

hibiting catecholamine-induced stimulation of adenylate

cyclase activity (Schrader et al. 1977, Baumann et al.

1981, Belardinelli et al. 1989, Romano et al. 1989).

Furthermore, adenosine also decreases the release of

catecholamines from the sympathetic nerves (Richardt

et al. 1987). Therefore, release of adenosine from ven-

tricular myocardium is an important compensatory

mechanism which inhibits the inotropic and detri-

mental metabolic effects of catecholamines.

The purpose of the present study was to characterize

the interactions of catecholamines, adenosine, and the

described cardiodepressant mediators released after is-

chaemia from the ®rst heart, as these interactions are

manifested by effects on the contractile parameters of

the second sequentially perfused heart (double-heart

model). As noradrenaline over¯ow becomes progres-

sively greater with longer periods of ischaemia, se-

quential perfusion of two isolated hearts was performed

after different periods (10, 20, 30 min) of global is-

chaemia in the ®rst heart. In these experiments, the

effects of the coronary ef¯uent on the second se-

quentially perfused heart were investigated in the

presence of a b blocker or an adenosine A1-receptor

antagonist in combination with an adenosine A2-re-

ceptor antagonist, or in the absence of receptor an-

tagonists. In addition, the release of endogenous

catecholamines and adenosine from the ®rst heart was

measured.

MATERIALS AND METHODS

`Double-heart model' ± sequential perfusion of two

isolated heart preparations

Sequential perfusion of two isolated hearts was per-

formed according to the technique described by

Schrader for the guinea-pig heart (Schrader &

Bardenheuer 1981), with further modi®cation as de-

scribed recently (Felix et al. 1997, Stangl et al. 1997).

Experimental protocol

After an equilibration period with perfusion at constant

pressure (60 cmH2O), the hearts were separately per-

fused at constant ¯ow of 10 mL min±1. This was fol-

lowed by sequential perfusion without (control group)

or with preceding stop ¯ow ischaemia of Heart I.

In order to investigate the modulatory action of

noradrenaline over¯ow on the observed cardiodepres-

sant effect in the second heart, three different groups

were constituted with, respectively, different ischaemic

durations. In groups I (n � 6), II (n � 6) and III

(n � 5), sequential perfusion was started after 10, 20

and 30 min of global ischaemia of the ®rst heart, re-

spectively. In additional experiments, the release of

noradrenaline into the coronary ef¯uent of Heart I was

determined in samples collected at 30-s intervals from 0

to 300 s of reperfusion (see Table 1) after a 10-

(n � 5), 20- (n � 3) and 30-min (n � 5) period of

global ischaemia by high-performance liquid chro-

matographic analyses (HPLC) measurements.

In other experiments, the second heart was also

treated with the b1-receptor antagonist metoprolol after

various durations of global myocardial ischaemia

(10 min: n � 4, 20 min: n � 4, 30 min: n � 5,

respectively). In these experiments, the intracoronary

infusion of metoprolol (2.8 lmol L±1) was started

10 min prior to sequential perfusion and continued

until the end of the experiment.

A separate series of experiments was performed to

investigate the implications of endogenous adenosine on

the catecholamine-mediated effects on Heart II. In these

experiments, Heart II was treated with an A1-receptor

antagonist in combination with an A2-receptor antago-

nist to inhibit the effects of endogenous adenosine. The

A1-adenosine receptor antagonist 1,3-dipropyl-8-

cyclopentylxanthine (DPCPX, 2 lmol L±1) and the

A2-adenosine receptor antagonist 3,7-dimethyl-L-prop-

argylxanthine (DMPX, 20 lmol L±1) were infused in-

tracoronarily into Heart II (n � 5) after a 30-min period

Table 1 Release of noradrenaline in the coronary ef¯uent of guinea-pig hearts dependent on the duration of global ischaemia

Noradrenaline content in the coronary ef¯uent (pg mL±1)

Duration of Prior to 0±30 s of 30±60 s of 60±90 s of 90±120 s of 150±180 s of 270±300 s of

global ischaemia ischaemia reperfusion reperfusion reperfusion reperfusion reperfusion reperfusion

10 min (n = 5) n.d. n.d. n.d. n.d. n.d. n.d. n.d.

