Effects of cyanamide, an aldehyde dehydrogenase type 2 inhibitor, on glyceryl trinitrate- and isosorbide dinitrate-induced vasodilation in rabbit excised aorta and in anesthetized whole animal.

The contribution of aldehyde dehydrogenase type 2 (ALDH2) to bioactivation of glyceryl trinitrate (GTN) and isosorbide dinitrate (ISDN) was systematically examined in excised rabbit aorta and anesthetized whole animal with cyanamide, an ALDH2 inhibitor. In excised aortic preparation, the degree of inhibition by cyanamide in GTN-induced vasorelaxation (concentration ratio, calculated as EC(50) in the presence of cyanamide/EC(50) in the absence of cyanamide; 5.61) was twice that in ISDN-induced relaxation (2.

Possible involvement of hypothalamic nucleobindin-2 in hyperphagic feeding in Tsumura Suzuki obese diabetes mice.

The aim of this study was to clarify the hypothalamic neuropeptides that are associated with hyperphagic feeding in Tsumura Suzuki Obese Diabetes (TSOD) mice, a model of type 2 diabetes with polygenic abnormalities. TSOD mice showed an increase in body weight and hyperleptinemia from 1 month of age and hyperphagic feeding, hyperglycemia, hyperlipidemia and hyperinsulinemia from 3 to 12 months of age compared with age-matched non-diabetic control Tsumura Suzuki Non Obesity (TSNO) mice. The mRNA level of nucleobindin-2 (NUCB2), the precursor of the anorexigenic neuropeptide nesfatin-1, was significantly decreased in the hypothalamus of TSOD mice compared with that in TSNO mice from 3 to 12 months of age.

Role of plasma S-nitrosothiols in regulation of blood pressure in anesthetized rabbits with special references to hypotensive effects of acetylcholine and nitrovasodilators.

The regulatory role of plasma nitrosothiols (R-SNOs) under steady-state conditions and their possible contribution to pharmacological vasodilation were systematically examined in anesthetized rabbits. Nitrosocystein (Cys-NO), S-nitrosoglutathione (G-SNO), and S-nitrosoalbumin (Alb-SNO) were determined by HPLC-Saville's method with respective sensitivities of 1, 1, and 5 nM. These R-SNOs were not detected under steady-state conditions even in the presence of N-ethylmaleimide, a thiol protective agent used to prevent transnitrosation of R-SNOs.

Different disappearance rates of plasma nitrite (NO(2)(-)) contribute to apparent steady-state arterio-venous differences in anesthetized animals.

A possible cause of arterio-venous (A-V) differences in plasma nitrite (NO(2)(-)) levels under steady-state conditions and kinetic features of NO(2)(-) in arterial and venous blood were examined. In isolated rabbit blood, plasma NO(2)(-) in venous blood disappeared faster than that in arterial blood and was accompanied by a concomitant increase in nitrate (NO(3)(-)), implicating oxidation as the main pertinent metabolic pathway. When data were corrected with respective elimination constants and time durations before plasma separation, no A-V difference was estimated under steady-state.

A study of cardiovascular function in Tsumura Suzuki obese diabetes, a new model mouse of type 2 diabetes.

Diabetes mellitus is a well known and important risk factor for cardiovascular diseases, including heart failure. A new model of Type 2 diabetes, Tsumura Suzuki Obese Diabetes (TSOD) mice, was introduced recently into the research field of diabetes. The cardiac functions of TSOD mice were studied in comparison with Tsumura Suzuki Non Obesity (TSNO, non-diabetic control) mice, for the first time.

Functional proteomic analysis of experimental autoimmune myocarditis-induced chronic heart failure in the rat.

Experimental autoimmune myocarditis (EAM)-induced heart failure in rats is used to study the pathogenesis of heart failure. Based on a proteomic analysis of soluble (S) and membranous (M) fractions extracted from ventricles of rats with a stable chronic form of EAM-induced heart failure, we assessed changes in protein levels and their correlation to heart functions to gain insights into the pathogenesis and to explore new targets for the treatment of heart failure. Proteins were separated by two-dimensional gel electrophoresis and silver stained spots were analyzed.

Arteriovenous differences in NO2- kinetics in anesthetized rabbits.

Despite of the importance of plasma NO2- as an index of endothelial nitric oxide (NO) formation and a substrate for NO production, only a limited kinetic knowledge is available in vivo. To address this issue, we intravenously injected NaNO2 into anesthetized rabbits and quantified changes in arterial and venous plasma NO2- levels. Plasma NO2- levels in arterial blood (956 +/- 220 nM) were slightly, but significantly, higher than those in venous blood (889 +/- 214 nM) under control conditions.

Quantifying nanomolar levels of nitrite in biological samples by HPLC-Griess method: special reference to arterio-venous difference in vivo.

Nitrite (NO(2)(-)) is assumed to play an important role in regulation of vascular tone as a reservoir of nitric oxide (NO). To examine its physiological contribution, however, a sensitive method is required for determination of the true level of NO(2)(-) in biological samples. To this end, practical consideration to avoid NO(2)(-) contamination through the quantification procedure is important.

Which skeletal myoblasts and how to be transplanted for cardiac repair?

Clinical efficacy of skeletal myoblast (skMb) transplantation is controversial whether this treatment produces beneficial outcome in patients with dilated cardiomyopathy (DCM). Based on immunological tolerance between wild-type and DCM hamsters with the deletion of delta-sarcoglycan (SG) gene, skMb engraftment in TO-2 myocardium (3x10(5) cells in approximately 100mg heart) was verified by the donor-specific expression of delta-SG transgene constitutively produced throughout myogenesis. At 5 weeks after the transplantation, the cell rates expressing fast-myosin heavy chain (MHC) exceeded slow-MHC in delta-SG(+) cells.

