Clazosentan (AXV-034343), a selective endothelin A receptor antagonist, in the prevention of cerebral vasospasm following severe aneurysmal subarachnoid hemorrhage: results of a randomized, double-blind, placebo-controlled, multicenter phase IIa study.

Objective: The goal of this study was to investigate the safety and tolerability of the novel endothelin A (ETA) receptor antagonist clazosentan in patients with subarachnoid hemorrhage (SAH) and its potential to reduce the incidence and severity of cerebral vasospasm following surgical clipping of the aneurysm.

Methods: This Phase IIa multicenter study had two parts: a double-blind, randomized Part A (some patients given clazosentan [0.2 mg/kg/hr] and others given placebo), in which statistical inference was performed, and an open-label Part B (patients with established vasospasm given clazosentan [0.

The pharmacology of bosentan.

This article describes the pharmacological properties and the overall preclinical and clinical profiling of bosentan (Ro 47-0203), a non-peptide endothelin receptor antagonist with oral activity. Bosentan is a combined and competitive antagonist of both ETA and ETB receptors that is selective for the endothelin system. In vitro and in vivo, bosentan potently antagonises the vascular response elicited by the endothelins.

Piperidine renin inhibitors: from leads to drug candidates.

Non-peptidomimetic renin inhibitors of the piperidine type represent a novel structural class of compounds potentially free of the drawbacks seen with peptidomimetic compounds so far. Synthetic optimization in two structural series focusing on improvement of potency, as well as on physicochemical properties and metabolic stability, has led to the identification of two candidate compounds 14 and 23. Both display potent and long-lasting blood pressure lowering effects in conscious sodium-depleted marmoset monkeys and double transgenic rats harboring both the human angiotensinogen and the human renin genes.

Mineralocorticoid receptor affects AP-1 and nuclear factor-kappab activation in angiotensin II-induced cardiac injury.

Aldosterone is implicated in cardiac hypertrophy and fibrosis. We tested the role of the mineralocorticoid receptor in a model of angiotensin II-induced cardiac injury. We administered spironolactone (SPIRO; 20 mg.

Effect of bosentan on NF-kappaB, inflammation, and tissue factor in angiotensin II-induced end-organ damage.

Reports on the effectiveness of endothelin receptor blockers in angiotensin (Ang) II-induced end-organ damage are conflicting, and the mechanisms involved are uncertain. We tested the hypothesis that endothelin (ET)(A/B) receptor blockade with bosentan (100 mg/kg by gavage after age 4 weeks) ameliorates cardiac and renal damage by decreasing inflammation in rats harboring both human renin and angiotensinogen genes (dTGR). Furthermore, we elucidated the effect of bosentan on tissue factor (TF), which is a key regulator of the extrinsic coagulation cascade.

Angiotensin II (AT(1)) receptor blockade reduces vascular tissue factor in angiotensin II-induced cardiac vasculopathy.

Tissue factor (TF), a main initiator of clotting, is up-regulated in vasculopathy. We tested the hypothesis that chronic in vivo angiotensin (ANG) II receptor AT(1) receptor blockade inhibits TF expression in a model of ANG II-induced cardiac vasculopathy. Furthermore, we explored the mechanisms by examining transcription factor activation and analyzing the TF promoter.

Cloning, expression and functional characterization of rat napsin.

A full-length cDNA clone coding for rat napsin was identified by homology search of the ZooSeq rat EST database (Incyte). Northern blot analysis revealed high expression of napsin mRNA transcripts in kidney, lung and spleen. Western blot analysis showed that rat napsin is expressed in kidney as a 50-kDa, highly glycosylated, monomeric protein.

Blood pressure-independent effects in rats with human renin and angiotensinogen genes.

The blood pressure-independent effects of angiotensin II (Ang II) were examined in double transgenic rats (dTGR) harboring human renin and human angiotensinogen genes, in which the end-organ damage is due to the human components of the renin angiotensin system. Triple-drug therapy (hydralazine 80 mg/L, reserpine 5 mg/L, and hydrochlorothiazide 25 mg/L in drinking water) was started immediately after weaning. Triple-drug therapy normalized blood pressure and coronary resistance, only partially prevented cardiac hypertrophy, and had no effect on ratio of renal weight to body weight.

