ABSTRACT
Nitric oxide (NO) can activate protein kinase C (PKC) and the activation of mitochondrial ATP-sensitive potassium (K-ATP) channels is cardioprotective. However, interactions among NO, PKC, and mitochondrial K-ATP channels remain vague. To clarify the cardioprotective mechanism induced by nicorandil, we compared its ability to activate PKC isoforms with that of the mitochondrial K-ATP channel opener, diazoxide. We induced myocardial infarction in rats by 30 minutes of ischemia followed by reperfusion, then assessed the infarct size 3 weeks later. We also examined the translocation of PKC isoforms in the isolated perfused rat heart. Nicorandil and diazoxide reduced infarct size, and the effect of nicorandil, but not of diazoxide attenuated by the PKC inhibitor, chelerythrine, or by the NO quencher, carboxy PTIO. Immunoblotting revealed that nicorandil translocated PKC-delta to the mitochondria, and that this was inhibited by carboxy PTIO. The protective effect of nicorandil against myocardial infarction partly depended on the translocation of PKC-delta to the mitochondria, which we attributed to the NO donor effect of nicorandil. The PKC-delta- dependent activation of mitochondrial K-ATP channel opening might be synergistic with its direct effect, making nicorandil an efficient opener of such channels.
Subject(s)
Antihypertensive Agents/therapeutic use , Diazoxide/therapeutic use , Membrane Proteins/drug effects , Myocardial Ischemia/prevention & control , Nicorandil/therapeutic use , Nitric Oxide/physiology , Protein Kinase C/metabolism , Animals , Enzyme Activation/drug effects , Heart Rate/drug effects , Isoenzymes/drug effects , Isoenzymes/metabolism , Potassium Channels , Protein Kinase C-delta , Rats , Rats, Sprague-DawleyABSTRACT
The purpose of this study was to test a hypothesis that T-wave alternans (TWA) is improved in association with an improvement in cardiac sympathetic nervous system and systolic function by oral beta-blocker therapy in patients with non-ischemic heart disease (NIHD). TWA testing, (123)I-metaiodobenzylguanidine (MIBG) imaging and echocardiography were performed at the baseline and 3 months after beta-blocker therapy in 26 patients with NIHD and positive TWA. The alternans voltage (V(alt)), the heart-to mediastinal-ratio on the early (e-H/M) and delayed (d-H/M) images, the washout rate (WR), the left ventricular ejection fraction (LVEF), and the calculated rate of change by beta-blocker therapy in each parameter (ie, deltaV(alt), deltae-H/M, deltad-H/M, deltaWR and deltaLVEF) were measured. After therapy, TWA turned negative in 8 patients (group A) and remained positive in 18 (group B); V(alt) was significantly decreased in group B (p<0.001). In group A, e-H/M, d-H/M and LVEF were significantly increased (e-H/M: p<0.05, d-H/M and LVEF: p<0.01), as were e-H/M and LVEF in group B (p<0.05). There were significant correlations between deltaV(alt) and deltae-H/M (r=-0.61, p<0.01), deltad-H/M (r=-0.82, p<0.0001), deltaWR (r=0.60, p<0.01) and deltaLVEF (r=-0.70, p<0.01). In patients with NIHD, the TWA is improved in association with the improvement in cardiac sympathetic nervous system abnormalities and left ventricular systolic dysfunction by beta-blocker therapy.
