Angiotensin receptor blockers and beta-arrestin-dependent aldosterone production

Grant Winners

  • Anastasios Lymperopoulos Ph.D. – College of Pharmacy
  • Samalia Dabul – College of Pharmacy
  • Ashley Siryk – College of Pharmacy

Deans

  • Andres Malave, Ph.D. – College of Pharmacy
  • Lisa Deziel-Evans, Pharm.D., Ph.D. – College of Pharmacy

Abstract

Award Winners

Heart failure (HF) represents one of the most significant health problems worldwide and new and innovative treatments are urgently needed. Aldosterone is one of a number of hormones with detrimental effects on themyocardium, whose circulating levels are elevated in chronic HF. Aldosterone can contribute significantly to HF progression after myocardial infarction (MI) and to the morbidity and mortality of the disease. Aldosterone is a mineralocorticoid produced and secreted by the cells of the zona glomerulosa of the adrenal cortex in response to either elevated serum potassium levels or to angiotensin II (AngII) acting through its type 1 receptors (AT1Rs). AT1Rs belong to the superfamily of G protein-coupled receptors (GPCRs). Upon agonist activation, they couple to either Gproteins or the βarrestins (βarrestin-1 and -2, βarr1 and -2), which initially desensitize (terminate) G protein signaling from the receptor and, subsequently, mediate their own, G protein-independent, signal transduction. We have recently shown that, by, acting on the AT1R, βarr1 mediates AngII-induced aldosterone production in vitro and physiologically in vivo. This finding calls for a testing of all the currently available in clinical practice AT1Rantagonist drugs (angiotensin receptor blockers, ARBs, or sartans) at their ability to block activation of ßarr1 by theAT1R in the adrenal cortex, thereby preventing aldosterone synthesis and secretion and ameliorating HF. ARBs are very important cardiovascular drugs in the treatment of hypertension, diabetic nephropathy and HF, Thus, in the present proposal, we will study the relative potencies of various ARBs at inhibiting ßarr1 activation and hence aldosterone production from AngII in adrenocortical zona glomerulosa (H295R) cells in culture in an effort to ultimately identify which agent(s) is(are) the most potent inhibitors of that effect and hence, the most efficacious drugs in this class.