Chronic angiotensin II receptor blockade induces cardioprotection during ischemia by increased PKC-epsilon expression in the mouse heart

This study was performed to investigate the role of chronic pretreatment with angiotensin II type 1 receptor antagonists (ARB) and angiotensin converting enzyme inhibitors (ACE-I) in myocardial infarction (MI) and ischemic preconditioning (iPC). Little is known about molecular mechanisms of MI and iPC, especially about protein kinase C (PKC) isozyme levels induced by chronic pharmacologic pretreatment with ARB and ACE-I. To address one of the most important signal molecules in iPC, the PKC system was investigated in an ischemia/reperfusion model using isolated mouse hearts

The calcium channel blocker felodipine attenuates the positive hemodynamic effects of the beta-blocker metoprolol in severe dilated cardiomyopathy - A prospective, randomized, double-blind and placebo-controlled study with invasive hemodynamic assessment

Background: In addition to standard therapy with ACE-inhibitors, digitalis and diuretics, beta-adrenergic receptor blockers have become a widely accepted strategy in the treatment of chronic heart failure. The role of calcium antagonists in CHF however remains controversial. To evaluate if a combination therapy of metoprolol and felodipine might improve hemodynamic parameters, a randomized and placebo-controlled study was designed. Methods and results: Sixty-three patients with DCMP, LVEF 3 months in NYHA II-III on standard medication were prospectively treated with either a) a combination of metoprolol+felodipine (MF group, n=20), b) metoprolol+felodipine-placebo (MP group, n=23), or c) metoprolol-placebo+felodipine-placebo (PP group, n=20). Compared to baseline, LVEF and LVEDD significantly improved after 6 months in the MP group (LVEF: 36 +/- 2% vs 29 +/- 2%, p<0.01; LVEDD: 68 +/- 3 mm vs 64 +/- 3 mm, p<0.05), whereas in the other treatment groups only minor changes were observed. A significant benefit in hemodynamic parameters as determined by right heart catheterization was noted also only in the MP group with a marked reduction in PAP mean (17 vs 24 mmHg, p<0.01), PCWP (10 vs 15 mmHg, p<0.001) resulting in a significant increase in cardiac and stroke volume index at rest with no marked changes in the MF and PP group. Conclusion: beta-blocker treatment in CHF patients improves left ventricular function and additionally invasive hemodynamic measurements both at rest and during exercise. In contrast, the combined therapy with the long-acting calcium antagonist felodipine neutralizes these beneficial effects of metoprolol therapy to almost placebo level, providing evidence based on hemodynamic measurements that this combination should be avoided in patients with CHF. (C) 2008 Elsevier Ireland Ltd. All rights reserved

Fostriecin, an Inhibitor of Protein Phosphatase 2A, Limits Myocardial Infarct Size Even When Administered After Onset of Ischemia

Background - The role of protein phosphatases (PPs) during ischemic preconditioning in the rabbit heart was examined. Methods and Results - Fostriecin, a potent inhibitor of PP2A, was administered to isolated rabbit hearts starting either 15 minutes before or 10 minutes after the onset of a 30-minute period of regional ischemia and continuing until the onset of reperfusion. After 2 hours of reperfusion, infarct size was measured with triphenyltetrazolium chloride. In a second study with isolated rabbit cardiomyocytes, the effect of fostriecin pretreatment was assessed by measuring changes in cell osmotic fragility during simulated ischemia. PP1 and PP2A activities of isolated control and ischemically preconditioned cells were also measured. In a third series of experiments, left ventricular biopsies of isolated rabbit hearts were obtained before and at selected times during 60 minutes of global ischemia, and the tissue was assayed for PP1 and PP2A activities. In isolated hearts pretreated with fostriecin, only 8% of the ischemic zone infarcted, significantly less than that in untreated control hearts (33%; P\u3c0.001) but comparable to that in ischemically preconditioned hearts (9%; P\u3c0.001 versus control). Significant protection was also observed in the hearts treated only after the onset of ischemia (18% infarction; P\u3c0.05 versus control). In isolated myocytes, fostriecin also provided protection comparable to that produced by metabolic preconditioning. Preconditioning had no apparent effect on the activity of either PP1 or PP2A in isolated ventricular myocytes or ventricular tissue obtained from heart biopsies. Conclusions - Fostriecin, a potent inhibitor of PP2A, can protect the rabbit heart from infarction even when administered after the onset of ischemia. But inhibition of either PP1 or PP2A does not appear to be the mechanism of protection from ischemic preconditioning

Fostriecin, an Inhibitor of Protein Phosphatase 2A, Limits Myocardial Infarct Size Even When Administered After Onset of Ischemia

Background - The role of protein phosphatases (PPs) during ischemic preconditioning in the rabbit heart was examined. Methods and Results - Fostriecin, a potent inhibitor of PP2A, was administered to isolated rabbit hearts starting either 15 minutes before or 10 minutes after the onset of a 30-minute period of regional ischemia and continuing until the onset of reperfusion. After 2 hours of reperfusion, infarct size was measured with triphenyltetrazolium chloride. In a second study with isolated rabbit cardiomyocytes, the effect of fostriecin pretreatment was assessed by measuring changes in cell osmotic fragility during simulated ischemia. PP1 and PP2A activities of isolated control and ischemically preconditioned cells were also measured. In a third series of experiments, left ventricular biopsies of isolated rabbit hearts were obtained before and at selected times during 60 minutes of global ischemia, and the tissue was assayed for PP1 and PP2A activities. In isolated hearts pretreated with fostriecin, only 8% of the ischemic zone infarcted, significantly less than that in untreated control hearts (33%; P\u3c0.001) but comparable to that in ischemically preconditioned hearts (9%; P\u3c0.001 versus control). Significant protection was also observed in the hearts treated only after the onset of ischemia (18% infarction; P\u3c0.05 versus control). In isolated myocytes, fostriecin also provided protection comparable to that produced by metabolic preconditioning. Preconditioning had no apparent effect on the activity of either PP1 or PP2A in isolated ventricular myocytes or ventricular tissue obtained from heart biopsies. Conclusions - Fostriecin, a potent inhibitor of PP2A, can protect the rabbit heart from infarction even when administered after the onset of ischemia. But inhibition of either PP1 or PP2A does not appear to be the mechanism of protection from ischemic preconditioning