Macitentan, also called Actelion-1 or -6-(2-(5-bromopyrimidin-2-yloxy)ethoxy)-pyrimidin-4-yl]-NЈ-propylaminosulfonamide], is a new dual ET A / ET B endothelin (ET) receptor antagonist designed for tissue targeting. Selection of macitentan was based on inhibitory potency on both ET receptors and optimization of physicochemical properties to achieve high affinity for lipophilic milieu. In vivo, macitentan is metabolized into a major and pharmacologically active metabolite, ACT-132577. Macitentan and its metabolite antagonized the specific binding of ET-1 on membranes of cells overexpressing ET A and ET B receptors and blunted ET-1-induced calcium mobilization in various natural cell lines, with inhibitory constants within the nanomolar range. In functional assays, macitentan and ACT-132577 inhibited ET-1-induced contractions in isolated endothelium-denuded rat aorta (ET A receptors) and sarafotoxin S6c-induced contractions in isolated rat trachea (ET B receptors). In rats with pulmonary hypertension, macitentan prevented both the increase of pulmonary pressure and the right ventricle hypertrophy, and it markedly improved survival. In diabetic rats, chronic administration of macitentan decreased blood pressure and proteinuria and prevented end-organ damage (renal vascular hypertrophy and structural injury). In conclusion, macitentan, by its tissuetargeting properties and dual antagonism of ET receptors, protects against end-organ damage in diabetes and improves survival in pulmonary hypertensive rats. This profile makes macitentan a new agent to treat cardiovascular disorders associated with chronic tissue ET system activation.

Background-Endothelin (ET)-1 is a potent vasoconstrictor that contributes to vascular remodeling in hypertension and other cardiovascular diseases. Endogenous ET-1 is produced predominantly by vascular endothelial cells. To directly test the role of endothelium-derived ET-1 in cardiovascular pathophysiology, we specifically targeted expression of the human preproET-1 gene to the endothelium by using the Tie-2 promoter in C57BL/6 mice. Methods and Results-Ten-week-old male C57BL/6 transgenic (TG) and nontransgenic (wild type; WT) littermates were studied. TG mice exhibited 3-fold higher vascular tissue ET-1 mRNA and 7-fold higher ET-1 plasma levels than did WT mice but no significant elevation in blood pressure. Despite the absence of significant blood pressure elevation, TG mice exhibited marked hypertrophic remodeling and oxidant excess-dependent endothelial dysfunction of resistance vessels, altered ET-1 and ET-3 vascular responses, and significant increases in ET B expression compared with WT littermates. Moreover, TG mice generated significantly higher oxidative stress, possibly through increased activity and expression of vascular NAD(P)H oxidase than did their WT counterparts. Conclusions-In this new murine model of endothelium-restricted human preproET-1 overexpression, ET-1 caused structural remodeling and endothelial dysfunction of resistance vessels, consistent with a direct nonhemodynamic effect of ET-1 on the vasculature, at least in part through the activation of vascular NAD(P)H oxidase.

The ovulatory process is activated by a surge of LH, a pituitary gonadotropin, which initiates a cohort of dramatic changes in biochemical, physical, and gene expression in the ovary, leading to follicle rupture and oocyte release. Here we report the identification of endothelin-2 (EDN2) as a last moment-trigger of follicle rupture. In the ovary, EDN2 is exclusively and transiently expressed in the granulosa cells immediately before ovulation. Administration of EDN2 to the ovarian tissue induced rapid contraction, whereas addition of tezosentan, an endothelin receptor antagonist, diminishes the EDN2 effect. In vivo, treatment of tezosentan before ovulation substantially decreases gonadotropin-induced superovulation. As a target tissue of EDN2 action, we identified a layer of smooth muscle cells in the follicular wall of each follicle. Taken together, our data indicate that EDN2 induces follicular rupture by constricting periovulatory follicles.