20 min (n = 3) n.d. 2047 � 1250 94 � 34 33 � 8 13 � 7 n.d. n.d.

30 min (n = 5) n.d. 5819 � 2166* 500 � 194* 122 � 48* 46 � 19* n.d. n.d.

Each value (pg mL±1) represents the mean � SEM of at least three experiments performed in duplicate. *P < 0.05 vs. noradrenaline content in

the coronary ef¯uent after 20 min of global ischaemia; n.d.: not detectable.

Cardiodepressant mediators � V Stangl et al. Acta Physiol Scand 1999, 165, 387±393

388 Ó 1999 Scandinavian Physiological Society

of ischaemia of Heart I. The infusion of the two aden-

osine receptor antagonists was started 10 min prior to

sequential perfusion and then continued until the end of

the experiment. The high doses of the receptor antag-

onists were chosen to prevent all effects of adenosine up

to 1 lmol L±1 which is comparable with the concen-

trations of adenosine in the coronary ef¯uent of Heart I

after 30 min of ischaemia. Preliminary dose ®nding ex-

periments in isolated perfused hearts revealed that

DPCPX (2 lmol L±1) infused in combination with

DMPX (20 lmol L±1) blunted all effects of exogenous

adenosine up to 1 lmol L±1. The effects of intracoro-

nary infusion of the adenosine antagonists on Heart II

were also tested under control conditions without pre-

ceding ischaemia in Heart I (n � 3).

In additional experiments, the time course of the

release of adenosine into the coronary ef¯uent from

isolated hearts after ischaemia of 30 min was deter-

mined (n � 11).

High-Performance Liquid Chromatographic analyses

Catecholamines and adenosine were assayed using an

HPLC system consisting of the following: an LC

Module I system (Waters, Eschborn, Germany) con-

taining a system controller, an UV/VIS detector, an

autoinjector and a pump system, a 996 photodiode

array detector (Waters, Eschborn, Germany) for de-

termination of adenosine, and a 460 electrochemical

detector for quanti®cation of catecholamines (Waters,

Eschborn, Germany).

Sample collection and storage

The coronary ef¯uent was collected under basal con-

ditions, after 10, 20, and 30 min of global ischaemia.

The collection time for each sample for endogenous

catecholamine release was 30 s during the ®rst 5 min of

reperfusion. The samples were stored at ±80 °C until

analysed.

Determination of catecholamines

The determination of noradrenaline was performed as

previously described (Weicker 1988). Electrochemical

detection was used for quantitative analyses. It was

possible to detect noradrenaline in the range of

10±10000 pg mL±1 coronary ef¯uent.

Determination of adenosine

For the analyses a Nova-Pak reversed-phase column

(150 ´ 3.9 mm, i.d., packed with 4 lm particles;

Waters, Eschborn, Germany) was used. The column

temperature was maintained at 30 °C with a thermostat

(Modell BFO-04, Peltier, TECHLAB, Germany). The

mobile phase consisted of a 90/10 (v/v) mixture of

ammonium acetate (20 mM, pH 3.5 adjusted with 25%

HCl) with methanol. Before use, the mobile phase was

®ltered through a 0.2-lm (pore size) ®lter membrane

(Schleicher & Schuell, Dassel, Germany) under reduced

pressure. The photodiode array detector was set at

260 nm for detecting adenosine. In addition, spectra

were recorded throughout the entire chromatogram.

The mobile phase was delivered at a ¯ow rate of

1 mL min±1. All chromatograms were recorded and the

areas under the peaks of the respective analytes were

integrated with a Millenium PDA, version 2.10 (Waters,

Eschborn, Germany). Peaks representing adenosine in

the chromatograms were identi®ed on the basis of their

retention times and the respective spectra.

Statistical analysis of the data

Results are expressed as mean � standard error of the

mean (SEM) for n determinations, unless otherwise

indicated. For comparison among groups, ANOVA non-

parametric repeated measurements with data alignment

was performed. When corresponding variables of dif-

ferent groups were compared, the Mann±Whitney

U-test was used. Differences were considered signi®-

cant only if P < 0.05.

