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Cardiovascular Research 2001 49(1):78-85; doi:10.1016/S0008-6363(00)00219-4
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Copyright © 2000, European Society of Cardiology

Myocardial interstitial norepinephrine and dihydroxyphenylglycol levels during ischemia and reperfusion

Tsuyoshi Akiyama* and Toji Yamazaki

Department of Cardiac Physiology, National Cardiovascular Center Research Institute, 5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan

* Corresponding author. Tel.: +81-6-6833-5012; fax: +81-6-6872-8092 takiyama{at}ri.ncvc.go.jp

Received 5 May 2000; accepted 3 August 2000


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 
Objective: The aim was to elucidate the relation between norepinephrine (NE) release and intraneuronal NE kinetics in the ischemic region of the in vivo heart. Methods: Using dialysis technique in the heart of anesthetized cats, we sampled dialysate from the ischemic region during 120-min coronary occlusion and reperfusion. Dialysate NE and dihydroxyphenylglycol (DHPG) contents were measured as indexes of myocardial interstitial NE and DHPG levels. Results: Within 20 min of occlusion, interstitial NE levels increased while DHPG levels decreased. This NE increase was suppressed by {omega}-conotoxin GVIA and enhanced by desipramine. These data suggest that axoplasmic NE levels increased by neuronal reuptake following exocytotic release, while intraneuronal DHPG production was suppressed due to the reduced monoamine oxidase activity. After 20 min of occlusion, interstitial NE levels increased markedly, accompanied by increased DHPG levels. This NE increase was suppressed by desipramine. These findings imply that NE mobilization from stored vesicles to axoplasma exceeded outward NE transport through uptake1 carrier in the amount of NE, and that a substantial increase in axoplasmic NE levels compensated for the reduced monoamine oxidase activity. After reperfusion, interstitial NE levels rapidly decreased while DHPG levels increased further. Both responses in NE and DHPG were suppressed by desipramine, indicating the involvement of recovered neuronal reuptake function. Conclusions: In the ischemic region, intraneuronal DHPG production was affected by alterations in monoamine oxidase activity, NE mobilization from stored vesicles, and carrier-mediated NE transport. The involvement of these factors in intraneuronal NE kinetics varied with the time of occlusion and reperfusion.

KEYWORDS Autonomic nervous system; Ca-channel; Ischemia; Neurotransmitters; Reperfusion


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 References
 
In the isolated perfused rat heart, it has been demonstrated that myocardial ischemia evokes an excessive norepinephrine (NE) efflux from cardiac sympathetic nerve endings [1–5]. The outward NE transport through uptake1 carrier has been proposed as an important mechanism responsible for the ischemia-induced NE release [1,5]. Carrier-mediated NE efflux from axoplasma to the interstitial space is associated with alterations in axoplasmic free NE levels [6]. The axoplasmic NE concentration is regulated by various factors such as vesicle transport into stored vesicles, leakage from stored vesicles, inward and outward NE transport through uptake1 carrier, and intraneuronal degradation (Fig. 1). To better understand the ischemia-induced NE release, it is important to know intraneuronal NE kinetics during myocardial ischemia.


Figure 1
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  		Fig. 1 Schema of putative factors affecting NE kinetics in the cardiac sympathetic nerve endings. NE, norepinephrine; DHPG, dihydroxyphenylglycol; MAO, monoamine oxidase.

 
To examine intraneuronal NE kinetics in the heart, the measurement of dihydroxyphenylglycol (DHPG) production has been widely used. In the cardiac sympathetic nerve endings, axoplasmic free NE is subjected to deamination by monoamine oxidase [7] and DHPG is exclusively produced [8–11]. DHPG is a highly lipophilic metabolite that penetrates the membrane of sympathetic nerve endings by diffusion [12]. Thus, extraneuronal DHPG levels indicate the axoplasmic NE concentration and provide certain information about intraneuronal NE kinetics. In the in vivo heart, however, there has been no study simultaneously investigating NE release and DHPG production during myocardial ischemia.

Previously, using the dialysis technique in the in vivo heart, we demonstrated that coronary occlusion evokes massive NE release in the ischemic region [13], and that carrier-mediated NE release is partly involved in this NE release [14,15]. Moreover, we have reported that dialysis technique makes it possible to simultaneously monitor myocardial interstitial NE and DHPG levels [16]. Therefore, we consider it possible to elucidate the relation between NE release and intraneuronal NE kinetics in the ischemic region of the in vivo heart. In the present study, we applied dialysis technique to the heart of anesthetized cats and investigated myocardial interstitial NE and DHPG levels during coronary occlusion and reperfusion.


