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Cardiovascular Research 2007 74(3):438-444; doi:10.1016/j.cardiores.2007.02.018
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Copyright © 2007, European Society of Cardiology

Cardiac epinephrine synthesis and ischemia-induced myocardial epinephrine release

Yosuke Kurokoa, Toji Yamazakib,*, Noriyuki Tokunagaa, Tsuyoshi Akiyamab, Hirotoshi Kitagawab, Kozo Ishinoa, Shunji Sanoa and Hidezo Morib

aDepartment of Cardiovascular Surgery, Okayama University Graduate School of Medicine and Dentistry, Okayama, 700-8558, Japan
bDepartment of Cardiac Physiology, National Cardiovascular Center Research Institute, 5-7-1 Fujishiro-dai, Suita, Osaka, 565-8565, Japan

* Corresponding author. Tel.: +81 6 6833 5012x2379; fax: +81 6 6872 8092. Email address: yamazaki{at}ri.ncvc.go.jp

Received 4 September 2006; revised 13 February 2007; accepted 14 February 2007


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 
Objective: Phenylethanolamine-N-methyltransferase (PNMT), the enzyme that synthesizes epinephrine (EPI) from norepinephrine (NE) in the adrenal gland, is present in extra-adrenal tissues including heart. Ischemia evokes an excessive NE accumulation in the myocardial interstitial spaces. Therefore, cardiac PNMT activity with high NE levels may contribute to cardiac EPI synthesis and release evoked by ischemia.

Methods: We measured dialysate EPI levels in the left ventricle of anesthetized rabbits using a cardiac microdialysis technique. The dialysate EPI level served as an index of the myocardial interstitial EPI level. Locally administered NE-induced dialysate EPI responses were measured. The left circumflex coronary artery was occluded for 60 min and the dialysate EPI and NE levels in the ischemic region were measured. Coronary occlusion-induced EPI responses were compared with and without administration of a PNMT inhibitor (SKF29661) in the presence and absence of desipramine (catecholamine transport blocker).

Results: Local administration of NE (250, 2500 ng/ml) increased the EPI levels to 734±125 and 2088±367 pg/ml respectively. These increases in dialysate EPI were suppressed by the PNMT inhibitor. Acute myocardial ischemia significantly increased the EPI levels to 3607±1069 pg/ml in the ischemic region, and these were suppressed by the PNMT inhibitor (1417±581 pg/ml). The pretreatment with desipramine suppressed ischemia-induced EPI release, which did not differ with (725±155 pg/ml) and without administration of a PNMT inhibitor (743±172 pg/ml).

Conclusion: The cardiac PNMT in the left ventricle is capable of synthesizing EPI with markedly elevated NE levels in the myocardial interstitial space.

KEYWORDS Autonomic nervous system; Interstitial space; Ischemia; Reperfusion; Neurotransmitters


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 References
 
It is generally accepted that myocardial ischemia evokes an excessive catecholamine accumulation in the myocardial interstitial space [1,2]. This high catecholamine level in the myocardial interstitium is thought to aggravate the progression of myocardial cell injury and incidence of malignant arrhythmia [3,4]. From in vitro and in vivo studies, several mechanisms are presently suggested to induce release of norepinephrine (NE) from the nerve endings [1,5,6]. The outward NE transport through uptake1 carrier has been proposed as an important mechanism responsible for the ischemia-induced NE release. With respect to epinephrine (EPI), however, it is uncertain whether the mechanism of release differs between EPI and NE.

EPI is synthesized mainly from NE in the adrenal medulla by phenylethanolamine N-methyltransferase (PNMT) [7] and released into the bloodstream [8]. Myocardial ischemia evokes an excessive NE and EPI accumulation in the myocardial interstitial space although the blood supply is blocked. Therefore, regional release mechanism has been suggested to induce release of EPI in the ischemic region. Early studies reported that PNMT activity was measured in homogenates from the heart [9,10]. Excessive NE level and cardiac PNMT activity may provide the prerequisite for cardiac EPI synthesis evoked by ischemia. We speculate that ischemia may promote EPI synthesis and release by high NE accumulation via cardiac PNMT activity.

