Abstract-3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) significantly reduce cardiovascular mortality associated with hypercholesterolemia. There is evidence that statins exert beneficial effects in part through direct effects on vascular cells independent of lowering plasma cholesterol. We characterized the effect of a 30-day treatment with atorvastatin in normocholesterolemic, spontaneously hypertensive rats (SHR). Systolic blood pressure was significantly decreased in atorvastatin-treated rats (184Ϯ5 versus 204Ϯ6 mm Hg for control). Statin therapy improved endothelial dysfunction, as assessed by carbachol-induced vasorelaxation in aortic segments, and profoundly reduced angiotensin II-induced vasoconstriction. Angiotensin type 1 (AT 1 ) receptor, endothelial cell NO synthase (ecNOS), and p22phox mRNA expression were determined with quantitative reverse transcription-polymerase chain reaction. Atorvastatin treatment downregulated aortic AT 1 receptor mRNA expression to 44Ϯ12% of control and reduced mRNA expression of the essential NAD(P)H oxidase subunit p22phox to 63Ϯ7% of control. Aortic AT 1 receptor protein expression was consistently decreased. Vascular production of reactive oxygen species was reduced to 62Ϯ12% of control in statin-treated SHR, as measured with lucigenin chemiluminescence assays. Accordingly, treatment of SHR with the AT 1 receptor antagonist fonsartan improved endothelial dysfunction and reduced vascular free-radical release. Moreover, atorvastatin caused an upregulation of ecNOS mRNA expression (138Ϯ7% of control) and an enhanced ecNOS activity in the vessel wall (209Ϯ46% of control). Treatment of SHR with atorvastatin causes a significant reduction of systolic blood pressure and a profound improvement of endothelial dysfunction mediated by a reduction of free radical release in the vasculature. The underlying mechanism could in part be based on the statin-induced downregulation of AT 1 receptor expression and decreased expression of the NAD(P)H oxidase subunit p22phox, because AT 1 receptor activation plays a pivotal role for the induction of this redox system in the vessel wall.

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Abstract-Endothelial NO synthase, being deficient in arginine and/or tetrahydrobiopterin, produces in addition to NO a significant concentration of superoxide (O 2 Ϫ ). We investigated whether such an imbalance between O 2 Ϫ and NO production is present in dysfunctional aortas of Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) with failing hearts after myocardial infarction. Heart failure was induced by permanent occlusion of the left coronary artery, resulting in a large infarction of the free left ventricular wall. Eight weeks after myocardial infarction, when WKY and SHR had compensated heart failure and congestive heart failure, respectively, calcium ionophore-induced NO release (assessed by a NO-sensitive microsensor) from aortic endothelial cells was significantly reduced from 478Ϯ48 to 216Ϯ16 nmol/L and 693Ϯ131 to 257Ϯ53 nmol/L in WKY and SHR, respectively. Concomitantly, significant increases in calcium ionophore-stimulated O 2 Ϫ production (assessed by an electrochemical sensor) could be observed in aortic endothelial cells from infarcted WKY rats (22Ϯ3.2 versus sham, 10.1Ϯ1.2 nmol/L) and SHR (102Ϯ8 versus sham, 67Ϯ5 nmol/L). A dramatic increase in endothelial peroxynitrite concentration (chemiluminescence method) from 35Ϯ4 to 90Ϯ3 nmol/L for WKY and from 60Ϯ5 to 170Ϯ10 nmol/L for SHR also was detected. Thus, the markedly decreased NO availability probably caused by impaired endothelial NO synthase activity with enhanced O 2 Ϫ and peroxynitrite production appears to be attributable to endothelial dysfunction in normotensive rats with chronic heart failure and especially in hypertensive rats with severe congestive heart failure. Key Words: heart failure Ⅲ endothelium Ⅲ nitric oxide Ⅲ rats, spontaneously hypertensive Ⅲ rats, WKY N umerous studies showed that impaired endotheliumdependent vasodilation and cardiac dysfunction in heart failure (HF) appear to be attributable to decreased endothelial NO synthesis and/or possibly to increased NO degradation by enhanced generation of superoxide (O 2 Ϫ ). Large deficiencies of endothelial NO synthase (eNOS) mRNA and protein as well as basal and stimulated NO production were observed in aortic endothelial cells 1 and cardiac microvessels 2 from conscious dogs with pacing-induced overt congestive heart failure (CHF). In the same animal model at the onset of cardiac decompensation, reduced basal cardiac NO production was associated with a fall of cardiac contractility and an elevated left ventricular end-diastolic pressure. 3 Similarly, impaired basal and stimulated NO productions, which were indirectly assessed by vascular cyclic GMP, were demonstrated in aortas 4 and pulmonary arteries 4,5 from Wistar-Kyoto rats (WKY) with chronic HF after myocardial infarction (MI). In comparison, a normal acetylcholine-induced relaxation with reduction of basal NO release was found in small mesenteric arteries from this rat HF model. 6,7 Conflicting data exist with regard to eNOS expression and activity in human beings with chronic HF. Increased cardiac express...

Atrial electrical remodeling changed the efficacy of the antiarrhythmic agents in a different way. The favorable efficacy profile of amiodarone during electrical remodeling, particularly the marked increase in AERP prolongation in early electrical remodeling, may explain its superior clinical efficacy over existing antiarrhythmic drugs.

Chronic heart failure (CHF) is one of the most common causes of death in Western countries. The aim of this study was to establish and validate a model of CHF in the rat. This rat model should result in parameters and symptoms that can be extrapolated to the clinical situation of patients with end-stage heart failure. At present only palliative therapy is possible for patients with heart failure but the aim for the future is to nd a causal therapy of heart failure treatment. The rat model should be a valuable method for the early testing of new therapeutic approaches in patients with congestive heart failure. SummaryCommon models of chronic heart failure (CHF) do not always result in parameters and symptoms that can be extrapolated to the clinical situation of patients with end-stage heart failure. The aim of this study was to establish and validate a new model of CHF in the rat. CHF was induced in Wistar Kyoto (WKY/NHsd) and spontaneously hypertensive (SHR/NHsd) rats by creating a permanent (8-week) occlusion of the left coronary artery 2 mm distal to the origin from the aorta by a modi ed technique. This resulted in a large infarction of the free left ventricular wall. The focus of attention was the validation of the geometric properties of the left ventricle and its contractility. The validation of the geometric properties of the left ventricle was done by a non-invasive magnetic resonance imaging (MRI) technique and by planimetry (stereology). Cardiodynamics (e.g. contractility) were evaluated in the isolated 'working heart' model. We were able to establish a new and predictive model of heart failure in the spontaneously hypertensive rat 8 weeks after coronary artery ligation. At this time point, the WKY rat did not show any symptoms of CHF. The model represents characteristic parameters and symptoms that can be extrapolated to the clinical situation of patients with end-stage heart failure (NYHA III-IV). Upon inspection, severe clinical symptoms of congestive heart failure were prominent, such as dyspnoea, subcutaneous oedema, pale-bluish limbs and impaired motion. Non-invasive sequential measurements by NMR techniques showed lung oedema, hydrothorax, large dilated left and right ventricular chambers and hypertrophy of the septum. The infarcted animals showed a reduced heart power, diminished contractility and enhanced heart work, much more so in the SHR/NHsd rat than in the WKY/NHsd rat. Furthermore the infarcted animals showed enhanced levels of hydroxyproline/proline ratios, again much more so in the SHR/NHsd rat than in the WKY/NHsd rat.