Hypertension is a major risk factor for the development of cardiovascular disease, i.e., stroke heart failure and peripheral vascular disease. Arteries from animals with genetic and mineralocorticoid-NaCl hypertension are known to exhibit increases in steady-state Cl- turnover and vasoconstrictor responsiveness. The relationship between Cl- and vascular contraction has not been clearly defined. The proposed research program focuses on the cellular/molecular mechanisms underlying altered Cl- permeability and its contribution to increased vascular reactivity in hypertension. The overall plan is designed to probe the physiological role of specific Cl- transporters/channels in modulating transmembrane signaling events (Ca2+, pHi, membrane potential) involved in contractile agonist stimulation of vascular smooth muscle cells (VSMC) isolated from arteries (aorta, caudal artery) of normotensive, spontaneously hypertensive (NaCl- sensitive and resistant strains), and aldosterone-NaCl hypertension. Combination of fluorescence microscopy, newly-developed digital imaging methods, and patch-clamp techniques will be used to probe the molecular mechanisms of VSMC Cl- homeostasis.
The specific aims are: 1) Define the cellular pathways involved in Cl- homeostasis in cultured, as well as freshly isolated VSMC. Ion-selective fluorescent dyes, fluorescence microcopy, and patch-clamp techniques will be used to analyze in detail different Cl- transporters/channels in intact, single VSMC; 2) Determine the molecular mechanisms involved in Cl- transporter/channel activation. Fluorescence microscopy in combination with digital image analysis methods and patch-clamp techniques will be used to make simultaneous spatial/temporal measurements of Cl- conductances and different ions following agonists stimulation; 3) Probe the cellular/molecular mechanisms underlying increased VSMC Cl- permeability and its contribution to increase VSMC reactivity. Furthermore, we will evaluate the contribution of increased Cl- permeability to enhanced vascular responsiveness in aorta and caudal artery using different Cl- flux inhibitors. These studies will contribute to our basic understanding of the cellular/molecular mechanisms underlying normal and altered VSMC ion permeability in relationship to VSMC dysfunction in the pathogenesis of hypertension, atherosclerosis and arterial vasospasm.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL045142-01
Application #
3364070
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1990-07-01
Project End
1995-06-30
Budget Start
1990-07-01
Budget End
1991-06-30
Support Year
1
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Type
Schools of Medicine
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
White, C R; Elton, T S; Shoemaker, R L et al. (1995) Calcium-sensitive chloride channels in vascular smooth muscle cells. Proc Soc Exp Biol Med 208:255-62
White, C R; Brock, T A (1994) Calcium-mobilizing agonists stimulate anion fluxes in cultured endothelial cells from human umbilical vein. J Membr Biol 142:171-9