Ca(2+) channel blocker benidipine promotes coronary angiogenesis and reduces both left-ventricular diastolic stiffness and mortality in hypertensive rats.

Background: The beneficial cardiac effects of some Ca(2+) channel blockers have been attributed to blood pressure reduction, but these pleiotropic effects require further investigation. We compared the effects of benidipine, which has beneficial cardiac effects, and nitrendipine, which does not, in an animal model of hypertensive diastolic heart failure (DHF).

Methods And Results: Male Dahl salt-sensitive rats were fed a high-salt diet from age 7 weeks to induce hypertension and were either vehicle or orally administered benidipine (3 mg/kg daily) or nitrendipine (10 mg/kg daily) from age 10 to 18 weeks.

Watching the conformational changes of maleonitriledithiolate chromophores inside the inclusion complexes with cyclodextrins: probed by ICD spectra and DFT calculations.

A series of inclusion complexes between cyclodextrins (alpha-, beta-, gamma-cyclodextrin and HP-beta-cyclodextrin, HP-beta-cyclodextrin = 2-hydroxypropyl-beta-cyclodextrin) and sodium maleonitriledithiolate (Na(2)mnt) were investigated by electronic spectra, induced circular dichroism (ICD) spectra, and quantum chemical studies. The inclusion complexes Na(2)mnt@alpha-cyclodextrin and Na(2)mnt@gamma-cyclodextrin did not show any ICD signals, whereas Na(2)mnt@HP-beta-cyclodextrin displayed two signs of splitting Cotton effects (CEs), with one positive CE couplet at 376 nm in the 365-410 nm region and the other negative at 277 nm in the 265-306 nm region. In addition, a dimeric host inclusion pattern of Na(2)mnt@HP-beta-cyclodextrin in solution was determined by the method of continuous variation.

AT1 blockade attenuates atherosclerotic plaque destabilization accompanied by the suppression of cathepsin S activity in apoE-deficient mice.

Although it has been suggested that the renin-angiotensin (RA) system and cathepsins contribute to the development and vulnerability of atherosclerotic plaque, the interaction of the RA system and cathepsins is unclear. Thus, we investigated the effects of an angiotensin II type 1 receptor (AT1) antagonist, olmesartan, on the levels of cathepsins in brachiocephalic atherosclerotic plaque and plaque stabilization in apolipoprotein E (apoE)-deficient mice receiving a high-fat diet. Under a high fat diet, treatment with olmesartan (3 mg/kg per day) maintained collagen and elastin at high levels and attenuated the plaque development and cathepsin S (Cat S) level in the atherosclerotic plaque of apoE-deficient mice.

Low folate levels may be an atherogenic factor regardless of homocysteine levels in young healthy nonsmokers.

Low folate and high homocysteine levels are emerging as important risk factors for atherosclerosis and predictors of early coronary heart disease. We evaluated folate and homocysteine levels, compared them with endothelial function, and analyzed their association with the methylenetetrahydrofolate reductase (MTHFR) and endothelial nitric oxide synthase genotypes. We recruited 71 young healthy male nonsmokers without overt cardiovascular or renal disease.

Mechanism of diastolic stiffening of the failing myocardium and its prevention by angiotensin receptor and calcium channel blockers.

Objective: To investigate the mechanism responsible for the increased cardiac stiffness associated with hypertensive heart failure in Dahl salt-sensitive (DS) rats and the effects of treatment with the combination of a calcium channel blocker [azelnidipine (AZE)] and angiotensin II type 1 receptor blocker [olmesartan (OLM)].

Methods: DS rats fed a high-salt diet from 7 weeks of age were treated (or not) from 12 to 19 weeks of age with the vasodilator hydralazine, OLM plus AZE, or the reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor apocynin. Rats fed a low-salt diet served as controls.

Microsomal triglyceride transfer protein gene polymorphism strongly influences circulating malondialdehyde-modified low-density lipoprotein.

Microsomal triglyceride transfer protein (MTP) plays a critical role in the assembly of lipoproteins. Therefore, we studied whether MTP gene polymorphisms are associated with atherosclerosis-promoting parameters, especially metabolic profiles and endothelial function, in healthy young men. One hundred one healthy men (mean age, 30.

Long-term administration of nifedipine attenuates cardiac remodeling and diastolic heart failure in hypertensive rats.

