Journal of cardiovascular pharmacology
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J. Cardiovasc. Pharmacol. · Sep 2005
Improved mitochondrial bioenergetics by anesthetic preconditioning during and after 2 hours of 27 degrees C ischemia in isolated hearts.
We examined if sevoflurane given before cold ischemia of intact hearts (anesthetic preconditioning, APC) affords additional protection by further improving mitochondrial energy balance and if this is abolished by a mitochondrial KATP blocker. NADH and FAD fluorescence was measured within the left ventricular wall of 5 groups of isolated guinea pig hearts: (1) hypothermia alone; (2) hypothermia+ischemia; (3) APC (4.1% sevoflurane)+cold ischemia; (4) 5-HD+cold ischemia, and (5) APC+5-HD+cold ischemia. Hearts were exposed to sevoflurane for 15 minutes followed by 15 minutes of washout at 37 degrees C before cooling, 2 hours of 27 degrees C ischemia, and 2 hours of 37 degrees C reperfusion. ⋯ APC attenuated the changes in NADH and FAD and further improved postischemic function and reduced infarct size. 5-HD blocked the cardioprotective effects of APC but not APC-induced alterations of NADH and FAD. Thus, APC improves redox balance and has additive cardioprotective effects with mild hypothermic ischemia. 5-HD blocks APC-induced cardioprotective effects but not improvements in mitochondrial bioenergetics. This suggests that mediation of protection by KATP channel opening during cold ischemia and reperfusion is downstream from the APC-induced improvement in redox state or that these changes in redox state are not attenuated by KATP channel antagonism.
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J. Cardiovasc. Pharmacol. · Sep 2005
Two inotropes with different mechanisms of action: contractile, PDE-inhibitory and direct myofibrillar effects of levosimendan and enoximone.
We characterized the Ca2+-sensitizing and phosphodiesterase (PDE)-inhibitory potentials of levosimendan and enoximone to assess their contributions to the positive inotropic effects of these drugs. In guinea pig hearts perfused in the working-heart mode, the maximal increase in cardiac output (55%, P<0.05) was attained at 50 nM levosimendan. The corresponding value for enoximone (36%) was significantly smaller (P<0.05) and was observed at a higher concentration (500 nM). ⋯ The PDE-inhibitory effects were probed on the PDE III and PDE IV isoforms. Levosimendan proved to be a 1300-fold more potent and a 90-fold more selective PDE III inhibitor (IC50 for PDE III 1.4 nM, and IC50 for PDE IV 11 microM, selectivity factor approximately 8000) than enoximone (IC50 for PDE III 1.8 microM, and IC50 for PDE IV 160 microM, selectivity factor approximately 90). Hence, our data support the hypothesis that levosimendan exerts positive inotropy via a Ca2+-sensitizing mechanism, whereas enoximone does so via PDE inhibition with a limited PDE III versus PDE IV selectivity.
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J. Cardiovasc. Pharmacol. · Aug 2005
Randomized Controlled Trial Multicenter Study Clinical TrialRACTS: a prospective randomized antiplatelet trial of cilostazol versus ticlopidine in patients undergoing coronary stenting: long-term clinical and angiographic outcome.
We compared the efficacy of cilostazol for the prevention of late restenosis and acute or subacute stent thrombosis with that of ticlopidine. Cilostazol has been used for antiplatelet therapy after coronary stent implantation, but the results are controversial. Patients scheduled for stent implantation were randomly assigned to receive either cilostazol (100 mg twice daily for 6 months, n=201) or ticlopidine (250 mg twice daily for 1 month, n=196). ⋯ Medication withdrawn because of drug-related side effects tended to be higher in the ticlopidine group than that in the cilostazol group (3.5% vs 8.2%, P=0.054). At follow-up angiography, the minimal luminal diameters (2.31+/-1.06 vs 2.10+/-1.16, P=0.057) tended to be larger and the restenosis rates lower (23.3% vs 30.9%, P=0.086) in the cilostazol group than in the ticlopidine group. Aspirin plus cilostazol is a comparable antithrombotic regimen to aspirin plus ticlopidine after elective coronary stenting, but the rate of target lesion revascularization was significantly lower in the cilostazol group than in the ticlopidine group.
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J. Cardiovasc. Pharmacol. · Jul 2005
Comparative StudyEdaravone prevented deteriorated cardiac function after myocardial ischemia-reperfusion via inhibiting lipid peroxidation in rat.
Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) has potent effects in the brain as a free radical scavenger in ischemia-reperfusion as well as in ischemic injuries. However, whether this free radical scavenger prevents deterioration of cardiac function and lethal ventricular arrhythmias after ischemia-reperfusion in rat heart is not clear. We aimed to assess whether free radical scavenging by edaravone maintains cardiac function and suppresses life-threatening ventricular tachyarrhythmia after myocardial ischemia-reperfusion. ⋯ Ees was significantly greater in the edaravone-treated than in untreated rats from 5 to 25 minutes after reperfusion (1789 +/- 866 in untreated versus 2809 +/- 273 mm Hg/mL in edaravone-treated rats at 25 minutes, P < 0.001). MDA level was significantly lower in edaravone-treated than in untreated rats (1.44 +/- 0.29 nmol/L in edaravone-treated versus 1.90 +/- 0.28 nmol/L in untreated group, P < 0.05). The results suggest that edaravone treatment before reperfusion prevented lethal reperfusion ventricular tachyarrhythmias and deteriorated cardiac function with ischemia and ischemia-reperfusion injuries through inhibiting lipid peroxidation in terms of scavenging for free radicals.
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J. Cardiovasc. Pharmacol. · Feb 2005
Effects of dobutamine on left ventriculoarterial coupling and mechanical efficiency in acutely ischemic pigs.
This study investigated the effects of dobutamine on left ventriculoarterial (VA) coupling and mechanical efficiency in acutely ischemic pigs. Experiments were performed in 12 pigs in which vascular properties, including peripheral resistance (R2), compliance (C), and arterial elastance (Ea), were estimated with a windkessel model, and left ventricular (LV) function by the slope (Ees) of the end-systolic pressure-volume relationship (ESPVR) and stroke work (SW). VA coupling was defined as Ees/Ea, and mechanical efficiency as SW/pressure-volume area (PVA). ⋯ SW and PVA increased to 3833 +/- 180 mm Hg x mL and to 7498 +/- 442 mm Hg x mL, respectively, while SW/PVA was unchanged. In ischemic pigs, dobutamine restored VA coupling through an increase in LV contractility and decrease in arterial elastance as a result of peripheral vasodilatation. However, myocardial oxygen consumption was increased, and mechanical efficiency impaired.