We have demonstrated the usefulness of dialysis technique for the in vivo monitoring of regional myocardial interstitial catecholamine kinetics [11,12]. In the present study, we extend this approach to assessment of PNMT activity using NE as a substrate of EPI synthesis. We examined the role of PNMT activity in the EPI release evoked by myocardial ischemia. Furthermore, we examined the contribution of neuronal catecholamine transport to EPI release evoked by ischemia.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 References
 
2.1 Animal preparation
Animal care proceeded in strict accordance with the Guide for the Care and Use of Laboratory Animals published by the US National Institute of Health (NIH Publication No. 85-23, revised 1996). Adult Japanese white rabbits (2.5–3.3 kg) were anesthetized with pentobarbital sodium (30–35 mg/kg i.v.). The level of anesthesia was maintained with a continuous intravenous infusion of pentobarbital sodium (1–2 mg/kg/h). The rabbits were intubated and ventilated with room air mixed with oxygen. Heart rate, arterial pressure, and electrocardiogram were simultaneously monitored with a data recorder. The fifth or sixth rib on the left side was partially removed to expose the heart. A snare was placed around the main branch of the left circumflex coronary artery (LCX) to act as the occluder for later coronary occlusion. With a fine guiding needle, a dialysis probe was implanted in the region perfused by LCX of the left ventricular wall. Judging from changes in the color of the ventricular wall during a brief coronary occlusion, the dialysis probe was located in the midst of the ischemic region. Heparin sodium (100 IU/kg) was administered intravenously to prevent blood coagulation.

2.2 Dialysis technique and epinephrine measurements
Materials suitable for cardiac dialysis probes have been described in detail elsewhere [13]. Briefly, we designed a handmade long transverse dialysis probe. A dialysis fiber (8 mm length, 0.31 mm o.d., and 0.20 mm i.d.; PAN-1200 50,000 molecular weight cutoff, Asahi Chemical Japan) was glued at both ends of a polyethylene tube. The dialysis probe was perfused with Ringer's solution or Ringer's solution containing pharmacological agents at a perfusion speed of 2 µl/min using a microinjection pump (Carnegie Medicine CMA/100). One sampling period was 15 min (1 sampling volume=30 µl). Each sample was collected in a microtube containing 3 µl of 0.1 N HCl to prevent amine oxidation. Dialysate EPI and NE level were measured by high-performance liquid chromatography with electrochemical detection (ECD-300, Eicom, Kyoto, Japan) as previously described [14,15]. Dialysate EPI level served as an index of myocardial interstitial EPI level. We commenced the protocol followed by a stabilization period of 2 h. Taking into consideration the dead space between the dialysis fiber and sample tube, we sampled the dialysate.

2.3 Experimental protocols
2.3.1 Dialysate EPI levels during local administration of NE
First, to elucidate cardiac PNMT activity, we locally administered NE. The concentration of NE was chosen to be in the same range as in the myocardial ischemic region based on the results of our previous study [6]. After control sampling, we locally administered NE (250 or 2500 ng/ml) through a dialysis probe for 60 min, with dialysate collected during the last 15 min. The same protocol was followed after administration of a PNMT inhibitor (SKF29661) [16] in separate rabbits. SKF29661 (50 mg/kg) was administered intraperitoneally 60 min before control sampling. To confirm whether PNMT activity was located in sympathetic nerve endings or myocardium, we performed chemical sympathetic denervation with hydroxydopamine (6-OHDA) and examined the dialysate EPI response to local NE infusion. Five days previously, rabbits were given 60 mg/kg 6-OHDA intravenously [17]. Dialysate EPI response to NE infusion was measured. Furthermore, we examined the effect of NE uptake2 inhibition on the EPI response to local NE infusion. We added corticosterone (1 mM) on the perfusate and measured the dialysate EPI response to local NE infusion.

