Protective effects of MCR-1329,a dual α1 and angII receptor antagonist,in mineralocorticoid-induced hypertension

Background with the prototypical structures of losartan and prazosin as the axis of our research,mcr-1329 emerged as a potential designed multiple ligand from a series of compounds designed to possess dual antagonistic activity on the α1 and at1 receptor. after confirming the activity of mcr-1329 in in vitro and acute in vivo models,the present study was undertaken to determine the efficacy of mcr-1329 in a mammalian test system. methods a rat model of deoxycorticosterone acetate (doca)-salt induced renal hypertension following unilateral nephrectomy was utilized to determine the effect of mcr-1329. for mechanistic evaluations,mcr-1329 was evaluated on rat aortic strips in vitro and on rat aortic smooth muscle cells to determine the role of mcr-1329 on phosphoinositide 3 kinase (pi3k) signaling. results results of the study showed that mcr-1329 prevents development of arterial hypertension. it was also observed that mcr-1329 upheld the intimal structures of major arteries like the thoracic aorta. acetylcholine (ach)-mediated relaxation remained intact in arteries from mcr-1329 treated animals. it was observed that mcr-1329 partially prevents thr-308 phosphorylation of akt following ligand-mediated receptor stimulation in vascular smooth muscle cells. addition of ly294002 to the reaction medium caused a near-complete inhibition of akt-phosphorylation. this suggested that mcr-1329 elicits its antihypertensive role by blocking activation of receptor-mediated pi3k-akt downstream signaling as well as through preservation of arterial integrity. conclusions mcr-1329 has the potential to be evaluated further for clinical development as a potential antihypertensive agent with multiple mechanisms of action. © 2016 published by elsevier sp. z o.o. on behalf of institute of pharmacology,polish academy of sciences.