Effect of L-DOPA/Benserazide on Propagation of Pathological α-Synuclein.

Parkinson's disease (PD) and related disorders are characterized by filamentous or fibrous structures consisting of abnormal α-synuclein in the brains of patients, and the distributions and spread of these pathologies are closely correlated with disease progression. L-DOPA (a dopamine precursor) is the most effective therapy for PD, but it remains unclear whether the drug has any effect on the formation and propagation of pathogenic abnormal α-synuclein . Here, we tested whether or not L-DOPA influences the prion-like spread of α-synuclein pathologies in a wild-type (WT) mouse model of α-synuclein propagation.

Distinct properties of telmisartan on agonistic activities for peroxisome proliferator-activated receptor γ among clinically used angiotensin II receptor blockers: drug-target interaction analyses.

A proportion of angiotensin II type 1 receptor blockers (ARBs) improves glucose dyshomeostasis and insulin resistance in a clinical setting. Of these ARBs, telmisartan has the unique property of being a partial agonist for peroxisome proliferator-activated receptor γ (PPARγ). However, the detailed mechanism of how telmisartan acts on PPARγ and exerts its insulin-sensitizing effect is poorly understood.

Antifibrotic effects of pirfenidone in rat proximal tubular epithelial cells.

Objective: Renal fibrosis is a common cause of renal dysfunction with chronic kidney disease. We previously investigated the renoprotective effects of the antifibrotic agent pirfenidone in a rat model of subtotal nephrectomy. Here, we further evaluated the antifibrotic effects of pirfenidone in rat proximal tubular epithelial cells.

In vitro and in vivo effects of endothelin-1 and YM598, a selective endothelin ET A receptor antagonist, on the lower urinary tract.

We investigated the contractile response of the lower urinary tract to endothelin-1 in vitro (rabbits) and in vivo (dogs). We also assessed the effects of a selective endothelin ET A receptor antagonist, (E)-N-[6-methoxy-5-(2-methoxyphenoxy)[2, 2'-bipyrimidin]-4-yl]-2-phenylethenesulfonamide monopotassium salt (YM598), on endothelin-1-induced contractile responses. In the in vitro study, endothelin-1 induced contractile responses in isolated rabbit bladder base, urethra, and prostate tissues.

A novel and selective endothelin ET(A) receptor antagonist YM598 prevents the development of chronic hypoxia-induced pulmonary hypertension in rats.

The preventive effects of the novel and selective endothelin ET(A) receptor antagonist YM598 on the development of pulmonary hypertension (PH) were investigated in chronic hypoxia-induced PH rats. Oral administration of YM598 at a dose of 1 mg/kg was started on the first day of chronic hypoxia exposure for 2 and 3 weeks to investigate the effects of this compound on hemodynamic and arterial blood gas variables, respectively. Cardiopulmonary organ weights were measured at the end of the 2-week administration period.

YM598, an orally active ET(A) receptor antagonist, ameliorates the progression of cardiopulmonary changes and both-side heart failure in rats with cor pulmonale and myocardial infarction.

The effects of the novel, selective endothelin-A (ETA) receptor antagonist YM598 on both-side heart failure were investigated. Right-side heart failure secondary to pulmonary hypertension was produced by a single subcutaneous injection of 60 mg/kg monocrotaline, and post-ischemic congestive left-side heart failure (CHF) produced by surgical left coronary artery ligation. In right-side heart failure rats, oral YM598 (0.

The orally active nonpeptide selective endothelin ETA receptor antagonist YM598 prevents and reverses the development of pulmonary hypertension in monocrotaline-treated rats.

We investigated the preventive and therapeutic effects of the selective endothelin ETA receptor antagonist potassium(E)-N-[6-methoxy-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)pyrimidin-4-yl]-2-phenylenthenesulfonamidate (YM598) on the development of pulmonary hypertension in monocrotaline-induced pulmonary hypertensive and hypoxemic rats. In the prevention study, oral administration of YM598 (0.1 and 1 mg/kg) or bosentan (30 mg/kg) for 4 weeks was started on the day following monocrotaline (60 mg/kg) injection.

Pharmacological characterization of YM598, an orally active and highly potent selective endothelin ET(A) receptor antagonist.

We describe here the pharmacology of (E)-N-[6-methoxy-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]-2-phenylethenesulfonamide monopotassium salt (YM598), a novel selective endothelin ET(A) receptor antagonist synthesized through the modification of the ET(A)/ET(B) non-selective antagonist, bosentan. YM598 inhibited [125I]endothelin-1 binding to cloned human endothelin ET(A) and ET(B) receptor, with K(i) of 0.697 and 569 nM, and inhibited endothelin-1-induced increases in intracellular Ca(2+) concentration in human and rat endothelin ET(A) receptor.

Progression of renal failure with anaemia and multiple effects of angiotensin-converting enzyme inhibitor in rats with renal mass reduction.

Several factors such as proteinuria and renal fibrosis may be important in the progression of many forms of chronic renal diseases. The purposes of the current study were to investigate the progressive renal failure of the rats with surgical renal mass reduction (RMR) and the effect of the angiotensin-converting enzyme (ACE) inhibitor, lisinopril, and to document correlation of several factors associated with progressive renal failure. Rats were subtotal (5/6) nephrectomized by resection of the renal poles and sham-operated.