2.3.2 Time course of dialysate EPI levels during the myocardial ischemia in the presence and absence of SKF29661
After control sampling, we occluded the main branch of LCX for 60 min and then released the occluder. We observed the time course of dialysate EPI levels in the ischemic region in six rabbits. We collected five consecutive 15-minute dialysate samples during coronary occlusion and reperfusion (vehicle group). To examine the involvement of PNMT activity on the EPI level, we intraperitoneally administered a PNMT inhibitor (SKF29661) 60 min before control sampling in separate rabbits (SKF group). We performed LCX occlusion and collected dialysate samples as described in vehicle group. We compared EPI responses to LCX occlusion between vehicle and SKF groups.

2.3.3 Influence of desipramine on dialysate EPI levels during myocardial ischemia with and without SKF29661
EPI can be released via non-exocytotic release at the sympathetic nerve terminals [18]. To elucidate the involvement of catecholamine transporter on EPI levels, we locally administered an inhibitor of NE uptake1 carrier desipramine (100 µM) through a dialysis probe. One hour thereafter, we performed LCX occlusion and collected dialysate samples in the above-described protocol in separate rabbits (desipramine group). Furthermore, we tried to determine the influence of desipramine on PNMT induced EPI release during myocardial ischemia. We co-administered intraperitoneally SKF29661 (50 mg/kg) and desipramine locally through a dialysis probe continuously 60 min before control sampling (desipramine+SKF group). We performed LCX occlusion and collected dialysate samples as described in vehicle group. We compared EPI responses to LCX occlusion between desipramine and desipramine+SKF groups.

At the end of each experiment, the rabbits were killed with an overdose of pentobarbital sodium, and the implant regions were checked to confirm that the dialysis probe had been implanted within the cardiac muscle.

2.4 Statistical methods
The effects of myocardial ischemia (NE infusion) and pretreatment were examined using two-way analysis of variance. When statistical significance was detected between two groups, the dialysate EPI levels with and without a PNMT inhibitor were compared by unpaired t-test. The dialysate NE levels were compared among four groups using one-way analysis variance followed by Newman–Keuls test for the multiple comparisons against each other. The data of heart rate and mean arterial pressure were compared among four groups using two-way analysis variance. When statistical significance was detected, the Newman–Keuls test was applied. Statistical significance was defined as P<0.05. Values are presented as means±SE.


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 References
 
3.1 Time course of heart rate and mean arterial pressure
Local administration of NE through a dialysis probe did not alter heart rate (HR) or mean arterial pressure (MAP) in vehicle or SKF groups. The time course of HR and MAP during myocardial ischemia and reperfusion is shown in Table 1. Coronary occlusion tended to cause a fall in HR and MAP, but no statistically significant alterations in HR or MAP were obtained against a baseline value within each group. Basal HR in vehicle group was lower than that in the other three groups.


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  		Table 1 Time course of heart rate and mean arterial pressure during coronary occlusion and reperfusion

 
3.2 Dialysate EPI response during local NE administration through a dialysis probe
Fig. 1 shows data obtained from local administration of exogenous NE through a dialysis probe. Dialysate EPI levels increased significantly with increases in the rate of NE infusion. Dialysate EPI levels reached 734.5±125, and 2081±367 pg/ml (n=6) at 250 and 2500 ng/ml of NE infusion, respectively. In the presence of SKF29661, dialysate EPI levels were significantly suppressed compared to those of the vehicle group. Dialysate EPI levels were 68±25, 282±70 pg/ml (n=6) at 250 and 2500 ng/ml of NE infusion, respectively. SKF29661 attenuated EPI responses to 10% of vehicle group. In sympathetic denervation with 6-OHDA, the dialysate EPI response to NE infusion (250 ng) was preserved (n=4, 760±193 pg/ml). With the perfusate containing the NE uptake2 inhibitor, corticosterone (1 mM), the dialysate EPI response to NE infusion (250 ng) was suppressed (n=6, 167±27 pg/ml).


