The hormone edothelin-1 (ET-1) acts via two receptors, ETA and ETB, to produce vasoconstriction, hypertrophy, and proliferation. The differential effect of ET-1 is dependent on its distribution into either tissue or plasma. The production of ET-1 and expression of ETA/ETB are significantly increased in many pathological states, such as hypertension, diabetes, and heart failure. In this issue, Iglarz et al. describe the activity of macitentan, a dual ETA/ETB antagonist. The agent was produced from a screen that selected for molecules with high partition coefficients to better target tissue instead of plasma. When tested against primary endothelial and smooth muscle tissues, the agent blunts contractility. In a rat pulmonary hypertension model, the agent attenuated hypertension and left ventricular hypertrophy. In a diabetic rat model, the agent blocked hypertension, proteinuria, and renal damage. These results suggest that macitentan could have use for the treatment of diabetes, hypertension, and cardiovascular disease.
See article at J Pharmacol Exp Ther 2008, 327:736–745.
- The American Society for Pharmacology and Experimental Therapeutics