Objective-Peroxisome proliferator-activated receptors (PPARs) may modulate in vitro the vascular production of vasoactive peptides such as endothelin-1 (ET-1). Thus, we investigated in vivo the interaction between PPARs and ET-1 in deoxycorticosterone acetate (DOCA)-salt rats that overexpress vascular ET-1. Methods and Results-Unilaterally nephrectomized 16-week-old Sprague-Dawley rats (Uni-Nx) were divided into 4 groups (nϭ6 each): control group, DOCA-salt group, DOCA-saltϩPPAR-␥ activator (rosiglitazone, 5 mg · kg). Systolic blood pressure was significantly increased in the DOCA-salt group (240Ϯ11 vs 121Ϯ2 mm Hg in Uni-Nx, PϽ0.01). Progression of hypertension was partially prevented by coadministration of rosiglitazone (172Ϯ3 mm Hg vs DOCA-salt, PϽ0.05) but not by fenofibrate. Both PPAR activators abrogated the increase in prepro-ET-1 mRNA content in the mesenteric vasculature of DOCA-salt rats. The media-to-lumen ratio was increased in DOCA-salt rats (10.3Ϯ0.9% vs 4.9Ϯ0.5% in Uni-Nx rats, PϽ0.01). Rosiglitazone and fenofibrate prevented the hypertrophic remodeling observed in DOCA-salt rats without affecting vascular stiffness. Rosiglitazone but not fenofibrate prevented endothelial dysfunction in pressurized mesenteric arteries. Finally, both rosiglitazone and fenofibrate prevented the vascular increase in superoxide anion production induced in DOCA-salt animals. Conclusions-PPAR-␣ and -␥ activators were able to modulate endogenous production of ET-1 and had beneficial vascular effects in endothelin-dependent hypertension. Key Words: PPAR activators Ⅲ rosiglitazone Ⅲ fenofibrate Ⅲ resistance arteries Ⅲ DOCA-salt P eroxisome proliferator-activated receptors (PPARs) are a family of ligand-activated transcription factors that have recently been found to be involved in the homeostasis of vascular biology. 1 Indeed, PPAR-␣ and -␥ isoforms have been characterized in multiple vascular cell types in rats and humans. [2][3][4][5][6] Moreover, PPAR activators prevent in vitro vascular smooth muscle cell growth 4 and inflammatory response 5 and also induce apoptosis, 6 suggesting at least a potential role in vascular remodeling.A recent study from our laboratory demonstrated that both PPAR-␣ and -␥ activators prevent vascular remodeling in angiotensin II-infused rats. 7 As angiotensin II, endothelin-1 (ET-1) is a potent vasoconstrictor. It is produced within the vascular wall and plays a critical role in vascular hypertrophy in many models of hypertension, such as deoxycorticosterone acetate (DOCA)-salt rats or stroke-prone spontaneously hypertensive rats. 8 Indeed, in those models of hypertension in which ET-1 plays a vasoconstrictor role, ET-1 was overexpressed in the vessel wall, and systolic blood pressure (SBP) was lowered by endothelin receptor antagonists. 8 Moreover, in these experimental models, ET-1 receptor antagonists also regressed vascular growth and inflammation and improved endothelial dysfunction. 8,9 Interestingly, PPAR-␥ activators are able to suppress ET-1 secretion from endothelial and vascular smo...