Gene therapy prevents disruption of dystrophin-related proteins in a model of hereditary dilated cardiomyopathy in hamsters.

Background: The TO-2 hamster is an animal model of dilated cardiomyopathy (DCM). It has genetic and clinical features in common with humans who carry the gene deletion or mutation of the delta-sarcoglycan (SG) gene, a component in dystrophin-related proteins (DRP). DRP stabilise the sarcolemma during cardiac contraction.

A novel scheme of dystrophin disruption for the progression of advanced heart failure.

The precise mechanism of the progression of advanced heart failure is unknown. We assessed a new scheme in two heart failure models: (I) congenital dilated cardiomyopathy (DCM) in TO-2 strain hamsters lacking delta-sarcoglycan (SG) gene and (II) administration of a high-dose of isoproterenol, as an acute heart failure in normal rats. In TO-2 hamsters, we followed the time course of the histological, physiological and metabolic the progressions of heart failure to the end stage.

A novel paradigm for therapeutic basis of advanced heart failure--assessment by gene therapy.

The precise mechanism(s) of the progression of advanced heart failure (HF) should be determined to establish strategies for its treatment or prevention. Based on pathological, molecular, and physiological findings in 3 animal models and human cases, we propose a novel scheme that a vicious cycle formed by increased sarcolemma (SL) permeability, preferential activation of calpain over calpastatin, and translocation and cleavage of dystrophin (Dys) commonly lead to advanced HF. The aim of this article was to assess our recent paradigm that disruption of myocardial Dys is a final common pathway to advanced HF, irrespective of its hereditary or acquired origin, but not intended to provide a comprehensive overview of the various factors that may be involved in the course of HF in different clinical settings.

Translocation and cleavage of myocardial dystrophin as a common pathway to advanced heart failure: a scheme for the progression of cardiac dysfunction.

Advanced heart failure (HF) is the leading cause of death in developed countries. The mechanism underlying the progression of cardiac dysfunction needs to be clarified to establish approaches to prevention or treatment. Here, using TO-2 hamsters with hereditary dilated cardiomyopathy, we show age-dependent cleavage and translocation of myocardial dystrophin (Dys) from the sarcolemma (SL) to the myoplasm, increased SL permeability in situ, and a close relationship between the loss of Dys and hemodynamic indices.

[A new paradigm for the progression of advanced heart failure].

To clarify the precise mechanism for the progression of advanced heart failure (AdHF), we assessed the scheme in two HF models, using (I) TO-2 strain hamsters sharing common genetic and clinical features to human families with the delta-sarcoglycan (SG) gene mutation and (II) administration of a high-dose (HD) of isoproterenol (Isp) to normal rats. Delta-SG is a component in dystrophin (Dys)-related proteins that stabilize the sarcolemma (SL) during repeated heart beats. In TO-2, we followed time course of hemodynamics, immunostaining and Western blotting of Dys and in situ SL permeability by Evans blue uptake with or without the gene therapy.

Efficacy of fluticasone propionate compared with beclomethasone dipropionate in bronchial asthma: improvement in compliance and symptoms by fluticasone.

Recent studies have shown that fluticasone propionate (FP) was more effective than beclomethasone dipropionate (BDP) inhalation even at a dose reduced by twofold or more in the treatment of bronchial asthma. Here, we further compared the effectiveness of FP and BDP, including rates of drug compliance. Forty-two symptomatic patients were treated by BDP (1000 +/- 345; mean +/- SD; microgram/day) for 8 weeks, followed by FP at one-half the respective dose, and peak expiratory flow and forced expiratory volume in 1 second were investigated.

Sarcolemmal fragility secondary to the degradation of dystrophin in dilated cardiomyopathy, as estimated by electron microscopy.

A common gene deletion or mutation of delta-sarcoglycan (delta-SG) in dystrophin-related proteins (DRPs) is identified in both TO-2 strain hamsters and human families with dilated cardiomyopathy. We have succeeded in the long-lasting in vivo supplementation of a normal delta-SG gene by recombinant adeno-associated virus vector, restoration of the morphological and functional degeneration, and improvement in the prognosis of the TO-2 hamster. To evaluate the integrity of the sarcolemma (SL) and the subsequent change of organelles in cardiomyocytes of the TO-2 strain hamster, we examined electron microscopy (EM) images focusing on the sarcolemmal stability at the end stage of heart failure.

[Somatic gene therapy of dilated cardiomyopathy].

The hereditary form of dilated cardiomyopathy (DCM) accounts for about 20% of human DCM and is a major cause of heart failure. TO-2 strain hamsters show DCM, a gene deletion of delta-sarcoglycan (SG), loss of all four SGs, alpha-, beta-, gamma- and delta-SG proteins, and are useful for developing gene therapy of the hereditary DCM. The delta-SG is a component of dystrophin-associated glycoprotein complex that stabilizes sarcolemma.

Rescue of hereditary form of dilated cardiomyopathy by rAAV-mediated somatic gene therapy: amelioration of morphological findings, sarcolemmal permeability, cardiac performances, and the prognosis of TO-2 hamsters.

The hereditary form comprises approximately 1/5 of patients with dilated cardiomyopathy (DCM) and is a major cause of advanced heart failure. Medical and socioeconomic settings require novel treatments other than cardiac transplantation. TO-2 strain hamsters with congenital DCM show similar clinical and genetic backgrounds to human cases that have defects in the delta-sarcoglycan (delta-SG) gene.