Tetsuya Matsumoto

Objectives This study evaluated oxidative stress in the failing ventricle in patients with dilated cardiomyopathy (DCM). Background Oxidative stress appears to increase in the failing myocardium and may contribute to ventricular dysfunction in patients with DCM. Tumor necrosis factor-alpha (TNF-alpha), which is expressed in the failing heart, may stimulate oxidative stress. Methods We measured plasma oxidized low density lipoprotein (oxLDL) by sandwich enzyme-linked immunosorbent assay using specific antibodies against oxLDL in the aortic root (AO) and the coronary sinus (CS) in control subjects (n = 8) and in 22 patients with DCM and mild congestive heart failure. We also measured the plasma levels of TNF-alpha and angiotensin Results There was no difference in oxLDL between the AO and CS in control subjects. In contrast, plasma oxLDL was significantly higher in the CS than the AO in patients with DCM, suggesting that the transcardiac gradient of oxLDL reflects oxidative stress in the failing heart in these patients. Plasma TNF-alpha levels were significantly higher in the CS than the AO with a significant positive correlation of the transcardiac gradient of TNF-alpha and the transcardiac gradient of oxLDL. Moreover, a significant negative correlation existed between the transcardiac gradient of oxLDL and left ventricular ejection fraction. The transcardiac gradient of plasma oxLDL was significantly lower in 6 patients who received carvedilol than in 16 patients who did not receive carvedilol. Conclusions These findings indicate that the transcardiac gradient of oxLDL may be a marker of oxidative stress in the heart and that left ventricular dysfunction may be partly due to the oxidative stress in patients with DCM. In addition, TNF-alpha may stimulate oxidative stress in the failing heart in patients with DCM. (J Am Coll Cardiol 2001;37:2086-92) (C) 2001 by the American College of Cardiology.

OBJECTIVES The goal of this study was to determine: 1) whether bradykinin (BK) directly stimulates tissue plasminogen activator (tPA) secretion in human coronary circulation, and 2) whether angiotensin-converting enzyme (ACE) inhibition favorably alters the fibrinolytic balance regulated by BK. BACKGROUND Bradykinin is a potent stimulator of tPA secretion in endothelial cells; however, the effect of BK on tPA release in the human coronary circulation has not been studied. METHODS Fifty-six patients with atypical chest pain were randomly assigned to two groups: 25 patients were treated with the ACE inhibitor enalapril (ACE inhibitor group), and 31 were not treated with ACE inhibitors (non-ACE inhibitor group). Graded doses of BK (0.2, 0.6, 2.0 mug/min), acetylcholine (ACh) (30 mug/min) and papaverine (PA) (12 mg) were administered into the left coronary artery. Coronary blood flow (CBF) was evaluated by Doppler flow velocity measurement. Blood samples were taken from the aorta (Ao) and the coronary sinus (CS). RESULTS Bradykinin induced similar increases in CBF in both groups. The net tPA release induced by BK was dose-dependently increased in both groups, and the extent of that increase in the ACE inhibitor group was greater than that in the non-ACE inhibitor group. Bradykinin did not alter plasminogen activator inhibitor-1 (PAI-1) levels in the Ao or CS in either group. Neither ACh nor PA altered tPA levels or PAI-1 levels in either group. CONCLUSIONS Intracoronary infusion of BK stimulates tPA release without causing any change in PAI-1 levels in the human coronary circulation. In addition, this effect of BK is augmented by an ACE inhibitor. (J Am Coll Cardiol 2001;37:1565-70) (C) 2001 by the American College of Cardiology.

S-Nitrosocaptopril (S-NO-Cap), a nitrate and an angiotensin-converting enzyme (ACE) inhibitor, may be produced after coadministration of nitroglycerin (NTG) and captopril (CAP). We synthesized S-NO-Cap and investigated its in vivo tolerance. In open-chest dogs, S-NO-Cap [300 μg intracoronary (i.c.)] and NTG (50 μg, i.c.) increased coronary blood flow (CBF) similarly (8.0 vs. 9.0 ml/min p = NS n = 5). After a 2-h i.c. NTG infusion at high dose (1.32 μmol/min), NTG (50 μg, i.c.) had no significant effect on CBF, whereas S-NO-Cap (300 μg, i.c.) still produced an attenuated increase in CBF (4.9 ml/min p &lt 0.05 vs. control). On the other hand, after a 2-h i.c. infusion of S-NO-Cap (1.32 μmol/min), the CBF response to S-NO- Cap (300 μg) showed no attenuation, whereas that to NTG (50 μg) was potentiated (8.8 vs. 12.6 ml/min p &lt 0.05 n = 6). Under basal conditions, S-NO-Cap (30-300 μg, i.c.) increased CBF dose dependently, whereas CAP (30- 300 μg, i.c.) had no effect on CBF, suggesting that S-NO-Cap dilates coronary vessels by a nitrate action but not by an ACE-inhibitory action. In nonsurgical dogs, 2-h intravenous (i.v.) infusion of S-NO-Cap (1.32 μmol/min) had a stable hypotensive effect, whereas that of NTG (1.32 μmol/min) gradually attenuated the effect. Plasma NO-/3, an oxidative product of nitric oxide (NO), increased after both infusions, suggesting that S-NO-Cap may act partially as an NO donor, similarly to NTG. Plasma ACE activity was reduced after an S-NO-Cap infusion (5.84 vs. 4.10 IU/L p &lt 0.01 n = 5), and plasma aldosterone was markedly increased after NTG infusion relative to that after S-NO-Cap infusion (243.0 vs. 38.6 pg/ml p &lt 0.05). Plasma norepinephrine increased after both infusions (393.6 vs. 289.0 pg/ml p = NS). As judged by the increase in CBF, whereas S-NO-Cap showed partial tolerance with NTG, no tolerance was found with S-NO-Cap itself. The in vivo coronary vascular response to S-NO-Cap may, therefore, be partially reduced by activation of the adrenergic or renin-angiotensin-aldosterone systems or both induced by NTG, because S-NO-Cap showed no cross-tolerance with NTG in our earlier in vitro study.