Drugs and chemicals

Metoprolol and adenosine were purchased from Sigma

Chemical (Deisenhofen, Germany). DPCPX (1,3-di-

propyl-8-cyclopentylxanthine) and DMPX (3,7-di-

methyl-L-propargylxanthine) were obtained from

Research Biochemical International (Biotrend Chemical

GmbH, Cologne, Germany).

RESULTS

Interaction of the cardiodepressant mediators

and catecholamines released from Heart I, after different

durations of ischaemia

Under control conditions, without preceding ischaemia

of Heart I, no relevant changes of left ventricular

haemodynamics were observed during sequential per-

fusion (Fig. 1a,b).

In contrast, in group I after 10 min of global is-

chaemia in Heart I, LVP (±23%), LVdP/dtmax (±46%),

LVdP/dtmin (±44%), and coronary perfusion pressure

(±23%) of Heart II decreased within 30 s when reper-

fusion was started (Fig. 1a,b). When sequential perfu-

sion was initiated after 20 min of global ischaemia of

Heart I (group II), the decrease in contractile parame-

ters in Heart II were less pronounced (LVP ±14%,

LVdP/dtmax ±28%, LVdP/dtmin ±34%). The decrease


Acta Physiol Scand 1999, 165, 387±393 V Stangl et al. � Cardiodepressant mediators

in coronary perfusion pressure (±26%) was not signif-

icantly different from that of group I. In contrast to

groups I and II, after 30 min of global ischaemia in

Heart I, the contractile parameters of Heart II at the

onset of sequential perfusion increased signi®cantly in

group III (LVP +24%, LVdP/dtmax +60%, LVdP/

dtmin +24%). Coronary perfusion pressure decreased by

24%. The heart rate did not change signi®cantly in

groups I, II and III. All parameters returned to baseline

values within 2±3 min (Fig. 1a,b).

As shown in Table 1, noradrenaline over¯ow in the

coronary ef¯uent of Heart I increased as a function of

the duration of ischaemia. After 10 min of ischaemia,

no noradrenaline was detectable in the coronary ef¯u-

ent. After 20 and 30 min of ischaemia in Heart I,

noradrenaline increased in the coronary ef¯uent

within 0.5 min to 2047 � 1250 pg mL±1 and 5819 �

2166 pg mL±1, respectively. The noradrenaline over-

¯ow returned to baseline within 3 min (Table 1).

Intracoronary infusion of the b1-receptor blocker

metoprolol (2.8 lmol L±1) into Heart II did not mod-

ulate the decrease in contractile parameters during se-

quential perfusion after 10 min of ischaemia in Heart I

(data not shown). However, when sequential perfusion

was started after 20 min ischaemia of Heart I, the

otherwise observed attenuation of the negative inotro-

pic effect was prevented by b-receptor blockade

(Fig. 2a). Furthermore, after 30-min ischaemia of Heart

I, the positive inotropic effect of the coronary ef¯uent

was completely reversed by the b-blocker treatment,

resulting in a marked decrease of left ventricular con-

tractile parameters. This decrease was almost identical

to the contractile changes in group I (Fig. 2b).

Modulation of the catecholamine effect in Heart II

by endogenous adenosine released after 30 min of global

ischaemia from Heart I

The release of adenosine was investigated after 30 min

of ischaemia in Heart I. The adenosine level in the

coronary ef¯uent was 0.07 � 0.03 lmol L±1 under

basal conditions prior to ischaemia. After 30 min of

ischaemia in Heart I, adenosine increased to

0.58 � 0.17 lmol L±1 within 0.5 min, and then de-

creased again within 5 min to 0.32 � 0.04 lmol L±1.

