CNS Neuroplasticity and Salt Sensitive Hypertension Induced by Prior Treatment with Sub-

39 Although sensitivity to high dietary NaCl is regarded to be a risk factor for cardiovascular 40 disease, the causes of salt-sensitive hypertension remain elusive. Previously we have shown 41 that rats pretreated with sub-pressor doses of either angiotensin II (ANG II) or aldosterone 42 (Aldo) show sensitized hypertensive responses to a mildly pressor dose of ANG II when tested 43 after an intervening delay. The current studies investigated whether such treatments will 44 induce salt-sensitivity. In studies employing an Induction-Delay-Expression experimental 45 design, male rats were instrumented for chronic blood pressure (BP) recording. In separate 46 experiments, ANG II, Aldo or vehicle were delivered either subcutaneously or 47 intracerebroventricularly during Induction. There were no sustained differences in BP during 48 Delay prior to being given 2% saline. While consuming 2% saline during Expression, both ANG 49 IIand Aldo-pretreated rats showed significantly greater hypertension. When hexamethonium 50 was used to assess autonomic control of BP, no differences in the decrease of BP in response 51 ganglionic blockade were detected during Induction. However, during Expression the fall was 52 greater in sensitized rats. In separate experiments, brain tissue collected at the end of Delay 53 showed increases in message or activation of putative markers of neuroplasticity (i.e., brain54 derived neurotrophic factor, p38 mitogen-activated protein kinase, cAMP response element55 binding protein). These experiments demonstrate that prior administration of non-pressor 56 doses of either ANG II or Aldo will induce salt-sensitivity. Collectively our findings indicate that 57 treatment with sub-pressor doses of ANG II and Aldo initiate central neuroplastic changes that 58 are involved in hypertension of different etiologies. 59