Central Sodium Sensing in Older Humans: Implications for Blood Pressure Regulation - PROJECT SUMMARY/ABSTRACT
The prevalence of hypertension is very high in older adults, and a major factor in hypertension is salt sensitivity
of blood pressure (BP) and elevated sympathetic nerve activity (SNA). However, we know very little about how
the human brain ‘senses’ sodium, and what molecular mechanisms are involved. Rodent studies have
identified specialized sodium chloride (NaCl)-sensing neurons in the circumventricular organs (CVOs), which
mediate NaCl-induced changes in SNA, arginine vasopressin (AVP), and BP. Recent data suggest the Na-K-
2Cl co-transporter (NKCC2) is not kidney specific but is also expressed in brain regions that regulate whole
body NaCl and water homeostasis. In addition, NKCC2 is accessible by drugs in the circulation since the
CVOs lack a complete blood brain barrier. The objective of this R21 is to identify key NaCl-sensing regions of
the brain in older adults and determine if NKCC2 mediates the neurohumoral response to acute
hypernatremia. We seek to translate the prior rodent findings to humans by assessing neuronal activation
(using blood oxygen level dependent functional magnetic resonance imaging, BOLD fMRI) as well as thirst,
AVP, SNA and BP during an acute hypernatremic stimulus, with and without an NKCC2 antagonist
(furosemide). This will enable us to assess the role of NKCC2 in NaCl sensing. The overall hypothesis is that
acute hypernatremia will elicit detectable changes in the BOLD fMRI signal and increase thirst, AVP, SNA, and
BP largely through NKCC2 in healthy older adults. Accordingly, the first specific aim is to identify the areas of
the human brain that respond to acute hypernatremia and determine the role of NKCC2 in central NaCl-
sensing. Acute hypernatremia will be induced with a 30-minute infusion of 3% NaCl delivered intravenously.
Brain activity during the hypertonic saline infusion will be measured in regions such as the organum
vasculosum laminae terminalis, subfornical organ, anterior cingulate cortex, hypothalamus, and insular cortex.
The second specific aim is to determine the effect of acute hypernatremia on thirst, AVP, SNA, and BP, and
determine the role of NKCC2 in mediating these responses. Salt sensitivity of BP will be individually assessed
and comparisons will be made between those with a salt resistant and salt sensitive phenotype; we anticipate
that acute hypernatremia will elicit changes in the BOLD fMRI signal and SNA & AVP in all subjects, but the
responses will be greater in those who are classified as salt sensitive. This would represent the first trial in
healthy human subjects to identify a putative brain NaCl-sensing co-transporter, and we think the scope and
innovative approaches are ideal for the R21 funding mechanism. Older adults are prone to hypertension, so it
is critically important to understand how normotensive older adults centrally sense sodium, to provide a needed
foundation for exploring the mechanistic underpinning of salt sensitive hypertension.