Differential Desensitization of Salt Appetite and Thirst by Brain Angiotensin

Grant Winners

  • Robert Speth, PhD – College of Pharmacy
  • Jamala Swindle – Farquhar College of Arts and Sciences
  • Luz Gonzalez – Farquhar College of Arts and Sciences

Dean

  • Andres Malave, PhD – College of Pharmacy

Abstract

High blood pressure is one of the leading causes of cardiovascular morbidity and mortality. A major causal factor is excessive salt intake associated with its high palatability. Angiotensin II, the primary hormone of the renin angiotensin system is a potent stimulator of salt appetite, which adds to its constellation of adverse cardiovascular actions. Recent studies from Dr. Daniels laboratory on the mechanisms by which angiotensin II acts in the brain to cause salt appetite have revealed a novel signaling pathway for this effect. Unlike the thirst response to angiotensin II, which is G protein-coupled and undergoes rapid desensitization, the salt appetite response does not involve a G protein and does not desensitize with repeated exposure to angiotensin II. This project will investigate the mechanisms whereby the thirst, but not the salt appetite effect of angiotensin II desensitize using receptor binding assays to measure angiotensin II receptors in the brain areas that mediate the thirst and salt appetite responses to angiotensin II. We will use two types of radioligands: an agonist and an antagonist for the G protein coupled responses mediated by brain angiotensin receptors. We will use two types of analysis of receptor binding: 1) saturation isotherm analysis that allows for determination of the total number of receptors expressed in the hypothalamus of desensitized brains versus control brains plus the receptors' affinity for the radioligands, and 2) receptor autoradiography to allow for assessment of angiotensin receptor binding in specific brain nuclei within the hypothalamus that mediate the effects of angiotensin II. It is anticipated that comparison of changes in binding of the agonist and antagonist radioligands will indicate whether the desensitization of the thirst response involves uncoupling of the receptors from their G proteins or internalization of the receptors.