Under control conditions, without preceding is-

chaemia of Heart I, an intracoronary infusion of

DPCPX (2 lmol L±1) in combination with DMPX

(20 mol L±1) (n � 3) into Heart II did not in¯uence

ventricular contractile performance prior to and during

sequential perfusion (data not shown). However, when

sequential perfusion was started after 30 min of is-

chaemia in Heart I, administration of the adenosine

receptor antagonists into Heart II caused a signi®cant

augmentation of the positive inotropic and lusitropic

effects in Heart II: LVdP/dtmax and LVdP/dtmin in-

creased by 154 and 71% as compared with an increase

by 60 and 24%, in the absence of the adenosine re-

ceptor blockers (Fig. 3). Heart rate increased by 15%

(not signi®cant). The decrease in coronary perfusion

pressure in Heart II observed after 30 min of ischaemia

of Heart I (±24%) was not modulated by the A1- and

A2-receptor antagonists. When metoprolol was infused

Figure 1 (a,b) Plot over time of changes in LVdP/dtmax (a) and

LVdP/dtmin (b) in Heart II prior to and during sequential perfusion

under control conditions (without preceding ischaemia, n � 6), after

10 min of ischaemia in Heart I (group I, n � 6), after 20 min of

ischaemia in Heart I (group II, n � 6) and after 30 min of ischaemia

(group III, n � 5). Mean values are expressed in percentage of ref-

erence mean values at time zero, which are assumed to be 100%;

vertical bars are SEM. Signi®cant differences (P < 0.05) are denoted

between groups I, II, and LVdP/dtmax in group III vs. control during

the period of 20 s until 60 s of sequential perfusion. In group III

changes in LVdP/dtmin were signi®cantly different vs. control from

20 s to 50 s of sequential perfusion.



into heart II in addition to the A1- and A2-receptor

antagonists, the positive inotropic effect observed in

heart II during sequential perfusion after 30 min of

ischaemia was again reversed by the b-blocker

treatment. This resulted in a marked decrease of left-

ventricular contractile parameters comparable with the

contractile changes observed in Group I.

DISCUSSION

Using the double-heart model, we have recently re-

ported, that after myocardial ischaemia of an isolated

heart, cardiodepressant mediators are released during

reperfusion which induce a pronounced negative ino-

tropic effect in a sequentially perfused second heart

used as a bioassay (Felix et al. 1997, Stangl et al. 1997).

In this model, the cardiodepressant effect is observed in

an isolated heart which is perfused under normoxic

conditions and which had never been rendered

ischaemic.

In the present study, we demonstrated that the

pronounced negative inotropic and lusitropic effects

observed in the second sequentially perfused heart are

counteracted by catecholamines released from Heart I

after ischaemic periods longer than 10 min. Moreover,

after 30 min of global ischaemia, catecholamines re-

leased from myocardial tissue completely reversed the

cardiodepressant effect of the coronary ef¯uent of

Heart I, resulting in a pronounced increase of the left

ventricular contractile parameters of the sequentially

perfused second heart (Fig. 3a,b). This antagonistic

catecholamine-mediated positive inotropic effect was in

turn attenuated by myocardial adenosine formation.

Pretreatment of Heart II with a b-receptor antagonist

completely prevented the catecholamine-induced in-

crease in contractility, thus completely unmasking again

the negative inotropic effect.

In isolated heart preparations, periods of ischaemia

exceeding 10 min are associated with a great amount of

noradrenaline release by a non-exocytotic mechanism

resulting in a noradrenaline over¯ow into the extra-

cellular space of the ischaemic myocardium (SchoÈmig

et al. 1984, SchoÈmig et al. 1987). This noradrenaline

Figure 2 (a,b) Effect of b1-receptor blockade (metoprolol

2.8 lmol L±1) on the negative inotropic effect (LVdP/dtmax, repre-

sentative for changes in contractile parameters) observed in Heart II

during sequential perfusion after 20 min (a) or 30 min (b) of global

ischaemia in Heart I. Each point represents the mean of responses.

Error bars � SEM.

Figure 3 Plot over time of changes in LVdP/dtmax in Heart II prior

to and during sequential perfusion after 30 min of ischaemia of Heart

I under control conditions (control), during infusion of the adenosine

A1-receptor antagonist (DPCPX, 2 lmol L±1) in combination with

the A2-receptor antagonist (DMPX, 20 lmol L±1), during infusion of

metoprolol alone (2.8 lmol L±1), and during infusion of metoprolol

in combination with DPCPX and DMPX. Each point represents the

mean of responses. Error bars � SEM.



over¯ow becomes progressively greater with longer

periods of ischaemia. In contrast, ischaemic periods of

less than 10 min are associated only with an exocytotic

local catecholamine release not resulting in a nor-

adrenaline over¯ow (Dart et al. 1984, SchoÈmig et al.

