Over the past decade many membrane functions have been reported to be abnormal in hypertension. These include sodium, potassium and calcium fluxes, sodium/calcium and sodium/hydrogen exchange, and sodium/potassium and calcium pumping. Because each of these functions is performed by a different integral protein and because the functions of integral proteins are influenced by the lipid bilayer matrix in which they are embedded, we hypothesized that the many abnormal plasma membrane functions in hypertension are secondary to an abnormality of the lipid bilayer of the plasma membrane in this disease (1). The proposed research will test this hypothesis. We have already observed that the microviscosity of the lipid bilayer of vascular smooth muscle in hypertension is increased (fluidity is decreased); 2). Two studies are proposed to determine the relationship of the lipid bilayer abnormality to hypertension: 1. We will determine whether this membrane abnormality is present in a genetically hypertensive strain of rats in which the arterial pressure has been kept at normal levels since birth by antihypertensive therapy. 2. In the segregating generations (F2 and backcrosses) of a cross between genetically normotensive (WKY) and hypertensive (SHRSP) rats, we will determine whether the lipid bilayer abnormality segregates with the elevated arterial pressure. At a mechanistic level we will determine how the lipid bilayer abnormality of vascular smooth muscle is influenced by relevant interventions and conditions: fatty acids, cholesterol, calcium and temperature. Parallel studies will be carried out on the effects of these interventions on membrane transport function (Na+, K+ and Ca2+ channels and Na+, K+ ATPase) and on vascular reactivity. The studies are designed to explore possible mechanisms by which the observed lipid bilayer abnormality could cause hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL046402-02
Application #
3365548
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1992-07-01
Project End
1995-06-30
Budget Start
1993-07-01
Budget End
1994-06-30
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Dominiczak, A F; McLaren, Y; Kusel, J R et al. (1993) Lateral diffusion and fatty acid composition in vascular smooth muscle membrane from stroke-prone spontaneously hypertensive rats. Am J Hypertens 6:1003-8