Subject(s)
Action Potentials/drug effects , Adrenergic beta-Antagonists/therapeutic use , Heart Diseases/drug therapy , Sympathetic Nervous System/drug effects , Systole/drug effects , Adrenergic beta-Antagonists/pharmacology , Adult , Aged , Arrhythmias, Cardiac/drug therapy , Arrhythmias, Cardiac/physiopathology , Arrhythmias, Cardiac/prevention & control , Electrophysiology , Female , Heart/innervation , Heart/physiopathology , Heart Conduction System/drug effects , Heart Diseases/physiopathology , Humans , Male , Middle Aged , Stroke Volume/drug effects , Sympathetic Nervous System/physiopathology , Time Factors , Ventricular Dysfunction, Left/drug therapyABSTRACT
We examined the relation between microvolt-level T-wave alternans and cardiac sympathetic nervous system abnormality using iodine-123 metaiodobenzylguanidine imaging in patients with idiopathic dilated cardiomyopathy. Our results strongly indicate that cardiac sympathetic denervation and accelerated sympathetic nervous activity play important roles in the presence of microvolt-level T-wave alternans in patients with idiopathic-dilated cardiomyopathy.
Subject(s)
3-Iodobenzylguanidine , Cardiomyopathy, Dilated/physiopathology , Electrocardiography/methods , Radiopharmaceuticals , Sympathetic Nervous System/physiopathology , Cardiomyopathy, Dilated/diagnostic imaging , Exercise Test , Female , Heart/innervation , Humans , Male , Middle Aged , Models, Cardiovascular , Radionuclide Imaging , Sympathetic Nervous System/diagnostic imagingABSTRACT
The slope of the regression line between carbon dioxide output (VCO2) and minute ventilation (VE) (SLOPE) is useful for evaluating ventilation-perfusion inequality during exercise. A cardiopulmonary exercise test was carried out in 8 pulmonary hypertension (PH) patients without hypoxemia (group PH), 38 male patients with old myocardial infarction (group OMI), and 20 healthy men (group Ctrl). The average SLOPE for each group was 36.3+/-3.3, 28.7+/-0.9 and 25.6+/-0.5, respectively. There were significant differences among them. Group OMI was divided into 3 groups: OMI class 0: peak oxygen consumption (VO2) > or =21 ml x kg(-1) min(-1); OMI class I: 14 ml x kg(-1) x min(-1) < or =peak VO2<21 ml x kg(-1) min(-1); OMI class II: peak VO2< 14ml x kg(-1) x min(-1). There were no significant differences in peak VO2 between the groups PH and OMI class I, but the SLOPE in the group PH was greater than the SLOPE in OMI class I (p=0.0019). Compared with OMI class II, group PH had a greater peak VO2 (p=0.0215), although their SLOPE was equivalent to that of OMI class II. These results suggest that PH patients have severe ventilation-perfusion inequality despite good exercise capacity. When performing a cardiopulmonary exercise test on PH patients, it is necessary to observe not only VO2 or VCO2, but also VCO2/VE, in order to prevent aggravation of the ventilation-perfusion inequality, which leads to exercise-induced hypoxemia.
Subject(s)
Exercise/physiology , Hypertension, Pulmonary/complications , Hypertension, Pulmonary/physiopathology , Respiration Disorders/etiology , Adult , Aged , Carbon Dioxide , Exercise Test , Female , Humans , Male , Middle Aged , Myocardial Infarction/physiopathology , Oxygen Consumption , Physical Endurance , Reference Values , Respiration , Ventilation-Perfusion RatioABSTRACT
The influence of ischemic preconditioning (IP) and mitochondrial ATP-sensitive potassium (mito-KATP) channel openers on chronic left ventricular (LV) remodeling remains unknown, so the effect of IP and mito-KATP channel openers on the LV pressure-volume curve was assessed in rats subjected to 30 min ischemia followed by a 3-week reperfusion. Infarct size was histologically determined at 3 weeks after reperfusion. The LV pressure-volume curve was significantly shifted left by IP, diazoxide and nicorandil compared with the controls. These effects were blocked by the selective mito-KATP channel blocker 5-hydroxydecanoate. The LV remodeling and the infarct size at 3 weeks after reperfusion correlated well, indicating that the reduction of LV remodeling in the ischemic-reperfused model was strongly influenced by attenuation of the ischemic injury. LV remodeling in the chronic phase is attenuated by IP and mito-KATP channel openers with concomitant reduction of infarct size.