1987, SchoÈmig 1988, Seyfarth et al. 1993).

Adenosine is released by the heart in association

with increased severity of ischaemia and is primarily a

chemical mediator of coronary hyperaemic ¯ow in

ischaemic myocardium (Berne 1980, Belardinelli et al.

1989). Furthermore, inhibition of exocytotic local cat-

echolamine release by adenosine (Richardt et al. 1987),

as well as inhibition of the cardiac effects of catechol-

amines, are important compensatory mechanisms for

salvaging jeopardized tissue in myocardial infarction

(Kacimi et al. 1993). In our study, administration of the

adenosine antagonists caused a signi®cant augmenta-

tion of the positive inotropic effects and a slight, but

not signi®cant increase in heart rate in Heart II during

sequential perfusion after 30-min ischaemia of Heart I,

thus unmasking the effects of cardiac catecholamines.

These results are in accordance to previous studies re-

porting that adenosine inhibits the catecholamine-

induced stimulation of adenylate cyclase activity

(Schrader et al. 1977, Baumann et al. 1981, Belardinelli

et al. 1989, Romano et al. 1991). Therefore, release of

adenosine from the heart is an important compensatory

mechanism which inhibits the inotropic and detri-

mental metabolic effects of catecholamines. Interest-

ingly, despite augmentation of the positive inotropic

and lusitropic effects observed in the second heart after

30 min of global ischaemia, the adenosine receptor

antagonists used in very high doses did not modulate

the coronary vascular response. This indicates that after

30 min of ischaemia the effects of adenosine are of

minor importance and the vasodilative properties of

other mediators should be considered.

It must be emphasized that, in our model, the effects

of cardiac mediators are ascertained in a non-ischaemic

heart perfused under normoxic conditions which was

used as a bioassay. This procedure allows investigation

of the interactions of different cardioactive mediators

released after myocardial ischaemia, independent of

cardiac malfunction induced by energy depletion owing

to ischaemia itself.

The pathophysiological signi®cance of the interac-

tions of the cardiodepressant mediators with endoge-

nous catecholamines and adenosine may be subject to

controversial discussion. Although extrapolations of

our ®ndings obtained by this arti®cial model, and their

application under clinical conditions, must take place

with caution, our data support the assumption that the

negative inotropic mediators released after myocardial

ischaemia may be bene®cial in providing the cardiac

myocyte with an endogenous protective mechanism.

The reversible decrease of myocardial contractility may

re¯ect a salutary effect in terms of energy balance, in

allowing the heart enhanced metabolic recovery before

full contractility is restored. Endogenous cardiac

adenosine release during ischaemia constitutes a further

negative feedback signal which counteracts the cate-

cholamine-induced positive inotropic effects, and

therefore also corrects an imbalance between oxygen

supply and consumption. Administration of b-blockers

in acute myocardial ischaemia inhibits the detrimental

effects of endogenous catecholamines and additionally

unmasks the negative inotropic effects of the cardio-

depressant mediators, thereby further decreasing myo-

cardial oxygen demand.

The present study was supported by the Deutsche Forschungs-

gemeinschaft (Fe 250/3.1). The technical assistance of Johannes

Hundertmark, Angelika Westphal, Adelheid Gatzke, and Thomas

DuÈsterhoÈft is gratefully acknowledged.

REFERENCES

Baumann, G., Schrader, J. & Gerlach, E. 1981. Inhibitory

action of adenosine in histamine- and dopamine-stimulated

cardiac contractility and adenylate cyclase in guinea pigs.

Circ Res 48, 259±266.

Belardinelli, L., Linden, J. & Berne, R.M. 1989. The cardiac

effects of adenosine. Prog Cardiovasc Dis 22, 73±97.

Berne, R.M. 1980. The role of adenosine in the regulation of

coronary blood ¯ow. Circ Res 47, 807±813.

Bertel, O., BuÈhler, F.R., Baitsch, G., Ritz, R. & Burkart, F.

