The baroreceptor (BR) activity transmitted to the central nervous system is determined not only by the mechanoelectrical transducing channels but also by various voltage-gated channels that influence membrane excitability of BR neurons. Hypothesis #1: The important paracrine factors prostacyclin (PGI/2) and nitric oxide (NO) directly influence excitability of BR neurons through modulation of voltage-gated K+ and Na+ channels. Effects of PGI/2 and No on membrane potential, spike firing properties, and K+ and Na+ currents of isolated BR neurons in culture will be demonstrated using patch-clamp techniques. Experiments will define the intracellular signal transduction pathways and mechanisms by which PGI/2 and NO influence channel activity. Hypothesis #2: PGI/2 and NO function as autocrine factors produced endogenously in response to mechanical deformation and consequently modulate excitability and mechanosensitivity of the BR neurons. Release of PGI2 and NO from isolated neurons will be measured and their impact on excitability evaluated by pharmacological inhibitors and antagonists. The influence of expression of PGH and NO synthases within individual BR neurons and effects of changing expression using gene transfer on mechano-sensitivity will be investigated. Hypothesis #3: Intracellular generation of reactive oxygen species (ROS) significantly modulates excitability of BR neurons by altering K+ and Na+ currents. Effects of ROS on excitability and K+ and Na+ currently will be demonstrated and the intracellular mechanisms defined. Prolonged oxidative stress will be induced by incubation of BR neurons with oxidized LDL and the impact on membrane excitability and K+ and Na+ currents investigated. The in vivo relevance of the results obtained from isolated BR neurons will be confirmed, when possible, in experiments using the isolated carotid sinus-BR preparation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL014388-28
Application #
6302101
Study Section
Project Start
2000-01-01
Project End
2000-12-31
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
28
Fiscal Year
2000
Total Cost
$192,770
Indirect Cost
Name
University of Iowa
Department
Type
DUNS #
041294109
City
Iowa City
State
IA
Country
United States
Zip Code
52242
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