Figure 1
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  		Fig. 1 Dialysate epinephrine levels evoked by norepinephrine perfusion through dialysis probe. SKF = SKF29661, *P<0.05 vs. value at 0–15 min of norepinephrine perfusion, {dagger} P<0.05 vs. concurrent value of vehicle group.

 
3.3 Dialysate EPI levels in the ischemic region
Coronary occlusion significantly increased dialysate EPI levels (Fig. 2). In the vehicle group, dialysate EPI levels were 59.6±39.8 pg/ml in the control and increased after coronary occlusion. During 60 min coronary occlusion, dialysate EPI levels markedly increased and reached 15030±7418 pg/ml (n=6) at 45–60 min of occlusion. After reperfusion, dialysate EPI levels decreased to 7193±3722 pg/ml, although their levels were higher than those in the control. In the presence of SKF29661, dialysate EPI levels also increased and reached 1493±196 pg/ml (n=6) at 45–60 min of occlusion. These increases in dialysate EPI levels after 30 min of coronary occlusion were significantly attenuated by SKF29661.


Figure 2
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  		Fig. 2 Time course of dialysate epinephrine levels during coronary occlusion. Values are means±SE. {dagger} P<0.05 vs. concurrent value of vehicle group.

 
3.4 Dialysate EPI levels in the ischemic region during local desipramine administration
Although coronary occlusion increased dialysate EPI levels, these levels were suppressed during local desipramine administration compared to the vehicle group (Fig. 3). During 60 min coronary occlusion, dialysate EPI levels increased and reached 743±171 pg/ml (n=6) at 45–60 min of occlusion. After reperfusion, dialysate EPI levels decreased to 400±181 pg/ml, although their levels were higher than those in the control. In the presence of SKF29661, dialysate EPI levels also increased and reached 725±154 pg/ml (n=6) at 45–60 min of occlusion. These increases in dialysate EPI levels were not attenuated by SKF29661.


Figure 3
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  		Fig. 3 Influence of desipramine on dialysate EPI levels during myocardial ischemia with and without SKF29661. DMI = desipramine, DMI+SKF=desipramine+SKF29661. Values are means±SE.

 
3.5 Comparison of peak dialysate NE levels of the 4 groups
EPI is synthesized from NE, and so myocardial interstitial NE levels might affect myocardial interstitial EPI levels. We compared with myocardial interstitial NE levels at 45–60 min of coronary occlusion in the vehicle group, the SKF29661 group, the desipramine group and the desipramine and SKF29661 group (Fig. 4) (n=6-6-6-6). In the latter two groups (desipramine, desipramine+SKF29661), ischemia-induced peak dialysate NE levels were significantly suppressed in comparison with that of the vehicle or SKF29661 group. Calculated ratios of interstitial EPI/NE were 1.5±0.4 and 12±4% at NE infusion (250 ng) and 45–60 min of occlusion, respectively.


Figure 4
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  		Fig. 4 Dialysate norepinephrine responses to 60 min coronary occlusion. SKF = SKF29661, DMI = desipramine, DMI+SKF=desipramine+SKF29661.Values are means±SE. *P<0.05 vs. value of vehicle group. {dagger} P<0.05 vs. value of SKF group.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
References
 