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 References
 
2.1 Animal preparation
The investigation conformed 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). Adult cats of either sex weighing 2.5–4.2 kg were anesthetized with pentobarbital sodium (30–35 mg/kg i.p.). The level of anesthesia was maintained with a continuous intravenous infusion of pentobarbital sodium (1–2 mg/kg/h). The animals were intubated and ventilated with a constant-volume respirator using room air mixed with oxygen. Heart rate, arterial pressure, and electrocardiogram were monitored and recorded continuously. A heating pad and lamp were used to keep the epicardial and core temperatures within the range of 36–38°C. Heparin sodium (200 U/kg) was administered intravenously and then 100 U/kg was given every 2 h to prevent blood coagulation.

With the animal in the lateral position, the fifth or sixth rib on the left side was partially removed to expose the heart. A small incision was made in the pericardium, and the dialysis probe was implanted in the region perfused by the left anterior descending coronary artery (LAD) of the left ventricular wall. A snare was placed around LAD just distal to the first diagonal branch, to act as the occluder for later coronary occlusion. To ensure that the sampling area was in the ischemic region, we examined the color and motion of the ventricular wall during a brief occlusion and confirmed that the dialysis probe was correctly located.

2.2 In vivo dialysis technique (Fig. 2)
Materials suitable for cardiac dialysis probe have been described in detail elsewhere [16,17]. Briefly, we designed a handmade long transverse dialysis probe. One end of a polyethylene tube (25 cm length, 0.5 mm O.D., and 0.2 mm I.D.) was dilated with a 27-gauge needle (0.4 mm O.D.). Each end of the dialysis fiber (13 mm length, 0.31 mm O.D., and 0.20 mm I.D.; PAN-1200 50 000 molecular weight cutoff, Asahi Chemical, Japan) was inserted into the polyethylene tube and glued. We used a fine guiding needle (30 mm length, 0.51 mm O.D., and 0.25 mm I.D.) for implantation of the dialysis probes. We connected a guiding needle to a dialysis probe with a stainless rod (5 mm length and 0.25 mm O.D.).


Figure 2
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  		Fig. 2 Schema of a dialysis technique in the heart. Dialysis probe was implanted in the ischemic region and perfused with a microinjection pump. Dialysate from ischemic region was sampled in a microtube. NE, norepinephrine; DHPG, dihydroxyphenylglycol; LAD, left anterior descending coronary artery.

 
Dialysis probes were perfused with Ringer's solution or Ringer's solution containing pharmacological agents at a speed of 10 µl/min using a microinjection pump (Carnegie Medicin CMA/100). Ringer's solution consisted of (in mM) 147.0 NaCl, 4.0 KCl, 2.25 CaCl2. One sampling period was 4 min (1 sampling vol=40 µl). Each sample was collected in a microtube containing 4 µl of 0.1 N HCl to prevent amine oxidation. Two thirds of the dialysate sample was used for the measurement of NE and the remaining one third for the measurement of DHPG. NE and DHPG assays were separately conducted using each high-performance liquid chromatography with electrochemical detection as previously described [18,19]. Dialysate NE and DHPG concentrations were used as indexes of myocardial interstitial NE and DHPG levels. Based on the results of our previous study [17], we discarded the first 120 min of dialysate and commenced the protocol 120 min after probe implantation. From the length and the internal diameter of the polyethylene tube, we calculated a dead space of 7.9 µl between the dialysis fiber and sample tube. We took account of this space at the start of each dialysate sampling.

2.3 Experimental protocols
After control sampling, we occluded LAD and sampled dialysate from the ischemic region during 120-min of coronary occlusion and reperfusion.

2.3.1 Protocol 1: vehicle
First, we observed the time course of dialysate NE and DHPG concentrations in the ischemic region in six cats. At 60 min after reperfusion, we locally administered tyramine (NE-releasing sympathomimetic amine, 60 µM) through a dialysis probe for 10 min and observed the responses of dialysate NE and DHPG.