The Ca2+ channel blocker nifedipine has been reported to reduce the rate of new overt heart failure. We investigated the effects of nifedipine on left ventricular remodeling, oxidative stress, and gene expression in the failing heart of Dahl salt-sensitive (DS) rats. DS rats fed a high-salt diet from 7 weeks of age were treated with a non-antihypertensive (1 mg/kg per day, Nif-L) or mild-antihypertensive dose of nifedipine (3 mg/kg per day, Nif-H) or with vehicle (Vehicle) from 12 to 19 weeks.

Relation of functional and morphological changes in mitochondria to myocardial contractile and relaxation reserves in asymptomatic to mildly symptomatic patients with hypertrophic cardiomyopathy.

Aims: To examine the relation between mitochondrial dysfunction and myocardial contractile and relaxation reserves in hypertrophic cardiomyopathy (HCM).

Methods And Results: Thirty HCM patients (LVEF >or=60%) underwent biventricular cardiac catheterization analysis both at rest and during atrial pacing as well as myocardial (99m)Tc-sestamibi scintigraphy at rest to calculate washout rate. Endomyocardial biopsy specimens were obtained for quantitative mRNA analysis and electron microscopy.

Beneficial effects of torasemide on systolic wall stress and sympathetic nervous activity in asymptomatic or mildly symptomatic patients with heart failure: comparison with azosemide.

Loop diuretics could adversely influence prognosis due to activation of neurohumoral mechanism in the long term. Previous study showed torasemide, a loop diuretic with anti-aldosteronergic properties, was associated with lower mortality in patients with chronic heart failure (CHF). We evaluated the effects of torasemide, in comparison with azosemide, in patients with CHF.

Dobutamine stress testing as a diagnostic tool for evaluation of myocardial contractile reserve in asymptomatic or mildly symptomatic patients with dilated cardiomyopathy.

Objectives: We performed dobutamine stress testing for evaluation of myocardial contractile reserve in asymptomatic or mildly symptomatic patients with dilated cardiomyopathy (DCM).

Background: Catecholamine sensitivity is reduced in failing hearts as a result of myocardial abnormalities in the beta-adrenergic receptor signaling pathway. However, little is known about adrenergic myocardial contractile reserve in asymptomatic or mildly symptomatic patients with DCM.

gamma-Secretase inhibitor reduces diet-induced atherosclerosis in apolipoprotein E-deficient mice.

Atherosclerosis is a chronic inflammatory disease resulting from interactions between lipids, macrophages and arterial wall cells. The Notch signaling pathway is involved in the activation of macrophages in atherosclerotic lesions. This study examined whether pharmacological inhibition of Notch signaling using a gamma-secretase inhibitor (GSI) can reduce atherosclerotic lesion formation.

Statin prevents plaque disruption in apoE-knockout mouse model through pleiotropic effect on acute inflammation.

Although it has been demonstrated that statins stabilize atherosclerotic lesions in animal models of advanced atherosclerosis, there is little evidence to suggest that statins have a preventive effect on plaque rupture itself. In the present study, we examined the effect of fluvastatin on plaque disruption using a simple and quick method of plaque disruption in carotid artery lesions in apolipoprotein E-deficient mice. Male apolipoprotein E-deficient mice received normal chow and underwent ligation of the left common carotid artery just proximal to its bifurcation.

Circulating malondialdehyde-modified low-density lipoprotein is strongly associated with very small low-density lipoprotein cholesterol concentrations in healthy men.

Background: Despite the importance of oxidized LDL and small LDL particles as atherogenic lipoproteins, the relationship between oxidized LDL and the distributions of size subclasses of lipoproteins is not fully proved. We investigated the relationship of circulating malondialdehyde-modified (MDA)-LDL, an oxidized form of LDL, and lipoprotein subclasses in healthy men.

Methods: The study group consisted of a total of 170 healthy Japanese men (55+/-9 y).

Pioglitazone attenuates cardiac hypertrophy in rats with salt-sensitive hypertension: role of activation of AMP-activated protein kinase and inhibition of Akt.

Objective: Cardiac hypertrophy is common in diabetes and an independent risk factor for cardiac morbidity and mortality. We investigated the effects of pioglitazone on cardiac hypertrophy and hypertrophic signaling in Dahl salt-sensitive hypertensive rats.

Methods: Dahl salt-sensitive rats were fed a high-salt diet from 7 weeks of age and treated with pioglitazone (2.