4.1 Changes in myocardial interstitial EPI levels during local administration of NE through a dialysis probe
Local administration of NE dose dependently increased dialysate EPI levels. The pretreatment with PNMT inhibitor SKF29661 significantly suppressed these increases. Therefore, the EPI levels in dialysate could serve as an index of PNMT activity during local administration of NE. To our knowledge, this is the first direct assessment of cardiac PNMT activity in in vivo heart. These results indicate that EPI can be regionally synthesized from NE with PNMT activity in the heart. Regionally administered NE in myocardial interstitium was taken up by cardiac sympathetic nerve endings via the uptake1 carrier or by extraneuronal cells via uptake2 carrier [19–21]. Several studies demonstrated the existence of PNMT in the myocardium rather than sympathetic nerve endings [17,22]. In sympathetic denervation with 6-OHDA, the dialysate EPI response to NE infusion was preserved. The dialysate EPI response was suppressed by pretreatment with corticosterone (an NE uptake2 inhibitor). Our data were also consistent with those studies. NE might be taken up by myocardial cell via uptake2 carrier and converted to EPI with PNMT. Recent study has shown that gene expression of the PNMT is localized not in cardiac ganglion, but in cardiomyocytes [23]. Therefore, our data suggest that high NE level in myocardial interstitium yields EPI synthesis by regional PNMT activity. NE that was taken up by extraneuronal cells was metabolized mainly to normetanephrine (NMN) or 3-methoxy-4-hydroxyphenylglycol (MHPG) by catechol O-methyltransferase (COMT) [19], but high NE was partly available for EPI synthesis with PNMT. These elevated NE levels were similar to the levels of myocardial ischemic regions in our previous studies [6,24]. Therefore, EPI synthesis with PNMT may gain relevance during myocardial ischemia.

4.2 Myocardial interstitial EPI levels during coronary artery occlusion
Coronary occlusion-induced progressive increases in dialysate EPI levels. These increases corresponded to increases in dialysate NE levels. Our data suggest that the high NE level evoked by myocardial ischemia yields EPI synthesis by regional PNMT activity. During myocardial ischemia, calculated ratio of interstitial EPI/NE was eight-times higher than that of NE infusion. In the ischemic heart, normal transport of NE is impaired because of a reduced sodium gradient [5], whereas another uptake system is operative by extraneuronal cells via the uptake2 carrier which is independent of the sodium gradient [25]. Actually myocardial ischemia evoked increases in myocardial interstitial NMN or MHPG via the uptake2 carrier [26]. The time course of dialysate EPI levels corresponded to increases in dialysate NE and NMN levels. Therefore, we consider that released NE is taken up by extraneuronal cells and PNMT activity for EPI synthesis is operative at high concentration of NE.

To confirm EPI synthesis via PNMT activity, we examined ischemia-induced dialysate EPI levels in the presence and absence of a PNMT inhibitor. PNMT inhibition suppressed the increase in dialysate EPI (synthesis by PNMT) and augmented the increase in dialysate NE (substrate of PNMT) levels. Thus, in the ischemic period as well as local administration of NE, PNMT activity plays an important physiological role in NE gradation and EPI synthesis. The PNMT activity in the ischemic left ventricle augmented EPI production by excess of substrate. The increased PNMT activity might reflect compensatory or adaptation processes secondary to impairments of the catecholamine uptake system and its degradation via monoamine oxidase [6].

At the myocardial interstitial space, local {omega}-conotoxin GVIA treatment attenuated the EPI release in response to cardiac sympathetic nerve stimulation [18]. Furthermore, local tyramine administration caused an increase in dialysate EPI level via a non-exocytotic mechanism. The previous study demonstrated that EPI is released from vesicle and axoplasma via exocytosis and carrier-mediated transport in the cardiac sympathetic nerve endings. In the resting state, myocardial interstitial EPI is extracted mainly from circulating EPI and taken up via catecholamine transporter to nerve endings. Therefore, in the sympathetic nerve endings containing EPI, the non-exocytotic release via outward transport would be involved in EPI release evoked by myocardial ischemia.