2.3.2 Protocol 2: {omega}-conotoxin GVIA
To examine the involvement of exocytotic NE release triggered by Ca2+ influx through N-type Ca2+ channels in the ischemia-induced NE release, we locally administered the voltage-dependent N-type Ca2+ channel blocker {omega}-conotoxin GVIA (10 µM) through a dialysis probe, and observed the responses of dialysate NE and DHPG in the ischemic region in seven cats.

2.3.3 Protocol 3: desipramine
To examine the involvement of NE transport through uptake1 carrier in the ischemia-induced NE release, we locally administered the inhibitor of uptake1 carrier desipramine (10 µM) through a dialysis probe, and observed the responses of dialysate NE and DHPG in the ischemic region in six cats.

At the end of the experiment the cats were sacrificed with pentobarbital sodium, and the implant sites were examined. The dialysis probes had been implanted in the middle layer of the myocardium of the left ventricular wall; no bleeding was found macroscopically.

2.4 Statistical methods
First to examine the influence of coronary occlusion and reperfusion, we analyzed the timecourse of heart rate, mean arterial pressure and dialysate NE and DHPG in the vehicle group by using one-way analysis variance with repeated measures. Second to examine the effect of pharmacological agents, we analyzed the differences in heart rate, mean arterial pressure, and dialysate NE and DHPG at each time among three groups by using one-way analysis variance. When a statistical significance was detected, the Newman–Keuls test was applied [20]. Statistical significance was defined as P<0.05. Values are presented as means±S.E.


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 References
 
3.1 Heart rate and mean arterial pressure
In protocol 1, heart rate significantly decreased from 184±13 in control to 143±12 beats/min at 10 min of coronary occlusion. During occlusion, heart rate gradually recovered and reached 164±10 beats/min at 120 min of occlusion. After reperfusion heart rate significantly decreased to 139±12 beats/min. Mean arterial pressure significantly decreased from 118±5 in control to 97±6 mmHg at 10 min of occlusion and maintained this level up to the reperfusion. After reperfusion, mean arterial pressure significantly decreased to 84±4 mmHg. In protocol 2 and 3, local administration of pharmacological agents did not influence the responses of heart rate or mean arterial pressure.

3.2 Dialysate NE and DHPG concentrations in the ischemic region
3.2.1 Protocol 1: vehicle (Fig. 3)
The control dialysate NE concentration was 17±3 pg/ml. The dialysate NE concentration gradually and significantly increased within 20 min of coronary occlusion. After 20 min of occlusion, the dialysate NE concentration markedly increased and reached 4908±790 pg/ml at 60 min of occlusion. This NE level was maintained up to the reperfusion. After reperfusion, the dialysate NE concentration rapidly decreased.


Figure 3
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  		Fig. 3 Dialysate NE and DHPG concentrations in the ischemic region, and responses of dialysate NE and DHPG to tyramine. NE, norepinephrine; DHPG, dihydroxyphenylglycol; r, reperfusion. Values are means±S.E. *P<0.05 vs. value of control; {dagger}P<0.05 vs. value at 120 min of occlusion.

 
The control dialysate DHPG concentration was 163±11 pg/ml. The dialysate DHPG concentration slightly but significantly continued to decrease within 20 min of occlusion and reached 121±21 pg/ml at 20 min of occlusion. After 20 min of occlusion, the dialysate DHPG concentration continued to increase and reached 421±74 pg/ml at 120 min of occlusion. After reperfusion, the dialysate DHPG concentration further increased to 869±167 pg/ml.

At 60 min after reperfusion, the dialysate NE concentration was significantly increased by tyramine (from 796±684 to 4584±1153 pg/ml). The dialysate DHPG concentration was slightly increased by tyramine, but this increase was not significant.

3.2.2 Protocol 2: {omega}-conotoxin GVIA (Figs. 4 and 5Go)
The control dialysate NE concentration was 11±1 pg/ml, which was significantly lower than that in the vehicle group. {omega}-Conotoxin significantly suppressed the increase in the dialysate NE concentration within 20 min of coronary occlusion. But after 20 min of occlusion, the dialysate NE concentration markedly increased and the dialysate NE concentration was almost the same as that in the vehicle group.


Figure 4
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  		Fig. 4 Influence of {omega}-conotoxin GVIA and desipramine on dialysate NE concentration in the ischemic region. NE, norepinephrine; r, reperfusion. Values are means±S.E. *P<0.05 vs. concurrent value in the vehicle.