No abstract

Abstract-Peroxisome proliferator-activated receptor (PPAR) activation may prevent cardiac hypertrophy and inhibit production of endothelin-1 (ET-1), a hypertrophic agent. The aim of this in vivo study was to investigate the effects of PPAR activators on cardiac remodeling in DOCA-salt rats, a model overexpressing ET-1. Unilaterally nephrectomized 16-week-old Sprague-Dawley rats (Uni-Nx) were randomly divided into 4 groups: control rats, DOCA-salt, DOCA-saltϩrosiglitazone (PPAR-␥ activator, 5 mg/kg per day), and DOCA-saltϩfenofibrate (PPAR-␣ activator, 100 mg/kg per day). After 3 weeks of treatment, mean arterial blood pressure was significantly increased in DOCA-salt by 36 mm Hg. Mean arterial blood pressure was normalized by coadministration of rosiglitazone but not by fenofibrate. Both PPAR activators prevented cardiac fibrosis and abrogated the increase in prepro-ET-1 mRNA content in the left ventricle of DOCA-salt rats. Coadministration of rosiglitazone or fenofibrate failed to prevent thickening of left ventricle (LV) walls as measured by echocardiography and the increase in atrial natriuretic peptide mRNA levels. However, rosiglitazone and fenofibrate prevented the decrease in LV internal diameter and thus concentric remodeling of the LV found in DOCA-salt rats. Taken together, these data indicate a modulatory role of PPAR activators on cardiac remodeling in mineralocorticoid-induced hypertension, in part associated with decreased ET-1 production. Key Words: endothelin Ⅲ remodeling Ⅲ fibrosis Ⅲ hypertension, mineralocorticoid Ⅲ collagen Ⅲ hypertrophy C ardiac remodeling can occur as an adaptive process in response to increased peripheral resistance and elevated blood pressure. This process, associated with increased cardiomyocyte size and collagen deposition, is a deleterious outcome in hypertension, since it can lead to heart failure. 1 The DOCA-salt rat is a model of severe hypertension and is characterized by increased tissue endothelin-1 (ET-1) content and cardiac hypertrophy and fibrosis. 2,3 ET-1 has been described to induce cardiomyocyte growth in vitro 4,5 and to promote collagen synthesis by cardiac fibroblasts. 6 We recently showed that increase of extracellular components (eg, procollagen I and III, fibronectin) in myocardium of DOCAsalt rats can be prevented by ET-type A receptor antagonists. 3,7 Moreover, some in vivo studies suggest a potential role for ET-1 in the development of left ventricular (LV) hypertrophy. 8 Peroxisome proliferator-activated receptors PPAR are transcription factors present in numerous tissues (the ␥-isoform highly abundant in adipose tissue and the ␣-isoform in tissues with high rates of mitochondrial fatty acid ␤-oxidation). Neonatal and adult rat cardiomyocytes also express PPAR-␣ and to a much lower extent PPAR-␥ isoform. 9 Recent data indicate that PPARs play a critical role in the pathophysiology of cardiac hypertrophy. For instance, heterozygous PPAR-␥ ϩ/Ϫ mice develop more accentuated LV hypertrophy than wild-type counterparts after aortic banding. 10 Moreover,...

There is now increasing evidence that endothelial dysfunction is an early event in the pathophysiology of cardiovascular diseases and can be corrected with certain therapies such as angiotensin converting enzyme inhibitors angiotensin type I receptor antagonists and stains independently of blood pressure lowering effects. Restoring endothelial function appears to be a crucial target since endothelial dysfunction predicts cardiovascular events in various situations such as coronary artery disease peripheral artery disease, or hypertension and in patients undergoing vascular surgery. Preclinical and clinical data strongly support that endothelin receptor antagonists belong to this restricted class of pharmacological agents able to act on the endothelium, and offer a potential therapeutic approach for numerous diseases associated with endothelial dysfunction. The purpose of this review will be therefore, 1) to propose mechanisms by which ET-1 can cause endothelial dysfunction; 2) to provide an overview of pathological situations associated with endothelial dysfunction related to ET-1; and 3) to assemble evidence on efficacy of endothelin receptor antagonists for improvement of endothelial function.

Starting from the structure of bosentan (1), we embarked on a medicinal chemistry program aiming at the identification of novel potent dual endothelin receptor antagonists with high oral efficacy. This led to the discovery of a novel series of alkyl sulfamide substituted pyrimidines. Among these, compound 17 (macitentan, ACT-064992) emerged as particularly interesting as it is a potent inhibitor of ET(A) with significant affinity for the ET(B) receptor and shows excellent pharmacokinetic properties and high in vivo efficacy in hypertensive Dahl salt-sensitive rats. Compound 17 successfully completed a long-term phase III clinical trial for pulmonary arterial hypertension.