entacapone and 3-4-dihydroxyphenylglycol

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.. 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.. 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.. 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.

Topics: Animals; Blood Pressure; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Catechols; Heart Rate; Male; Methoxyhydroxyphenylglycol; Microdialysis; Models, Animal; Myocardial Ischemia; Myocardium; Nitriles; Norepinephrine; Normetanephrine; Rabbits

Topics: Antiparkinson Agents; Benzamides; Biomarkers; Catechol O-Methyltransferase Inhibitors; Catechols; Chromatography, High Pressure Liquid; Humans; Male; Methoxyhydroxyphenylglycol; Moclobemide; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Nitriles; Norepinephrine; Pentanones; Selegiline

We studied the effects of catechol-O-methyltransferase (COMT) inhibition with entacapone on hemodynamics and catecholamine metabolism in healthy volunteers at rest and during a bicycle exercise test. Entacapone was given orally during two periods of seven days each to eleven healthy male volunteers; on the first period 400 mg t.i.d. and on the second 800 mg t.i.d. A submaximal exercise test giving a heart rate of about 163-167 beats/min with the highest predetermined work load was performed on a bicycle ergometer, and blood pressure, heart rate and ECG were recorded. The concentrations of adrenaline, noradrenaline, 3,4-dihydroxyphenylglycol (DHPG), 3-methoxy-4-hydroxyphenylglycol (MHPG) and 3,4-dihydroxyphenylacetic acid (DOPAC) in plasma were determined. Blood pressure, heart rate, ECG, and plasma concentrations of unconjugated adrenaline and noradrenaline were not influenced after single and repeated dosing of entacapone. The plasma concentrations of DHPG (a monoamine oxidase (MAO)-dependent metabolite) increased maximally by 245% compared to the control day. DOPAC (a MAO-dependent metabolite) increased maximally by 144% and MHPG (a COMT-dependent metabolite) decreased by 54%. The increase in DHPG and DOPAC was significantly greater with the 800 mg dose than with the 400 mg dose. The decrease in MHPG was significantly greater with the repeated dosing than with the single dose of entacapone. COMT inhibition by entacapone seems not to affect hemodynamics or plasma concentrations of unconjugated adrenaline and noradrenaline in healthy volunteers either at rest or during exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 3,4-Dihydroxyphenylacetic Acid; Adult; Catechol O-Methyltransferase Inhibitors; Catecholamines; Catechols; Chromatography, High Pressure Liquid; Electrocardiography; Exercise Test; Hemodynamics; Humans; Male; Methoxyhydroxyphenylglycol; Nitriles; Reference Values