br Conflict of interest statement br Introduction

Conflict of interest statement
Introduction Endothelins (ETs) are a family of multifunctional, naturally occurring peptides with long-lasting vasoconstrictor and pressor effects (Zhou et al., 2004). They are synthesized as a large protein, the pre-proET-1 or Big ET-1, which is subsequently cleaved to pro-ET-1 and then ET-1 by ET-converting enzymes (Thorin and Webb, 2010). ETs comprise three isoforms: ET-1, ET-2 and ET-3. Among these, ET-1 is the most active and dominant form and seems to play a vital role in cardiovascular regulation. ET-1 is synthesized mainly in endothelial SM-224 and is released and interacts with the vascular smooth muscle. ET-1 is also synthesized in vascular smooth muscle cells as well as in extravascular tissues such as the spleen, pancreas, lung, nervous system, and kidneys (Bourque et al., 2011). ET-1 is released continuously from endothelial cells by constitutive and regulated machinaries, producing intense constriction of the underlying smooth muscle and contributing to the maintenance of endogenous vascular tone. ET-1 exerts its effects via activating two G-protein-coupled ET receptors, designated as ETA and ETB (Kohan et al., 2011). This review sums up recent evidence regarding the potential use of ET receptor blockers in the management of cardiovascular disease, with more emphasis on selective ETA receptor antagonism.
Cardiovascular and renal effects of ET-1 ET-1 produces positive chronotropic and inotropic effects (Kedzierski and Yanagisawa, 2001). In the vascular system, ETA receptors are predominantly found in vascular smooth muscle cells and its activation leads to vasoconstriction. In contrast, ETB receptors are highly expressed in the endothelium as well as in vascular smooth muscle cells (Kohan et al., 2011). Whereas ETB receptors present in smooth muscle mediate vasoconstriction, those in endothelial cells cause vasodilation via facilitating the generation of NO and prostacyclin (Zhou et al., 2004, Bourque et al., 2011). However, the precise vascular effects of ET-1 depend on the animal species and vascular bed. In some blood vessels such as the rabbit saphenous vein, rabbit jugular vein, rat renal vascular bed, and porcine pulmonary vein, ETB receptors mediate vasoconstriction. In other vessels, ET-1 is thought to mediate vasoconstriction via the activation of both receptors (Davenport, 2002). In the kidney, ETs play a major role in the renal control of water and sodium excretion and the modulation of the total and regional blood flow and glomerular filtration rate (Chade et al., 2014). Although ET-1 causes equal constriction of afferent and efferent arterioles in vitro, the efferent arterioles are the predominant site of action of endogenous ET-1 (Agapitov and Haynes, 2002).
Conclusions and future perspectives It is now evident that selective ETA or nonselective endothelin receptor antagonism provides therapeutic potentials against a variety of cardiovascular diseases such as hypertension, PAH, and diabetic microvascular dysfunction (Fig. 1). However, PAH is currently the only licensed indication for ET receptor antagonist therapy. Evidence from experimental studies has revealed a beneficial effect for ambrisentan in the prevention of coronary restenosis after dilatation and stent implantation (Vatter and Seifert, 2006). In addition, ETA receptor antagonists seem to offer broader cardiovascular benefits. For instance, animal (Juan et al., 2004) and human (Raichlin et al., 2008) studies highlighted a beneficial role for ETA receptor antagonists in the treatment of hypertension associated with metabolic syndrome. Zibotentan, a selective ETA receptor antagonist, is now under clinical investigation for its ability of to improve blood flow in patients with peripheral artery disease, a major complication of atherosclerosis (ClinicalTrials.gov.2, 2014). Despite the encouraging clinical data regarding the efficacy of ETA receptor antagonists in a variety of pathophysiological settings, the safety profiles for these drugs have been disappointing due to high incidence of hepatotoxicity, headache and edema. The development of new ETA receptor antagonists with no or minimal side effects continues to be a therapeutic necessity. This can possibly be achieved via the investigation of the mechanism(s) by which ETA antagonists produce their adverse effects, dose adjustments to widen the therapeutic and safety windows, and customization of combination therapy.