title: Protective effects of MCR-1329, a dual α1 and angII receptor antagonist, in mineralocorticoid-induced hypertension.
abstract: 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.
authors.affiliation: Faculty of Pharmacy, Kalabhavan Campus, The M. S. University of Baroda, Vadodara, Gujarat, India.
authors.forename: Hardik
authors.initials: H
authors.lastname: Gandhi
authors.affiliation: Faculty of Pharmacy, Kalabhavan Campus, The M. S. University of Baroda, Vadodara, Gujarat, India.
authors.forename: Prashant
authors.initials: P
authors.lastname: Naik
authors.affiliation: Faculty of Pharmacy, Kalabhavan Campus, The M. S. University of Baroda, Vadodara, Gujarat, India.
authors.forename: Nitesh
authors.initials: N
authors.lastname: Agrawal
authors.affiliation: Faculty of Pharmacy, Kalabhavan Campus, The M. S. University of Baroda, Vadodara, Gujarat, India. Electronic address: mryadav11@yahoo.co.in.
authors.forename: Mangeram
authors.initials: M
authors.lastname: Yadav
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology*; D000804:Angiotensin II / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D064791:Desoxycorticosterone Acetate / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology; D008297:Male; D008901:Mineralocorticoids / Q000494:pharmacology*; D009025:Morpholines / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011224:Prazosin / Q000494:pharmacology; D020011:Protective Agents / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011945:Receptors, Angiotensin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D002867:Chromones; D008901:Mineralocorticoids; D009025:Morpholines; D020011:Protective Agents; D011945:Receptors, Angiotensin; D000804:Angiotensin II; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D064791:Desoxycorticosterone Acetate; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019808:Losartan; D011224:Prazosin
keywords: Angiotensin II; DOCA; Hypertension; Losartan; Prazosin