© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
Extraneuronal enzymatic degradation of myocardial interstitial norepinephrine in the ischemic region
aDepartment of Cardiac Physiology, National Cardiovascular Center Research Institute, 5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan
bDepartment of Cardiovascular Surgery, Okayama University Medical School, Okayama 700-8558, Japan
* Corresponding author. Tel.: +81-6-6833-5012x2380; fax: +81-6-6872-8092. E-mail address: yamazaki{at}ri.ncvc.go.jp
Objective: Catechol O-methyltransferase (COMT) is believed to exert degradative action at high norepinephrine (NE) levels. Although COMT exists in cardiac tissues, the contribution of cardiac COMT activity to regional NE kinetics, particularly in ischemia-induced NE accumulation, remains unclear. We investigated the role of cardiac COMT in NE kinetics in the ischemic region. Methods: We implanted a microdialysis probe into the left ventricular myocardium of anesthetized rabbits and induced myocardial ischemia by 60-min coronary artery occlusion. We monitored myocardial interstitial levels of NE and its metabolites in the presence and absence of a COMT inhibitor. We intraperitoneally administered entacapone (10 mg/kg) 120 min before control sampling. Results: In control, entacapone increased interstitial dihydroxyphenylglycol (DHPG, intraneuronal NE metabolite by monoamine oxidase (MAO)) levels and decreased interstitial normetanephrine (NMN, extraneuronal NE metabolite by COMT) and 3-methoxy-4-hydroxyphenylglycol (MHPG, extraneuronal DHPG metabolite by COMT) levels, but did not change interstitial NE levels. Coronary occlusion increased NE levels to 165±48 nM at 45–60 min of occlusion. This increase was accompanied by increases in DHPG and NMN levels (11.3±1.1 and 9.3±1.3 nM at 45–60 min of occlusion). Entacapone augmented the ischemia-induced NE and DHPG responses (333±51 and 22.9±2.4 nM at 45–60 min of occlusion). In contrast, the ischemia-induced NMN response was suppressed by entacapone (2.0±0.4 nM at 45–60 min of occlusion). Reperfusion decreased interstitial NE levels and increased interstitial DHPG and NMN levels. Entacapone suppressed changes in NE and NMN levels, but augmented the increase in dialysate DHPG. Conclusion: Myocardial ischemia evoked increases in myocardial interstitial NE and NMN levels. COMT inhibition augmented the increase in NE (substrate of COMT) levels and suppressed the increase in NMN (metabolite by COMT) levels. In the ischemic heart, COMT contributes to the removal of accumulated NE in the myocardium.
KEYWORDS Adrenergic agonists; Autonomic nervous system; Ischemia; Reperfusion; Neurotransmitters
Time for primary review 26 days
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