**17.4 Dual antagonist of angiotensin II and endothelin A receptors**

Known is the role of Ang II and ET1 in the pathogenesis of essential hypertension. These substances produce vasoconstriction through the activation of its receptors in vascular smooth muscle: the AT1 and ETA, respectively. Ang II promotes the production of endothelin and endothelin in turn increases the synthesis of Ang II.

Moreover, evidence suggests the interrelation between the endocrine and paracrine systems of Ang II and endothelin. Ang II increases the expression of RNA messenger in endothelial cells. Ang II stimulates the release of ET1 by endothelial cells involving AT1 receptors, Ca2+ mobilization and activation of kinase C protein. ARBs produce a significant decrease in BP and reduce endothelial dysfunction and cardiovascular mortality in hypertensive, diabetic and HF patients. Thus, the activation of ETA and/or ETB receptors of ET1 causes contraction of vascular smooth muscle cells and increases BP and an antagonist of ETA/ETB receptors like bosetan decreases BP in patients with essential hypertension. Thus the combination in one same drug of properties AT1/ETA receptors antagonists may have a greater effect than either drug alone and with fewer side effects. Today ETA receptor blockers have been modified to acquire AT1 receptor antagonism.

There are several compounds (MS-248 360, BMS-248360, SB-290 670) that in laboratory animals decreased BP, but these investigations are still in very early stages. (Kowal et al., 2004) But this new class of antihypertensive drug which simultaneously antagonizes the AT1 and ETA receptors promise to be a novel approach in the treatment of hypertension and other cardiovascular diseases.
