Although the endothelium-derived relaxing factor (EDRF) is generally acknowledged to be nitric oxide (including the Nobel committee, 1998), there is much uncertainty regarding the exact molecular identity of EDRF, specifically, whether it is free NO or a related nitrogen oxide species. Much of the reason for this uncertainty is due to the general perception that the dynamics of free NO are not suitable for its role as EDRF, specifically, that it is too short-lived. In this proposal, we will specifically examine this important issue, namely, we will identify and quantify the processes which determine the dynamics of NO in the vascular system. Our three Specific Aims are organized according to the three compartments involved: the vascular lumen, wall, ablumen.
In Specific Aim I we will address the dynamics of NO in the lumen. Specifically, we hypothesize that the major process which defines NO dynamics in this compartment is the irreversible consumption of NO by oxyhemoglobin within the erythrocyte. Even though this represents the major sink for NO in vivo, this process is slow enough that free NO can still function as EDRF; we will delineate the origin for this retardation, which is due to encapsulation of oxyhemoglobin within the erythrocyte. We will also examine the kinetic competence of the formation of nitrosothiol-hemoglobin as a possible carrier of NO.
In Specific Aim II we will test whether it is free NO which is the direct effector of vascular relaxation in the vessel wall. We will address this by testing the hypothesis that if it is free NO which is the messenger between the endothelial cell and the smooth muscle cell, then relaxation under a variety of conditions should directly correlate with the concentration of free NO (which we will measure directly with NO-specific electrodes).
In Specific Aim III we will address the lifetime of NO in the perivascular region surrounding a vessel, and test whether in addition to causing vasodilation a second role for NO is to extend the distance that oxygen diffuses away from the vessel. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL071189-02
Application #
6891412
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Goldman, Stephen
Project Start
2004-05-01
Project End
2008-04-30
Budget Start
2005-05-20
Budget End
2006-04-30
Support Year
2
Fiscal Year
2005
Total Cost
$303,750
Indirect Cost
Name
University of Alabama Birmingham
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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