1982. Plasma adrenaline and noradrenaline in patients with

myocardial infarction. Relationship of ventricular

arrhythmias of varying severity. Chest 82, 64±68.

Corr, P.B. & Gillis, R.A. 1978. Autonomic neural in¯uences

on the dysrhythmias resulting from myocardial infarction.

Circ Res 43, 1±9.

Dart, A.M., SchoÈmig, A., Dietz, R., Mayer, E. & KuÈbler, W.

1984. Release of endogenous catecholamines in the

ischemic myocardium of the rat. Part B: Effect of

sympathetic nerve stimulation. Circ Res 55, 702±706.

Felix, S.B., Stangl, V., Frank, T.M. et al. 1997. Release of a

stable cardiodepressant mediator after myocardial

ischaemia during reperfusion. Cardiovasc Res 35, 68±79.

Kacimi, R., Richalet, J.P. & Crozatier, B. 1993. Hypoxia-

induced differential modulation of adenosinergic and

muscarinergic receptors in rat heart. J Appl Physiol 75,

1123±1128.

Nadeau, R.A. & Dechamplain, J. 1979. Plasma catecholamines

in acute myocardial infarction. Am J Cardiol 98, 548±554.

Penny, W.J. 1984. The deleterious effects of myocardial

catecholamines on cellular electrophysiology and

arrhythmias during ischemia and reperfusion. Eur Heart J 5,

960±973.

Richardt, G., Waas, W., Kranzhofer, R., Mayer, E. &

SchoÈmig, A. 1987. Adenosine inhibits exocytotic release of

endogenous noradrenaline in rat heart: a protective

mechanism in early myocardial ischemia. Circ Res 61,

117±123.



Romano, F.D., Macdonald, S. & Dobson, J.G. Jr 1989.

Adenosine receptor coupling to adenylate cyclase of rat

ventricular myocyte membrane. Am J Physiol 257,

H1088±H1095.

Romano, F.D., Naimi, T.S. & Dobson, J.G. Jr 1991.

Adenosine attenuation of catecholamine-enhanced contrac-

tility of rat heart in vivo. Am J Physiol 260, H1635±H1639.

Rona, G. 1985. Catecholamine cardiotoxicity. J Mol Cell

Cardiol 17, 291±306.

SchoÈmig, A. 1988. Adrenergic mechanisms in myocardial

infarction: cardiac and systemic catecholamine release.

J Cardiovasc Pharmacol 12, S1±S7.

SchoÈmig, A., Dart, A. M., Dietz, R., Mayer, E. & KuÈbler, W.

1984. Release of endogenous catecholamines in the

ischemic myocardium of the rat, A: locally mediated

release. Circ Res 55, 689±701.

SchoÈmig, A., Fischer, S., Kurz, T., Richardt, G. & SchoÈmig, E.

1987. Nonexocytotic release of endogenous noradrenaline

in the ischemic and anoxic rat heart: mechanism and

metabolic requirements. Circ Res 60, 194±205.

Schrader, J. & Bardenheuer, H. 1981. Assessment of

vasoactive metabolites released from isolated guinea pig

during heart hypoxia and b-adrenergic stimulation. Basic Res

Cardiol 76, 365±368.

Schrader, J., Baumann, G. & Gerlach, E. 1977. Adenosine as

inhibitor of myocardial effects of catecholamines. P¯uÈgers

Arch 372, 29±35.

Seyfarth, M., Feng, Y., Hagl, S., Sebening, F., Richardt, G. &

SchoÈmig, G. 1993. Effect of myocardial ischemia on

stimulation-evoked noradrenaline release. Modulated

neurotransmission in rat, guinea pig, and human cardiac

tissue. Circ Res 73, 496±502.

Stangl, V., Felix, S.B., Meyer, R. et al. 1997. Cardiodepressive

mediators are released after ischemia from an isolated

heart. Role of coronary endothelial cells. JACC 29,

1390±1396.

Weicker, H. 1988. Determination of free and sulfoconjugated

catecholamines in plasma and urine by high-performance

liquid chromatography. Int J Sports Med 9, S68±S74.



cardiodepressant mediators are released after myocardial ischaemia: modulation by catecholamines and...

Documents