Atsushi Takaoka

Long-Term Beneficial Effect of Late Reperfusion for Acute Anterior Myocardial Infarction With Percutaneous Transluminal Coronary Angioplasty

BACKGROUND Although the short-term and long-term beneficial effects of early coronary revascularization by primary PTCA or thrombolytic therapy have been established for acute myocardial infarction, thrombolytic therapy >24 hours after the onset of acute myocardial infarction has not been shown to improve clinical outcome. The purpose of this study was to assess the effect of late revascularization by primary PTCA over a 5-year period. METHODS AND RESULTS Eighty-three patients with initial Q-wave anterior myocardial infarction >24 hours after onset were randomized into a PTCA group (n=44) and a no-PTCA group (n=39). Long-term follow-up was conducted with regard to end points, which included cardiac death, nonfatal recurrence of myocardial infarction, and development of congestive heart failure. Left ventricular ejection fraction and regional wall motion at 6 months after myocardial infarction were similar in the 2 groups. Left ventricular end-diastolic and end-systolic volume indexes were significantly smaller in the PTCA group than in the no-PTCA group (P<0.0001). With cardiac events as end points, a 5-year Kaplan-Meier event-free survival analysis revealed that the no-PTCA group had a worse prognosis than the PTCA group (P<0.0001). Patency of the infarct-related artery, left ventricular ejection fraction, end-diastolic volume index, and end-systolic volume index were significantly associated with cardiac events by a Cox proportional hazards analysis (hazard ratios 0.120, 0.845, 1.065, and 1.164, respectively). CONCLUSIONS In initial Q-wave anterior myocardial infarction, we conclude that even with late reperfusion, PTCA had beneficial effects on cardiac events over the 5-year period after myocardial infarction, with the prevention of left ventricular dilation after myocardial infarction being a possible mechanism.

Plasma brain natriuretic peptide as a biochemical marker for atrioventricular sequence in patients with pacemakers.

We hypothesized that plasma brain natriuretic peptide, like plasma atrial natriuretic peptide, may reflect hemodynamic changes elicited by different cardiac pacing modes. The aim of this study was to investigate whether plasma brain natriuretic peptide could be influenced by different pacing modes or electrical stimulation. The subjects consisted of 164 patients with permanent pacemakers (52 VVI, 30 AAI, 82 DDD pacemakers) and unimpaired heart function. Patients with atrial fibrillation or spontaneous beats were excluded. Plasma atrial natriuretic peptide and brain natriuretic peptide levels were measured at a rate of 70 beats/min after 45 minutes in the supine position. Under ECG monitoring, the pacing mode was switched from DDD to VVI in 12 patients and from DDD to AAI in 4 patients with a dual chamber pacemaker. Plasma atrial natriuretic peptide and brain natriuretic peptide levels were also measured 30 minutes, 60 minutes, and 1 week after mode switching. Plasma atrial natriuretic peptide and brain natriuretic peptide levels were significantly higher in the nonphysiological pacing group than in the physiological pacing group, whereas these values were similar in the DDD and AAI pacing groups. One week after switching from DDD to VVI, plasma atrial natriuretic peptide and brain natriuretic peptide levels were significantly increased, however no significant changes were observed after switching to AAI. Based on a multivariate regression analysis of noninvasive clinical parameters, only a low plasma brain natriuretic peptide was significantly correlated with physiological pacing. We conclude that: (1) plasma brain natriuretic peptide, like atrial natriuretic peptide, is influenced by the pacing mode, but is not influenced by electrical stimulation; and (2) low plasma brain natriuretic peptide is important in relation to physiological pacing.

Coronary effects of diadenosine tetraphosphate resemble those of adenosine in anesthetized pigs: involvement of ATP-sensitive potassium channels.

