Journal of cardiovascular pharmacology
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J. Cardiovasc. Pharmacol. · Nov 2004
Chronic administration of an endothelin-A receptor antagonist improves exercise capacity in rats with myocardial infarction-induced congestive heart failure.
The effects of long-term administration of YM598, a selective endothelin-A antagonist, on improving the exercise tolerance of chronic heart failure model rats were examined using a treadmill exercise loading test. Rats were acclimatized to the treadmill apparatus and the coronary artery was ligated to prepare a myocardial infarction-induced congestive heart failure (CHF) model. Starting 10 days postoperatively, when the acute phase of infarction was over, YM598 was administered orally once daily for approximately 25 weeks at a dose of 1 mg/kg. ⋯ Long-term administration of YM598 improved left ventricular function of CHF rats to the level of sham-operated rats, and reduced the workload placed on the right side of the heart. Histological examination revealed that long-term treatment with YM598 prevented fibrosis of the surviving left ventricular myocardium. In conclusion, long-term administration of YM598 to rats with CHF improved exercise tolerance and inhibited remodeling of cardiac muscles, leading to marked improvement of cardiac function.
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J. Cardiovasc. Pharmacol. · Nov 2004
CGS 26303 upregulates mRNA expression of heme oxygenase-1 in brain tissue of rats subjected to experimental subarachnoid hemorrhage.
Previous studies indicate that intravenous infusion of CGS 26303, an endothelin-converting enzyme inhibitor, prevents and reverses cerebral vasospasm after experimental subarachnoid hemorrhage. Attenuation of the vasospastic response could result from enhanced production of nitric oxide via activation of endothelial nitric oxide synthase, neuronal nitric oxide synthase, or inducible nitric oxide synthase in brain tissue. Carbon monoxide has the same attenuation effect and is synthesized by inducible heme-oxygenase- 1 or constitutive heme-oxygenase-2. ⋯ Expression of endothelial nitric oxide synthase, neuronal nitric oxide synthase or heme-oxygenase-2 mRNA in brain tissue in the groups of subarachnoid hemorrhage or subarachnoid hemorrhage treated with endothelin-converting enzyme inhibitor appeared to be the same as compared with control rats. The subarachnoid hemorrhage rats treated with endothelin-converting enzyme inhibitor showed a significant increase in the levels of heme-oxygenase-1 mRNA expression as compared with both subarachnoid hemorrhage and control rats. These data suggest that the reduction of cerebral vasospasm by CGS 26303 in rats subjected to experimental subarachnoid hemorrhage may result from both over-expression of heme-oxygenase-1 in brain tissue and suppression of endothelin biosynthesis in basilar arteries.
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J. Cardiovasc. Pharmacol. · Sep 2004
Comparative StudyEffect of levosimendan on balance between ATP production and consumption in isolated perfused guinea-pig heart before ischemia or after reperfusion.
Levosimendan is a novel drug developed for treatment of decompensated heart failure. Levosimendan is a calcium sensitizer that increases contractile force of the myocardium by enhancing the sensitivity of myofilaments to calcium without increasing intracellular calcium concentration. ⋯ At that concentration levosimendan did not cause any effect on the phosphorylation potential (1 x 10(5) M(-1) and 0.2 x 10(5) M(-1) in the pre-ischemic and post-ischemic heart, respectively) as assessed by P-NMR, although an increased beating rate (13%) and oxygen consumption (10%) was observed when adding the drug post-ischemically. Our findings are consistent with the results of a recent clinical trial (RUSSLAN), which showed that levosimendan does not induce ischemia and reduces the risk of worsening heart failure and death, in patients with left ventricular failure complicating acute myocardial infarction.
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J. Cardiovasc. Pharmacol. · Aug 2004
Antagonism by ranolazine of the pro-arrhythmic effects of increasing late INa in guinea pig ventricular myocytes.
The new anti-anginal drug ranolazine causes a slight (<10 milliseconds) prolongation of the QT interval, raising the concern that its use may be associated with an increased incidence of torsades de pointes ventricular tachyarrhythmias. The goal of this study was to show that ranolazine inhibits the late component of INa and attenuates prolongation of action potential duration when late INa is increased, both in the absence and presence of IK-blocking drugs. Currents and action potentials of guinea pig isolated ventricular myocytes were measured by whole-cell patch clamp. ⋯ Ranolazine (10 micromol/L) reduced by 89% the 13.6-fold increase in variability of APD caused by 10 nmol/L ATX-II. The effects of ATX-II (3 nmol/L) in combinations with either the IKr blocker E-4031 or the IKs blocker chromanol 293B to increase APD were attenuated 76 +/- 5% and 71 +/- 4%, respectively, by 10 micromol/L ranolazine. The results demonstrate that ranolazine reduces late INa and has an anti-arrhythmic effect when late INa is increased.
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J. Cardiovasc. Pharmacol. · Mar 2004
Effect of exogenous kappa-opioid receptor activation in rat model of myocardial infarction.
The involvement of opioid receptor activation during ischemia-reperfusion is somewhat controversial. While it is generally accepted that activation of the delta-opioid receptor (DOR) is cardioprotective, and may indeed be an important mediator of ischemic preconditioning, the role of the kappa-opioid receptor (KOR) is less well understood. To this end, we examined three different KOR agonists and their effects upon infarct size and arrhythmia development. ⋯ These effects were not blocked by nor-BNI. These data demonstrate that KOR activation provides a similar degree of infarct size reduction as DOR activation. KOR agonists also reduced arrhythmogenesis; however, these responses appear to be independent of KOR activation.