The present study describes the pharmacological profile of ((E)-alpha-[[1-butyl-5-[2-[(2-carboxyphenyl)methoxy]-4-methoxy-phenyl ]-1H-pyrazol-4-yl]methlene]-6-methoxy-1,3-benzodioxole-5-propanoic acid) (SB 234551), a high-affinity, nonpeptide endothelin type A (ETA)-selective receptor antagonist. In human cloned ETA and endothelin type B (ETB) receptors, SB 234551 produced a concentration-depen...

INTRODUCTION The treatment of scleroderma-related digital ulcers is challenging. The oral endothelin receptor antagonist (ERA) bosentan has been approved but it may induce liver toxicity. The objective of this study was to test whether ERAs bosentan and sitaxentan could be locally delivered using iontophoresis. METHODS Cathodal and anodal iontophoresis of bosentan and sitaxentan were performe...

Novel cyclic pentapeptides, WS7338A, B, C and D [cyclo-(AAl -AA2-DTrp-D-Glu-Ala)] were isolated as Endothelin (ET) receptor antagonists from the culture broth of Sfreptomyces sp. No. 7338. Based on conformational analysis of these seeds, we defined the minimum structural requirements for binding affinity and prepared a series of acylated tripeptides with ETA receptor binding affinity. Through e...

A series of potent indole-containing endothelin antagonists were evaluated in rat pharmacokinetic studies as part of a rational drug design program. Early compounds in this series were found to show poor gastrointestinal absorption, limiting their utility as oral agents. Structural modifications and pharmacokinetic studies indicated that reducing the overall H-bonding potential, through a reduc...

Vascular remodeling and rearrangement of the extracellular matrix formation are among the major adaptive mechanisms in response to a chronic blood pressure increase. Vasoactive peptides, such as endothelin, participate in hypertension-associated vascular fibrosis by stimulating collagen I formation and increasing contractility of arterial wall. In the present study, we tested the hypothesis tha...

Hypertension during preeclampsia is associated with an increase in plasma levels of tumor necrosis factor (TNF)-alpha, a cytokine known to contribute to endothelial dysfunction. Recently, our laboratory reported that a 2-fold increase in plasma TNF-alpha produces hypertension in pregnant rats. Endothelin is also elevated in preeclampsia and endothelin synthesis is enhanced by TNF-alpha. The pur...

The cardiac abnormalities associated with hypertension include left ventricular hypertrophy and vascular changes. The latter may affect the cardiac microvasculature and predispose to myocardial ischemia. To test the hypothesis that endothelin-1 contributes to changes in the microcirculation of the heart, we studied cardiac microvessels of the deoxycorticosterone acetate-salt (DOCA-salt) model o...

Partial exchange transfusion with a cell-free hemoglobin (Hb) polymer during transient middle cerebral artery occlusion (MCAO) reduces infarct volume but fails to increase blood flow, as might be expected with the induced decrease in hematocrit. In ischemic brain, endothelin antagonists are known to produce vasodilation. In nonischemic brain, pial arterioles constrict after Hb exchange transfus...