Cyclosporin A protects against angiotensin II-induced end-organ damage in double transgenic rats harboring human renin and angiotensinogen genes.

Leukocyte infiltration and adhesion molecule activation play a central role in the pathogenesis of angiotensin II (Ang II)-induced end-organ damage in double transgenic rats (dTGR) harboring human renin and angiotensinogen genes. We tested the hypothesis that the immunosuppressive agent cyclosporine (CsA) protects against the Ang II-induced myocardial and renal damage in dTGR. Furthermore, we investigated the influence of CsA on interleukin-6 (IL-6) and inducible nitric oxide synthase (iNOS) expression and the DNA binding activity of transcription factor necrosis factor-kappaB (NF-kappaB).

NF-kappaB inhibition ameliorates angiotensin II-induced inflammatory damage in rats.

We recently reported that the activation of nuclear factor-kappaB (NF-kappaB) promotes inflammation in rats harboring both human renin and angiotensinogen genes (double-transgenic rats [dTGR]). We tested the hypothesis that the antioxidant pyrrolidine dithiocarbamate (PDTC) inhibits NF-kappaB and ameliorates renal and cardiac end-organ damage. dTGR feature hypertension, severe renal and cardiac damage, and a 40% mortality rate at 7 weeks.

Cloning and characterization of marmoset renin: comparison with human renin.

The poor interspecies conservation of the renin-angiotensin system prevents the use of nonprimate in vivo models to test renin inhibitors. Thus the small New-World monkey marmoset is used in many instances as a model. However, large differences between the potencies of renin inhibitors as measured in human and marmoset plasma were observed.

Pharmacology of tezosentan, new endothelin receptor antagonist designed for parenteral use.

Tezosentan (Ro 61-0612) [5-isopropyl-pyridine-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-+ ++pyri din-4-yl)-pyrimidin-4-ylamide] is a new endothelin (ET) receptor antagonist specifically designed for parenteral use. Tezosentan competitively antagonizes the specific binding of (125)I-labeled ET-1 and of the selective ET(B) receptor ligands (125)I-labeled ET-3 and (125)I-labeled sarafotoxin S6c on cells and tissues carrying ET(A) and ET(B) receptors, with inhibitory constants in the nanomolar range, and has high water solubility. Tezosentan exhibits high functional inhibitory potency for inhibiting contraction induced by ET-1 on isolated rat aorta (ET(A) receptors; pA(2) = 9.

Involvement of endothelin/nitric oxide balance in hepatic ischemia/reperfusion injury.

Introduction: Endothelin (ET) and nitric oxide (NO) act as opponents in the regulation of the hepatic microcirculation. During ischemia/reperfusion (I/R) ET levels are increased, whereas no rise in NO levels is observed. This imbalance may be responsible for microcirculatory disturbances.

Piperidine-renin inhibitors compounds with improved physicochemical properties.

Piperidine renin inhibitors with heterocyclic core modifications or hydrophilic attachments show improved physical properties (lower lipophilicity, improved solubility). Tetrahydroquinoline derivative rac-30 with a molecular weight of 517 and a log D(pH 7.4) of 1.

Substituted piperidines--highly potent renin inhibitors due to induced fit adaptation of the active site.

The identification, synthesis and activity of a novel class of piperidine renin inhibitors is presented. The most active compounds show activities in the picomolar range and are among the most potent renin inhibitors ever identified.

Endothelin antagonism with bosentan: a review of potential applications.

Endothelin receptor antagonists have been proposed for the treatment of a variety of disorders in which the endothelins may act as pathogenic mediators, such as congestive heart failure, systemic and pulmonary hypertension, and cerebral vasospasm. Bosentan (Ro 47-0203) is a nonpeptide competitive antagonist, which can be a good tool for studying the endothelin system because it may be administered either acutely or chronically. It is specific for the endothelin system and blocks the actions of endothelin at both mammalian receptors (A and B).