 

Figure 5
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  		Fig. 5 Influence of {omega}-conotoxin GVIA and desipramine on dialysate DHPG concentration in the ischemic region. DHPG, dihydroxyphenylglycol; r, reperfusion. Values are means±S.E. *P<0.05 vs. concurrent value in the vehicle.

 
The dialysate DHPG concentration in control was 145±13 pg/ml. This mean value was 89% of that in vehicle. The dialysate DHPG concentration decreased within 20 min of occlusion and increased after 20 min of occlusion. After reperfusion, the dialysate DHPG concentration increased further. During occlusion and reperfusion, there were no significant differences in the dialysate DHPG response between protocols 1 and 2.

3.2.3 Protocol 3: desipramine (Figs. 4 and 5Go)
The control dialysate NE concentration was 96±16 pg/ml, which was about five times that in the vehicle group. The dialysate NE concentration was higher than that in the vehicle group within 20 min of coronary occlusion. But desipramine significantly suppressed the increase in the dialysate NE concentration at 40 min of occlusion. Compared with the data in protocol 1, the dialysate NE concentration was suppressed by 54% at 40 min of occlusion and by 38% at 60 min of occlusion. The dialysate NE concentration gradually increased and reached almost the same level as that in the vehicle group at 100 min of occlusion. After reperfusion, the dialysate NE concentration transiently increased.

The control dialysate DHPG concentration was 126±9 pg/ml. This mean value was 77% of that in vehicle. Desipramine did not alter the dialysate DHPG response within 20 min of occlusion. After 20 min of occlusion the dialysate DHPG concentration gradually increased and reached 159±16 pg/ml at 120 min of occlusion. After reperfusion, the dialysate DHPG concentration increased to 252±21 pg/ml. Compared with protocol 1, the increase in dialysate DHPG concentration was significantly suppressed after 40 min of occlusion and reperfusion.


   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
References
 
Using dialysis technique in the in vivo heart, we observed myocardial interstitial NE and DHPG levels in the ischemic region during coronary occlusion and reperfusion. According to the responses of DHPG production to the interventions tested, we divided the ischemic period into two phases.

4.1 Within 20 min of coronary occlusion
Myocardial interstitial NE levels gradually and significantly increased within 20 min of occlusion. The N-type Ca2+ channel blocker {omega}-conotoxin GVIA significantly suppressed this increase. Thus, this increase could be mainly due to exocytotic NE release triggered by Ca2+ influx through N-type Ca2+ channels [21,22]. Desipramine evoked the increase in myocardial interstitial NE levels in this phase. This increase could be due to the inhibition of inward NE transport through uptake1 carrier [23]. Therefore, we consider the inward NE transport, which is the normal transport of uptake1 carrier, to remain active in this phase.

Myocardial interstitial DHPG levels slightly but significantly decreased within 20 min of occlusion. This indicates that DHPG production is suppressed in this phase. When exocytotic NE release is activated under the condition of intact reuptake function, inward NE transport through uptake1 carrier raises axoplasmic NE levels and DHPG production is enhanced [11,24]. Our NE data suggest that neuronal reuptake and exocytotic release remain active in this phase. Therefore, it could be difficult to interpret the suppressed DHPG production as an alteration in axoplasmic NE levels. Monoamine oxidase, the enzyme involved in the formation of DHPG, is an oxygen-requiring enzyme [25]. The decrease in DHPG production may be explained by the reduction in monoamine oxidase activity rather than decrease in axoplasmic NE as a substrate.

4.2 During the 20–120 min of coronary occlusion
Myocardial interstitial NE levels markedly increased after 20 min of occlusion. This increase was not suppressed by {omega}-conotoxin GVIA, but was significantly suppressed by desipramine at 40 min of occlusion. This result is compatible with earlier in vitro studies [1,5]. Desipramine inhibits both directions of NE transport through uptake1 carrier [1,5,6]. Therefore, outward NE transport through uptake1 carrier could be involved in this increase.

In contrast to the early phase of ischemia, myocardial interstitial DHPG levels began to increase after 20 min of occlusion. This enhancement of DHPG production indicates that monoamine oxidase activity dose not vanish. A substantial increase in axoplasmic free NE provides more substrate to monoamine oxidase, which compensates for the reduction in monoamine oxidase activity [26]. Therefore, we consider axoplasmic NE levels to be substantially high in this phase. Intraneuronal degradation and outward NE transport through uptake1 carrier could contribute to the decrease in axoplasmic NE levels. Our DHPG data indicate that net leakage from stored vesicles to axoplasma exceeds intraneuronal degradation and outward NE transport through uptake1 carrier in the amount of NE.

