Biomedical subjects

Satoshi Sakai

Publications and source records attributed to Satoshi Sakai.

5 recordsLinked to original sources

PubMed2003

[Combination of oral endothelin-A receptor antagonist and oral prostacyclin analogue is superior to each drug alone in ameliorating pulmonary hypertension in rats].

OBJECTIVES: To investigate whether the combination of an oral endothelin (ET)-A receptor antagonist and an oral prostacyclin(PGI2) analogue is superior to the single use of each drug alone for treating pulmonary hypertension(PH). BACKGROUND: Treatment with intravenous PGI2 or an ET-A receptor antagonist was effective for PH; however, the effect of both administrations is unclear. METHODS: We administered the oral ET-A receptor antagonist TA-0201 and/or the oral PGI2 analogue beraprost sodium(BPS) to monocrotaline-induced PH rats for 19 days in the following groups: normal rats with vehicle treatment (Control group), PH rats with vehicle treatment (PH group), PH rats with TA-0201 treatment (PH + TA group), PH rats with BPS treatment (PH + BPS group), and PH rats with TA-0201 and BPS treatment (PH + TA + BPS group). RESULTS: Right ventricular systolic pressure and Pp/Ps were markedly higher in the PH group than in the Control group. The increased right ventricular systolic pressure and Pp/Ps were significantly and comparably depressed in the PH + TA group and PH + BPS group; it was more greatly depressed in the PH + TA + BPS group than in the groups with each drug alone. The indices of right ventricular hypertrophy showed the same tendency as the increase in right ventricular systolic pressure in the five groups. The expression of beta-myosin heavy chain mRNA in right ventricle was markedly augmented in the PH group; the enhancement was inhibited in the PH + TA + BPS group to the greatest degree. Medial wall thickness of the pulmonary artery was markedly increased in the PH group; the increase was depressed in PH + TA + BPS group. Combined treatment also ameliorated PH even if it started from the post-onset of PH. CONCLUSIONS: The combination of an oral ET-A receptor antagonist and an oral PGI2 analogue is superior to the single use of each drug alone in inhibiting the progression of PH.

Administration, Oral↗

PubMed2002

A combination of oral endothelin-A receptor antagonist and oral prostacyclin analogue is superior to each drug alone in ameliorating pulmonary hypertension in rats.

OBJECTIVES: We sought to investigate whether the combination of an oral endothelin (ET)A receptor antagonist and an oral prostacyclin (PGI(2)) analogue is superior to the single use of each drug alone for treating pulmonary hypertension (PH). BACKGROUND: Treatment with intravenous PGI(2) or an ET(A) receptor antagonist was effective for PH; however, the effect of both agents is unclear. METHODS: We administered the oral ET(A) receptor antagonist TA-0201 and/or the oral PGI(2) analogue beraprost sodium (BPS) to rats with monocrotaline-induced PH for 19 days. The groups were: normal rats with vehicle treatment (Control group), PH rats with vehicle treatment (PH group), PH rats with TA-0201 treatment (PH + TA group), PH rats with BPS treatment (PH + BPS group) and PH rats with TA-0201 and BPS treatment (PH + TA + BPS group). RESULTS: Right ventricular (RV) systolic pressure and the ratio of RV systolic pressure to systemic systolic blood pressure (Pp/Ps) were markedly higher in the PH group than in the Control group. The increased RV systolic pressure and Pp/Ps were significantly and comparably depressed in the PH + TA and PH + BPS groups; it was more greatly depressed in the PH + TA + BPS group than in the groups with each drug alone. The indexes of RV hypertrophy showed the same tendency as the increase in RV systolic pressure among the five groups. The expression of beta-myosin heavy chain messenger ribonucleic acid in the RV was markedly augmented in the PH group; the enhancement was inhibited in the PH + TA + BPS group to the greatest degree. Medial wall thickness of the pulmonary artery was markedly increased in the PH group; the increase was depressed in the PH + TA + BPS group. Combined treatment also ameliorated PH, even if it started after the onset of PH. CONCLUSIONS: The combination of an oral ETA receptor antagonist and an oral PGI(2) analogue is superior to the single use of each drug alone in inhibiting the progression of PH.

Administration, Oral↗

PubMed2002

Peroxisome proliferator-activated receptor-gamma activators inhibit endothelin-1-related cardiac hypertrophy in rats.

