Endothelin-1 (ET-1), the predominant isoform of the endothelin peptide family, has potent vasoconstrictor, mitogenic, pro-inflammatory and antinatriuretic properties which have been implicated in the pathophysiology of a number of cardiovascular diseases. ET-1 effects are mediated through activation of the G-protein-coupled ETA and ETB receptors, which are found in a variety of cells including endothelial, vascular smooth muscle and mesangial cells. Overexpression of ET-1 has been consistently described in salt-sensitive models of hypertension and in models of renal failure, and has been associated with disease progression. The development of a range of peptidic and nonpeptidic ET-1 receptor antagonists represents an exciting breakthrough in cardiovascular therapeutics. Endothelin antagonists improve endothelium-dependent relaxation and ameliorate vascular and cardiac hypertrophy as well as glomerulosclerosis; interestingly, these beneficial effects seem to occur independently of their capacity to lower blood pressure. The comparison between selective ETA and combined ETA/ETB antagonists in experimental models of cardiovascular diseases reveals no differences in terms of their effects on blood pressure, LV hemodynamics or remodeling. In the case of salt-sensitive hypertension, ETA receptor blockade leads to the prevention of vascular hypertrophy and renal function improvement, being likely that these effects are also mediated by ETB receptors based on the fact that the concomitant blockade of ETB receptors prevents the beneficial effects of ETA antagonists. As a whole, the available data indicate that the use of ET-1 receptor antagonists might be of therapeutic interest to prevent hypertension induced end-organ damage; however, the comparative efficacy of selective ETA vs. dual ETA/ETB blockade to prevent target organ injuries in humans still remains to be investigated.
Keywords: endothelin, endothelin a and endothelin b receptors, endothelin antagonists, hypertension, inflammation