Diadenosine tetraphosphate (Ap4A) is an adenine nucleotide with vasodilatory properties. We examined the effects of Ap4A on coronary circulation in comparison with those of adenosine, its metabolite, in anesthetized pigs. Left atrial (LA) infusion of Ap4A at increasing doses of 100, 200, and 300 micrograms/kg/min increased coronary blood flow (CBF) and decreased systemic blood pressure (BP) and coronary vascular resistance (CVR). Ap4A had no effect on large epicardial coronary artery diameter (CoD). Likewise, LA infusion of adenosine at doses of 150 and 300 micrograms/kg/min increased CBF and decreased BP and coronary vascular resistance (CVR) but did not affect CoD. Therefore, the vasodilatory effects of Ap4A and adenosine were predominant in small coronary resistance vessels and negligible in large coronary arteries. Pretreatment with glibenclamide (2 mg/kg, intravenously, i.v.), a specific blocker of ATP-sensitive potassium channels (KATP), attenuated alterations of CBF, BP, and CVR induced by Ap4A and by adenosine. In contrast, treatment with cromakalim (0.5 microgram/kg/min i.v.), an activator of KATP, enhanced the coronary effects of Ap4A and adenosine. Therefore, the opening of KATP in the pig coronary circulation is involved in the in vivo vasodilatory effects of Ap4A and adenosine. Treatment with 8-phenyltheophylline (8-PT, 4 mg/kg i.v.), an adenosine receptor antagonist, suppressed CBF increases induced by Ap4A (20 micrograms/kg/min, intracoronarily, i.c.) and adenosine (5 micrograms/kg/min i.c.) by 68 and 90%, respectively. These findings suggest that the in vivo coronary effects of Ap4A are largely caused by the opening of KATP through rapid degradation to adenosine to activate adenosine receptors.

Cardioprotective Effects Of Nicorandil In Rabbits Anaesthetized With Halothane: Potentiation Of Ischaemic Preconditioning Via KATP Channels

1. The roles of ATP‐sensitive K+ channels (KATP channels) in ischaemic or pharmacological preconditioning in the rabbit heart remain unclear. Infarct limitation by ischaemic preconditioning was abolished by the KATP channel blocker glibenclamide under ketamine/xylazine anaesthesia, but not under anaesthesia induced by pentobarbital. Infarct limitation by the KATP channel opener pinacidil was detected under ketamine/xylazine anaesthesia, but not under pentobarbital anaesthesia. Thus, these effects appear to be anaesthetic dependent.

Heterogeneity in the vasorelaxing effect of nicorandil on dog epicardial coronary arteries : Comparison with other NO donors

The relaxation responses to nicorandil, nitroglycerin (NTG), and cromakalim were compared in isolated dog large (>1.5 mm inside diameter) and small (<0.3 mm inside diameter) epicardial coronary arteries. Nicorandil and NTG produced more potent relaxing effects in large coronary arteries. In contrast, cromakalim produced greater relaxation in small arteries. No significant differences were observed in the nitric oxide (NO)-induced response after treatment with superoxide dismutase. The responses to 8-bromo-cyclic guanosine monophosphate (cGMP), SIN-1, and atrial natriuretic peptide did not differ in arteries of different sizes. Treatment with L-cysteine had no significant effect on the relaxation responses to NTG in both large and small coronary arteries. Oxyhemoglobin and glibenclamide inhibited relaxation induced by nicorandil in large and small coronary arteries. Oxyhemoglobin had a greater suppressive effect on the response to nicorandil in large coronary arteries than in small coronary arteries. Methylene blue inhibited the response to nicorandil in large coronary arteries. These findings suggest that nicorandil behaves predominantly as a nitrate in large epicardial coronary arteries rather than small epicardial arteries and that this difference between large and small coronary arteries with regard to the nitrate action of nicorandil may be the result of a pathway in which nicorandil is converted to NO.