Desipramine inhibited the carrier-mediated outward transport of axoplasmic NE at 40 min of occlusion. Therefore one would expect that desipramine should further raise axoplasmic NE levels and enhance DHPG production. In the present study, however, desipramine significantly suppressed the increase in myocardial interstitial DHPG levels during occlusion. This result is in line with earlier in vitro studies [3,5] and suggests that increase in axoplasmic NE levels during ischemia is suppressed by desipramine. But suppression by desipramine can not be explained by inhibitory action on uptake1 carrier. Desipramine might have an additional action in reducing the net leakage of NE from storage vesicles [3,5].

Neither {omega}-conotoxin GVIA nor desipramine suppressed the increase in myocardial interstitial NE after 80 min of occlusion. Desipramine continued to suppress DHPG production after 80 min of occlusion. These results suggest another mechanism for NE release insensitive to {omega}-conotoxin GVIA and desipramine, which may not be associated with any alteration in axoplasmic NE levels. Recently, several groups have reported other mechanisms for NE release during ischemia, including exocytotic release independent of Ca2+ influx through N-type Ca2+ channel [15,27,28]. These mechanisms may be involved in NE release in the late phase of ischemia.

4.3 After reperfusion
Myocardial interstitial NE levels rapidly decreased after reperfusion. Washout of retained NE from the interstitial space may contribute to this decrease after reperfusion. In the presence of desipramine, however, myocardial interstitial NE levels further increased after reperfusion. This result indicates that uptake1 carrier resumes normal transport function after reperfusion, and that the inward NE transport through uptake1 carrier is largely involved in the decrease in interstitial NE levels.

Myocardial interstitial DHPG levels further increased after reperfusion. This enhancement of DHPG production may result from the recovery of monoamine oxidase activity by reoxygenation. Desipramine significantly suppressed this increase in myocardial interstitial DHPG levels after reperfusion. This finding indicates that inward NE transport after reperfusion raises axoplasmic NE levels and enhances DHPG production.

The myocardial interstitial NE concentration was substantially increased in the ischemic region by tyramine. DHPG production was slightly increased by tyramine. Tyramine is carried into the axoplasma through uptake1 carrier and subsequently transported to stored vesicles through vesicle transporter, and then tyramine displaces NE from stored vesicles into axoplasma as well as from axoplasma into the interstitial space [29,30]. If the vesicle transport from axoplasma into stored vesicles is impaired, tyramine displaces only axoplasmic NE into the interstitial space, leading to a decrease in axoplasmic NE and decrease in DHPG production [30]. Therefore, our results suggest that not only uptake1 carrier but also vesicular transport system resumes normal function after reperfusion.

4.4 Methodological considerations
With the same preparation, myocardial blood flow in the ischemic region was decreased to about 20% of that in control by coronary occlusion [13]. Decreased myocardial blood flow may reduce the washout of NE and DHPG from the interstitial space and influence myocardial interstitial NE and DHPG levels. The washout factor may be partly involved in the gradual increase in myocardial interstitial NE within 20 min of occlusion. But considering the decrease in myocardial interstitial DHPG levels within 20 min of occlusion, washout would not be an important factor raising myocardial interstitial NE and DHPG levels in our experiment.

Our findings suggest an additional action of desipramine on intraneuronal NE kinetics. Furthermore, studies with brain synaptosomes have observed that desipramine suppress Ca2+ influx through voltage-dependent Ca2+ channels and reverse-mode of Na+–Ca2+ exchange at high concentration [31]. Thus, desipramine might have additional inhibitory actions on ischemia-induced NE release except inhibition of uptake1 carrier. Further studies are needed to elucidate the effect of desipramine on ischemia-induced NE release.

Dialysis technique made it possible to estimate simultaneously NE release and DHPG production and administer pharmacological agents in the in vivo cardiac ischemic region. Our in vivo findings of NE release were compatible with earlier in vitro studies using isolated perfused heart. But findings of DHPG production highlighted the complexity in the mechanisms responsible for NE release during ischemia.

Time for primary review 31 days.


   Acknowledgements
 
This study was supported by grants in aid for scientific research from the Ministry of Education, Science, and Culture of Japan and by a grant from the Technology Agency, Encourage System of COE.


   References
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 

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