Superoxide-dependent cathepsin activation is associated with hypertensive myocardial remodeling and represents a target for angiotensin II type 1 receptor blocker treatment.

The elastolytic activity of cathepsins in the myocardium is implicated in hypertensive heart failure (HF). Given that reactive oxygen species are also implicated in protease activation associated with cardiac remodeling, we examined the role of the reactive oxygen species-induced cathepsin activation system in cardiac remodeling during the development of hypertensive HF. Dahl salt-sensitive hypertensive rats maintained on a high-salt diet were treated with vehicle, the cathepsin inhibitor E64d, or the angiotensin receptor blocker olmesartan from 12 to 19 weeks of age.

The effects of endothelial nitric oxide synthase gene polymorphisms on endothelial function and metabolic risk factors in healthy subjects: the significance of plasma adiponectin levels.

Objective: Genetic variants of the endothelial nitric oxide synthase (eNOS) gene, Glu298Asp and T-786C, have been reported to be associated with cardiovascular disease. Adiponectin is an adipocyte-derived plasma protein with insulin-sensitizing and vascular protective effects; its levels are typically low in metabolic syndrome. Therefore, eNOS gene polymorphisms may also be associated with specific metabolic profiles, including plasma adiponectin levels and atherogenic lipids.

Angiogenic activity of bFGF and VEGF suppressed by proteolytic cleavage by neutrophil elastase.

Neutrophil elastase (NE), a serine protease released from the azurophil granules of activated neutrophil, proteolytically cleaves multiple cytokines, and cell surface proteins. In the present study, we examined whether NE affects the biological abilities of angiogenic growth factors such as basic-fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF). NE degraded bFGF and VEGF in a time- and concentration-dependent manner, and these degradations were suppressed by sivelestat, a synthetic inhibitor of NE.

Impact of the high-molecular-weight form of adiponectin on endothelial function in healthy young men.

Objective: Adiponectin is an adipocyte-derived, antiatherogenic protein that is present in plasma as a large multimeric structure of high molecular weight (HMW) and in a trimer or hexamer form (non-HMW). The biological activities of these isoforms have not yet been elucidated. We therefore examined the effect of these isoforms on endothelial function in healthy young men.

Mechanisms underlying the impairment of ischemia-induced neovascularization in matrix metalloproteinase 2-deficient mice.

Matrix metalloproteinases (MMPs) have been implicated in the process of neovascularization. However, the exact roles of individual MMPs in vessel formation are poorly understood. To study the putative role of MMP-2 in ischemia-induced neovascularization, a hindlimb ischemia model was applied to MMP-2(+/+) and MMP-2(-/-) mice.

Attenuation of ventricular hypertrophy and fibrosis in rats by pitavastatin: potential role of the RhoA-extracellular signal-regulated kinase-serum response factor signalling pathway.

1. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) manifest pleiotropic effects that may contribute to their therapeutic efficacy. However, the mechanism of the beneficial action of statins on cardiac hypertrophy and fibrosis remains unclear.

Elastolytic cathepsin induction/activation system exists in myocardium and is upregulated in hypertensive heart failure.

Cathepsins are cysteine proteases that participate in various types of tissue remodeling. However, their expressions during myocardial remodeling have not been examined. In this study, we investigated their expressions in the left ventricular (LV) myocardium of rats and humans with hypertension-induced LV hypertrophy or heart failure (HF).

Pitavastatin improves cardiac function and survival in association with suppression of the myocardial endothelin system in a rat model of hypertensive heart failure.

Statin therapy may be associated with lower mortality in patients with heart failure, but the underlying mechanism of such an association is unknown. We have evaluated the effects of pitavastatin on cardiac function and survival in a rat model of hypertensive heart failure and investigated the molecular mechanism of the observed effects. Dahl salt-sensitive rats fed with high-salt diet from 7 weeks of age developed compensatory left ventricular hypertrophy at 12 weeks and heart failure at 19 weeks.

Underuse of medications for chronic diseases in the oldest of community-dwelling older frail Japanese.

Objectives: To test the following hypotheses: (1) the rate of polypharmacy, defined as six or more prescribing medications, is lower in the oldest old (> or =85) than in younger older people (65-84); (2) beneficial medication use is lower in the oldest old; (3) the underuse of these medications in the oldest old is associated with physical or cognitive impairment or comorbid conditions.

Design: A cross-sectional study of the baseline data from the Nagoya Longitudinal Study for Frail Elderly.

Setting: Community-based.