Endothelins are powerful
vasoconstrictor agents produced by endothelial cells and identified by Yanagisawa et al. in 1988. Two types of receptors for
endothelins have been identified: ET(A) receptors are located on smooth muscle cells of the vascular wall and are responsible for
endothelin-induced vasoconstriction while ET(B) receptors are located on endothelial cells and induce these cells to release NO and
prostacyclin. Moreover, these
peptides not only cause a potent and prolonged vasoconstriction but are also known to enhance cell proliferation and to stimulate extracellular matrix accumulation. High levels of plasma or tissue
endothelins have been found in patients with
heart failure, diabetes,
stroke,
primary pulmonary hypertension,
liver cirrhosis and other diseases. Given these effects of
endothelins, blocking their receptors might be a new way to reduce blood pressure and to treat other illnesses. Accordingly, many
endothelin antagonists have been developed and evaluated in animals and humans.
Enrasentan is a mixed ET(A) and ET(B) receptor antagonist with a higher affinity for ET(A) receptors, although it cannot be considered a selective antagonist. In an animal model of
hypertension and
cardiac hypertrophy the
drug has reduced blood pressure, prevented
cardiac hypertrophy and preserved myocardial function. In rats with
hyperinsulinemia and
hypertension enrasentan normalized blood pressure and prevented cardiac and renal damage. In rats with
stroke the
drug reduced the ischemic area in the brain.
Enrasentan has been added to conventional treatment in patients with
heart failure (NYHA Class 2-3) and no addictive effect of the
drug has been observed. This is in contrast with results obtained in animal models and still has not been explained. In conclusion, many possible clinical applications can be suggested for this
drug, but further studies are necessary to better evaluate its therapeutic efficacy.