Myocardial ischemia-induced increases in dialysate EPI levels were suppressed by the pretreatment with desipramine. Desipramine suppressed peak EPI levels by 5% of vehicle group. Marked suppression of EPI release can be explained by two possible mechanisms. First, desipramine inhibits both directions of NE transport through uptake1 carrier [5,27]. Ischemia-induced outward NE transport through uptake1 carrier is inhibited by desipramine, and so myocardial interstitial NE levels are also attenuated [6]. In this way, desipramine reduced the substrate of EPI via PNMT and EPI synthesis in extraneuronal cells. Alternatively, EPI is released via carrier-mediated outward transport of EPI from sympathetic nerve endings. The present study could not clarify whether EPI specific transporter or NE transporter is involved in carrier-mediated outward transport of EPI. But desipramine inhibits transports of both EPI and NE. Thus, both actions of desipramine on NE and EPI caused a marked decrease in the EPI release evoked by myocardial ischemia. Although desipramine markedly suppressed the EPI release evoked by myocardial ischemia, it is uncertain which factor is more responsible for EPI release.

Finally, to elucidate which of these two mechanisms is mainly involved in the EPI release evoked by myocardial ischemia, we compared ischemia-induced EPI release between desipramine alone and the combination of desipramine and SKF29661 pretreatments. Myocardial ischemia-induced EPI release did not differ between the two groups. This result indicates that the EPI synthesis by PNMT might not be involved in the EPI release evoked by myocardial ischemia. In the presence of desipramine, myocardial interstitial NE levels were markedly suppressed. These NE levels might not be operative as the substrate of EPI whereas only the markedly higher NE level in vehicle group might be operative as the substrate of EPI and yield EPI synthesis via PNMT activity. Thus, PNMT in the left ventricle is capable of synthesizing EPI with markedly elevated NE in the myocardial interstitial space. As well as COMT system [28], cardiac PNMT plays an important physiological role in NE degradation during high concentrations of myocardial interstitial NE. Since EPI preferentially interacts with beta2-adrenergic receptors in heart [29]. Regional EPI might promote exocytotic NE release by activating presynaptic beta2-adrenergic receptors. Future work should concentrate on these aspects of cardiac PNMT.

4.3 Methodological considerations
In general, EPI is released from the adrenal medulla and carried to the heart via the bloodstream [9]. In the present study, we administered a PNMT inhibitor SKF29661 intraperitoneally to block EPI synthesis. SKF29661 may inhibit EPI synthesis at the adrenal grand and reduce blood EPI levels. In this way, administration of SKF29661 might affect EPI uptake and the content of EPI at the cardiac sympathetic nerve endings. There was no significant difference in the control dialysate EPI level between vehicle and SKF29661 group. Therefore, we believe that extraction of EPI from plasma EPI does not change the quantitative results obtained from the cardiac dialysis.

Animal studies demonstrated that two enzymes are involved in EPI synthesis: PNMT and nonspecific N-methyltransferase [30]. Nonspecific N-methyltransferase is less inhibited by the PNMT inhibitor SKF29661. This nonspecific N-methyltransferase was reported to be present in the heart, but the predominant cardiac enzyme is apparently PNMT. Actually pretreatment with SKF29661 suppressed NE-induced EPI release by 10% of vehicle group. Therefore, it is thought that nonspecific N-methyltransferase exerts little effect on the EPI release evoked by NE administration or myocardial ischemia.

In conclusion, there is a PNMT activity in the heart. Under local administration of NE or ischemic conditions, PNMT in the left ventricle is capable of synthesizing EPI with markedly elevated NE in the myocardial interstitial space. We consider two mechanisms to be involved in the increment of EPI during myocardial ischemia, namely EPI synthesis by cardiac PNMT in extraneuronal cells and the non-exocytotic release from the sympathetic nerve endings.


   Acknowledgements
 
This work was supported by Grants-in-Aid for scientific research (17591659) from the Ministry of Education, Culture, Sports, Science and Technology. The authors thank Glaxosmithkline for the supply of SKF29661.


   Notes
 
Time for primary review 15 days


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 

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