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  • pde inhibitors br Conclusions and future perspectives It


    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 (, 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.
    Introduction G protein-coupled receptors (GPCRs) comprise a diverse family of seven transmembrane domain-containing receptors represented by over 800 genes in humans. GPCRs respond to a range of stimuli, including peptides, hormones, growth factors, lipids, odorants, and light [1]. Upon ligand binding, GPCRs activate heterotrimeric G proteins, consisting of an α, β, and γ subunits, which subsequently activate downstream effectors and signalling cascades. Cardiovascular tissues (heart, pde inhibitors and smooth muscle) express more than 150 GPCRs [2], but in many cases their signalling and physiological roles remain incompletely understood. Two GPCR subtypes of interest in the myocardium are the endothelin receptor (ETR) and the α1-adrenergic receptor (α1-AR). Upon ligand binding, these receptors canonically activate the Gαq protein leading to activation of phospholipase C, hydrolysis of phosphatidylinositol 4,5-bisphosphate into diacylglycerol (DAG) and inositol 1, 4, 5-triphosphate (IP3), and a subsequent increase in intracellular Ca2+ levels and protein kinase C (PKC) activation. ETR and α1-AR, in response to endothelins or the endogenous catecholamines epinephrine and norepinephrine respectively, mediate signalling events important for cardiac function and pathology (reviewed in [3]). The ETR family contains two subtypes, ETA and ETB, that are expressed at similar levels in the heart [[4], [5], [6], [7]]. ETR subtypes are able to regulate multiple signalling pathways including phospholipase D, phospholipase A2, Na+/H+ exchangers, cAMP and cGMP production, mitogen activated protein kinase (MAPK) pathways, and tyrosine kinases [[8], [9], [10], [11], [12], [13], [14], [15]]. In the heart, ETR signalling has inotropic and chronotropic effects [16, 17] and mediates cardiac remodeling in hypertrophy, myocardial infarction, and congestive heart failure [[18], [19], [20]]. In these various cardiac pathologies, ETR signalling through endothelin-1 is increased and the associated cardiac hypertrophy can be blocked with an ETAR-specific antagonist [[21], [22], [23], [24]]. The α1-AR family consists of multiple subtypes, including the α1A-, α1B- and α1D-ARs [25, 26]. A role for α1-ARs has been demonstrated in the regulation of phospholipase D, phospholipase A2, MAPK pathways, Na+/H+ exchangers, tyrosine kinases, as well as cAMP and cGMP production [10, 14, 15, [27], [28], [29], [30], [31], [32]]. Cardiac α1-ARs have some inotropic and chronotropic effects and also regulate cardiac remodeling in hypertrophy and following myocardial infarctions (reviewed in [33, 34]). All three subtypes are expressed in cardiomyocytes but only α1A-AR and α1B-AR are detectable at the protein level [35]. Differences between the receptor subtypes in mediating cardiac pathologies have been identified through the use of transgenic mice. Cardiac specific overexpression of α1B-AR led to an exacerbated hypertrophic response to pressure overload and dilated cardiomyopathy, whereas overexpression of α1A-AR did not affect the response [[36], [37], [38], [39]].