Functional effects of endothelin and regulation of endothelin receptors in isolated human nonfailing and failing myocardium.

Background: An activated endothelin (ET) system may be of pathophysiological relevance in human heart failure. We characterized the functional effects of ET-1, ET receptors, and ET-1 peptide concentration in left ventricular myocardium from 10 nonfailing hearts (NF) and 27 hearts in end-stage failure due to idiopathic dilative cardiomyopathy (DCM).

Methods And Results: Inotropic effects were characterized in isolated muscle strips (1 Hz; 37 degrees C).

Renin inhibition by substituted piperidines: a novel paradigm for the inhibition of monomeric aspartic proteinases?

Background: The aspartic proteinase renin catalyses the first and rate-limiting step in the conversion of angiotensinogen to the hormone angiotensin II, and therefore plays an important physiological role in the regulation of blood pressure. Numerous potent peptidomimetic inhibitors of this important drug target have been developed, but none of these compounds have progressed past clinical phase II trials. Limited oral bioavailability or excessive production costs have prevented these inhibitors from becoming new antihypertensive drugs.

Monocyte infiltration and adhesion molecules in a rat model of high human renin hypertension.

Hypertension and kidney damage in the double transgenic rat (dTGR) harboring both human renin and human angiotensinogen genes are dependent on the human components of the renin angiotensin system. We tested the hypothesis that monocyte infiltration and increased adhesion molecule expression are involved in the pathogenesis of kidney damage in dTGR. We also evaluated the effects of long-term angiotensin-converting enzyme (ACE) inhibition, AT1 blockade, and human renin inhibition on monocyte recruitment and inflammatory response in dTGR.

Effects of human prorenin in rats transgenic for human angiotensinogen.

The physiological role of prorenin is unknown; however, the possibility that prorenin inhibits renin locally has been suggested. We tested the hypothesis that prorenin may be an endogenous competitor for renin uptake in the tissue. We also investigated whether prorenin can be activated to active renin and affect mean arterial pressure (MAP).

Hypertension-induced end-organ damage : A new transgenic approach to an old problem.

Angiotensin (Ang) II-induced organ damage has fascinated students of hypertension since the work of Wilson and Byrom. We are investigating a double transgenic rat (dTGR) model, in which rats transgenic for the human angiotensinogen and renin genes are crossed. These rats develop moderately severe hypertension but die of end-organ cardiac and renal damage by week 7.

A new family of orphan G protein-coupled receptors predominantly expressed in the brain.

The cloning of a cDNA encoding a G protein-coupled receptor homologous to the endothelin type B receptor, but unable to bind endothelin, was recently reported and termed ET(B)R-LP. We report here the isolation of a human cDNA encoding a receptor that is highly related to ET(B)R-LP and which was therefore termed ET(B)R-LP-2. Comparison of the two amino acid sequences revealed 68% overall homology and 48% identity.

Ro 61-1790, a new hydrosoluble endothelin antagonist: general pharmacology and effects on experimental cerebral vasospasm.

Endothelin (ET) receptor antagonists are of great potential clinical interest for the treatment pathological conditions associated with vasospasm, such as subarachnoid hemorrhage (SAH). We developed for parenteral use a compound of a class of trifunctionalized heteroarylsulfonamide pyrimidines specially designed for high water solubility. Ro 61-1790 [5-methyl-pyridine-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-+ ++pyri din-4-yl)-pyrimidin-4-ylamide] is a competitive ET antagonist with an affinity to ETA receptor in the subnanomolar range.

A new functional isoform of the human CRF2 receptor for corticotropin-releasing factor.

We have identified the human counterpart of the corticotropin-releasing factor receptor subtype 2beta. Its functional response to human urocortin was demonstrated after stable expression in HEK-293 cells. The receptor was also shown to bind sauvagine, corticotropin-releasing factor and urocortin.