Endothelin Receptor Antagonists: Another Potential Alternative for Cardiovascular Diseases

Abstract

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.

L-Norvaline and Alpha-tocopherol Treatment Protect Against Diabetes-Induced Oxidative Stress in Testes of Male Rats

“…As reported earlier, intraperitoneal administration of single dose of streptozotocin significantly enhanced the serum glucose level in fasted male rats [12,19,20]. High diabetic condition had empowered the level of not only glucose but also the production of free radicals that induced testicular damage and vascular impairment [21,22].…”

O-GlcNAcylation: a novel pathway contributing to the effects of endothelin in the vasculature

“…In these animals, ET-1 not only induces vasoconstriction, but it also activates transcriptional factors responsible for the coordinated increase in many cytokines and enzymes, thus enhancing inflammation, oxidative stress, and tissue damage (37,65,79,81,122,139,140,154,155), which are all important in hypertension-associated vascular dysfunction.…”

“…They will be referred to excellent reviews on O-GlcNAcylation (54,55,63,84,90,110,167,169,177). Detailed information on ET peptides, ET receptors, ET signaling, models for the study of ET in disease conditions, and development and therapeutic use of ET A /ET B receptor antagonists can be found on excellent and more comprehensive reviews on these specific topics (6,8,11,12,30,31,34,37,67,79,81,115,122,131,141,142,154,160,166).…”

DOCA-salt treatment enhances responses to endothelin-1 in murine corpus cavernosumThis article is one of a selection of papers published in the special issue (part 1 of 2) on Forefronts in Endothelin.

“…ET-1 is important in salt-sensitive forms of experimental hypertension, such as mineralocorticoid hypertension (Schiffrin 2005;Tostes and Muscara 2005). Salt-sensitive hypertensive animals display increased tissue ET-1 expression and abnormal vascular responses to ET-1; however, treatment of these animals with both selective ET A or dual ET A / ET B receptor antagonists results in regression of vascular damage, hypertrophy, and endothelial dysfunction (Schiffrin 2005).…”