No cross-tolerance between S-nitrosocaptopril and nitroglycerin in dog coronary arteries in vivo

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 microg; intracoronary (i.c.)] and NTG (50 microg, 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 micromol/min), NTG (50 microg, i.c.) had no significant effect on CBF, whereas S-NO-Cap (300 microg, i.c.) still produced an attenuated increase in CBF (4.9 ml/min; p < 0.05 vs. control). On the other hand, after a 2-h i.c. infusion of S-NO-Cap (1.32 micromol/min), the CBF response to S-NO-Cap (300 microg) showed no attenuation, whereas that to NTG (50 microg) was potentiated (8.8 vs. 12.6 ml/min; p < 0.05; n = 6). Under basal conditions, S-NO-Cap (30-300 microg, i.c.) increased CBF dose dependently, whereas CAP (30-300 microg, 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 micromol/min) had a stable hypotensive effect, whereas that of NTG (1.32 micromol/min) gradually attenuated the effect. Plasma NO3-, 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 < 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 < 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.

Tilisolol hydrochloride dilates coronary arteries through an ATP-sensitive K+-channel opening mechanism in dogs

SummaryTilisolol is a beta-blocking agent with vasodilatory properties that was recently shown to possess a potassium (K+) channel opening activity. We investigated whether tilisolol has vasodilatory effects on coronary circulation in dogs. Mongrel dogs were chronically instrumented for measurements of circumflex coronary artery diameter (CoD) and coronary blood flow (CBF). We compared the effects of tilisolol on dog coronary arteries with those of two beta-blockers, propranolol and arotinolol. Both propranolol (1 mg/kg, intravenously, IV) and arotinolol (0.25 mg/kg, IV) decreased CoD and increased coronary vascular resistance (CVR). Tilisolol (2 mg/kg, IV) decreased CVR but had no significant effect on CoD. To investigate the mechanism of the coronary action of tilisolol, we examined differences in the response to tilisolol in the absence and presence of glibenclamide, an ATP-sensitive K+ channel blocker. Tilisolol (1,2,4 and 8 mg/kg, IV) produced a dose-dependent decrease in CVR without glibenclamide, whereas pretreatment with glibenclamide significantly suppressed this effect. Without glibenclamide, tilisolol had no significant effect on CoD at doses of 1–4 mg/kg (IV). However, at the higher dose of 8 mg/kg (IV), tilisolol significantly increased CoD (1.00±0.15%, p<0.01). After pretreatment with glibenclamide, tilisolol (1–8 mg/kg, IV) produced a significant decrease in CoD. Therefore, we concluded that tilisolol exerts its vasodilatory effect on the coronary circulation through an ATP-sensitive K+ channel opening mechanism, and that its vasodilatory action is more prominent in coronary resistance vessels than in large coronary arteries.

Nicorandil Improves Ischemic Changes in Epicardial ECG During Short-Term Coronary Occlusion by Opening ATP-Sensitive Potassium Channels in Pigs

The aims of this study were to investigate whether nicorandil(NIC), an ATP-sensitive potassium channel (KATP) opener and nitrate, hasantiischemic effects during transient ischemia in pigs, and to investigatewhether its effects are due to its KATP-opening action ornitrate action. Myocardial ischemia was induced by ligating the proximalportion of the left anterior descending coronary artery for 1 minute inanesthetized open-chest pigs, and was measured as the magnitude ofST-segment elevation on epicardial electrocardiogram (ECG). EpicardialST-segment elevation during coronary occlusion was significantlyreduced by pretreatment with NIC (3 mg, intracoronary [ic]), butnot by pretreatment with nitroglycerin (NTG, 0.2 mg, ic). Pretreatment withglibenclamide (GLB, a KATP blocker, 6 mg, ic) significantly augmented theST-segment elevation during coronary occlusion. The augmentation ofST-segment elevation by GLB was significantly reduced by subsequentadministration of NIC, but not by that of NTG (0.2 mg, ic). There were nosignificant differences between hemodynamic variables immediately beforecoronary occlusion with and without pretreatment. The intracoronaryadministration of NIC (3 mg) significantly shortened the endocardialmonophasic action potential durations at 50% (MAPD50) and90% repolarization (MAPD90) by 28.3 ± 6.9% and 17.0± 4.7%, respectively. These results suggest that theintracoronary administration of NIC has antiischemic effects duringtransient ischemia via KATP activation in myocardium