Endothelin-1 (ET-1) causes cardiac hypertrophy, and ET receptor antagonists inhibit the development of cardiac hypertrophy in vitro and in vivo. Peroxisome proliferator-activated receptor gamma (PPAR gamma), a member of the family of nuclear receptors, suppresses activator protein-1 (AP-1). We investigated the effects of the thiazolidinediones troglitazone and pioglitazone, activators of PPAR gamma, on cardiac hypertrophy due to pressure overload provoked by abdominal aortic banding (AB) in rats. Rats were divided into four groups: sham operation with vehicle treatment (n=5); AB surgery with vehicle treatment (n=6); AB surgery with troglitazone treatment (100 mg x kg(-1) x day(-1); n=5); and AB surgery with pioglitazone treatment (10 mg x kg(-1) x day(-1); n=8). Treatments were started 7 days before AB surgery, and left ventricular (LV) hypertrophy was assessed 24 h after surgery. The ratio of LV weight/body weight (BW) was significantly increased in AB rats compared with sham-operated rats; treatment of AB rats with troglitazone or pioglitazone significantly inhibited the increase in LV weight/BW. Expression of ET-1 mRNA was markedly enhanced in the left ventricles of AB rats; treatment with troglitazone or pioglitazone lowered expression significantly. Suppression of cardiac hypertrophy by pioglitazone treatment was accompanied by a decrease in expression of the gene encoding brain natriuretic factor, a molecular marker for cardiac hypertrophy, in AB rats. Because the ET-1 gene has AP-1 response elements in its 5'-flanking region, the thiazolidinediones troglitazone and pioglitazone may inhibit cardiac hypertrophy partly through suppression of AP-1-induced ET-1 gene up-regulation.

Analysis of Variance↗

PubMed2002

Stimulation of peroxisome-proliferator-activated receptor alpha (PPAR alpha) attenuates cardiac fibrosis and endothelin-1 production in pressure-overloaded rat hearts.

Endothelin-1 (ET-1) production is increased in hypertrophied hearts accompanied with fibrosis. ET-1 is a potent mitogen of fibroblasts and ET receptor antagonists are reported to inhibit the proliferation of fibroblasts and cardiac fibrosis. Peroxisome-proliferator-activated receptor alpha (PPAR alpha), one of the nuclear hormone receptors, suppresses activator protein-1 (AP-1), one of the nuclear transcription factors. Activation of PPAR alpha is reported to inhibit thrombin-induced ET-1 production by repressing the AP-1 signalling pathway in vascular endothelial cells. We investigated effects of the PPAR alpha activator fenofibrate (80 mg/kg per day, per os) on mRNA levels of ET-1, collagen type I and type III and histological features of myocardial fibrosis in hypertrophied rat hearts due to pressure-overload by abdominal aortic banding (AB). The treatment with fenofibrate or vehicle was started 7 days before the AB operation. Four days after the AB operation, fenofibrate treatment significantly reduced ET-1 mRNA expression compared with vehicle treatment in AB rat hearts. Collagen type I and type III mRNA expression, and interstitial and perivascular fibrosis were attenuated in the fenofibrate-treated AB rat group. Since the ET-1 gene has AP-1 response elements in the 5'-flanking region, it is suggested that myocardial fibrosis is effectively inhibited by fenofibrate through suppression of AP-1-mediated ET-1 gene augmentation in the pressure-overloaded heart caused by aortic banding in rats.

Animals↗

PubMed2002

Aging-induced decrease in the PPAR-alpha level in hearts is improved by exercise training.

Peroxisome proliferator-activated receptor (PPAR)-alpha, a transcriptional activator, regulates genes of fatty acid (FA) metabolic enzymes. To study the contribution of PPAR-alpha to exercise training-induced improvement of FA metabolic capacity in the aged heart, we investigated whether PPAR-alpha signaling and expression of its target genes in the aged heart are affected by exercise training. We used hearts of sedentary young rat (4 mo old), sedentary aged rat (23 mo old), and swim-trained aged rat (23 mo old, training for 8 wk). The mRNA and protein expression of PPAR-alpha in the heart was significantly lower in the sedentary aged rats compared with the sedentary young rats and was significantly higher in the swim-trained aged rats compared with the sedentary aged rats. The activity of PPAR-alpha DNA binding to the transcriptional regulating region on the FA metabolic enzyme genes, the mRNA expression of 3-hydroxyacyl CoA dehydrogenase (HAD) and carnitine palmitoyl transferase-I, which are PPAR-alpha target genes, and the enzyme activity of HAD in the heart altered in association with changes of the myocardial PPAR-alpha mRNA and protein levels. These findings suggest that exercise training improves aging-induced downregulation in myocardial PPAR-alpha-mediated molecular system, thereby contributing to the improvement of the FA metabolic enzyme activity in the trained-aged hearts.

3-Hydroxyacyl CoA Dehydrogenases↗