The
endothelins are synthesized in vascular endothelial and smooth muscle cells, as well as in neural, renal, pulmonal, and inflammatory cells. These
peptides are converted by
endothelin-converting enzymes (ECE-1 and -2) from 'big
endothelins' originating from large
preproendothelin peptides cleaved by
endopeptidases.
Endothelin (ET)-1 has major influence on the function and structure of the vasculature as it favors vasoconstriction and cell proliferation through activation of specific ET(A) and ET(B) receptors on vascular smooth muscle cells. In contrast, ET(B )receptors on endothelial cells cause vasodilation via release of
nitric oxide (NO) and
prostacyclin. Additionally, ET(B) receptors in the lung are a major pathway for the clearance of ET-1 from plasma. Indeed, ET-1 contributes to the pathogenesis of important disorders as arterial
hypertension,
atherosclerosis, and
heart failure. In patients with atherosclerotic
vascular disease (as well as in many other disease states), ET-1 levels are elevated and correlate with the number of involved sites. In patients with acute
myocardial infarction, they correlate with 1-year prognosis. ET receptor antagonists have been widely studied in experimental models of
cardiovascular disease. In arterial
hypertension, they prevent vascular and myocardial
hypertrophy. Experimentally, ET receptor blockade also prevents endothelial dysfunction and structural vascular changes in
atherosclerosis due to
hypercholesterolemia. In experimental
myocardial ischemia, treatment with an ET receptor antagonist reduced
infarct size and prevented
left ventricular remodeling after
myocardial infarction. Most impressively, treatment with the selective ET(A) receptor antagonist
BQ123 significantly improved survival in an experimental model of
heart failure. In many clinical conditions, such as
congestive heart failure, both mixed ET(A/B )as well as selective ET(A) receptor antagonism ameliorates the clinical status of patients, i.e. symptoms and hemodynamics. A randomized clinical trial showed that a mixed ET(A/B) receptor antagonist effectively lowered arterial blood pressure in patients with arterial
hypertension. In patients with
primary pulmonary hypertension or
pulmonary hypertension related to scleroderma, treatment with a mixed ET(A/B) receptor antagonist resulted in an improvement in exercise capacity. ET receptor blockers thus hold the potential to improve the outcome in patients with various cardiovascular disorders. Randomized clinical trials are under way to evaluate the effects of ET receptor antagonism on morbidity and mortality.