Endothelin in cardiovascular control: The role of endothelin antagonists

Abstract

Endothelin (ET) is a potent vasoconstrictor associated with various cardiovascular diseases. ET mediates its effects through ET receptors on vascular smooth muscle cells as well as on the vascular endothelium. Furthermore, a neurotransmitter role for ET has been suggested on the basis of experimental and human in vivo studies. ET antagonists are potent tools for studying the effects of ET and its receptors. They have been widely used in vitro and in experimental models of cardiovascular disease, where ET levels are elevated and reactivity to ET is altered. Promising clinical trials in hypertension, coronary artery disease, and congestive heart failure are discussed in this review. Different forms of renal failure are associated with markedly increased ET levels, and ET antagonists experimentally improve renal function in these models. Extrapolating from experimental and first clinical experience, ET antagonists could be useful in the treatment of hypertension, coronary artery disease, congestive heart failure, and renal failure, especially in combination with other drugs, ie, angiotensin converting enzyme inhibitors. The inhibition of ET-induced stimulation of nociception allows for speculation that ET antagonists might even have analgesic properties.

Avosentan for Overt Diabetic Nephropathy

“…eGFR fell to a greater extent with avosentan 50 mg/d, and anemia, hypoglycemia, and hypotension were reported more frequently by the investigators in patients who received avosentan. Avosentan reduced albuminuria by 40 to 50% in patients who had an average baseline albuminuria close to 1.5 g/g creatinine; exhibited reasonable BP control 8,9 ; and received extensive treatment with angiotensin-converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers (ARBs), other antihypertensive drugs, diuretics, and statins. In another study on diabetic nephropathy, a 50% reduction in albuminuria was associated with a relative risk reduction for ESRD of approximately 50%.…”

“…[17][18][19] For avosentan, a predominant type A antagonist, these effects were seen mainly at dosages of Ն5 mg/d, but they were not found to be life threatening in shorter term studies of patients with less advanced renal disease. 8,9 It may be that at All parameters were measured in a central laboratory, eGFR was calculated with the six-item MDRD formula. For each ACR value, the geometric mean of three consecutive first morning urine values was entered into the database.…”

“…5,6 In shortterm (up to 12 weeks) proof-of-concept clinical studies, avosentan, a predominant ET A receptor antagonist, reduced proteinuria in people who had diabetes and were on maximal dosages of inhibitors of the renin-angiotensin system. [7][8][9] This antiproteinuric effect was achieved without significant changes in BP.…”

Endothelin‐A receptor antagonist inhibits angiotensin II and noradrenaline in man

“…Although three isoforms of ET have been described, in man mainly ET‐1 is present [1]. Different ET receptors have been cloned, ET A ‐, ET B ‐and ET C ‐receptors [2]. Under physiological conditions, the constrictor effects of ET‐1 are mediated via ET A ‐receptors, which are located on vascular smooth muscle cells [3].…”

Avosentan Reduces Albumin Excretion in Diabetics with Macroalbuminuria

“…9,10 The endothelin system regulates a number of renal functions and can induce proteinuria by various mechanisms. [11][12][13][14][15] Plasma and urinary endothelin-1 (ET-1) levels are elevated in patients with diabetes and correlate with reduced renal function, increased BP and albuminuria, 16 and severity and duration of diabetes. 17 Endothelin receptor antagonists (ERAs) have demonstrated renoprotective effects in experimental models of diabetic and nondiabetic nephropathy, 18 -20 independent of their effects on BP, as well as in a preliminary clinical trial.…”