The long term objective of this project is to define the mechanisms responsible for the changes that occur in the reactivity of arteries with aging.
The specific aims of this application are designed to test several hypotheses concerning the possible mechanisms including: 1) the function of arterial wall Na+-K+-ATPase (Na-pump); 2) the intrinsic reactivity of the contractile system; 3) Beta-adrenergic relaxation of contracted arteries; and 4) membrane cholesterol and phospholipids. Studies will be conducted using several isolated arteries from the NIA's colony of Fischer 344 rats at ages of 1 to 33 months. Studies of Na-pump function will be performed under conditions of maximal activity in Na+ loaded arteries and of resting activity in arteries using the Rb86-uptake procedure. Studies of Na-pump activity will include: a) dependence on intracellular (Na+) and extracellular (Rb+); b) dose-dependence of ouabain inhibition of Na-pump activity; c) effect of cell Na+ increase on agonist dose-response relations to norepinephrine, secrotonin and K+. Activation with Ca+2 following detergent (saponin) increased membrane permeability will be performed to determine the intrinsic properties of the contractile apparatus. The effects of substrates Mg+2, MgATP-2 and calmodulin on these responses will be determined. Relaxation responses of precontracted arteries will be tested using forskolin (adenyl cyclase activation), isoproterenol (Beta-receptor), and acetylcholine (endothelium mediated). The contributiion of membrane cholesterol and phospholipid content to altered arterial wall function (vascular reactivity, Na-pump function and 42K efflux) will be stuided by: a) determining the aging changes of various lipid classes in arteries; b) altering membrane cholesterol content with cholesterol acceptor or donor particles; c) measuring NE activated phosphotidylinositol (PI) hydrolysis and d) altering membrane PI content with PI loading; and depleting procedures. Schild analysis will be applied to test for the occurrence of conformational changes in Alpha- and Beta-adrenergic receptors. These studies will help direct attention to several arterial smooth muscle membrane and cellular mechanisms that may be responsible for the altered vascular reactivity that occurs in aging and will further serve to focus future research efforts.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG004908-01A1
Application #
3115430
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1985-09-30
Project End
1988-08-31
Budget Start
1985-09-30
Budget End
1986-08-31
Support Year
1
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Graduate Hospital (Philadelphia)
Department
Type
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19146
Bialecki, R A; Tulenko, T N (1993) Acute exposure to cholesterol increases arterial nitroprusside- and endothelium-mediated relaxation. Am J Physiol 264:C32-9
Cox, R H (1991) Potassium channel activators in vascular smooth muscle. Adv Exp Med Biol 308:27-43
Tulenko, T N; Bialecki, R; Gleason, M et al. (1990) Ion channels, membrane lipids and cholesterol: a role for membrane lipid domains in arterial function. Prog Clin Biol Res 334:187-203
Cox, R H (1990) Effects of putative K+ channel activator BRL-34915 on arterial contraction and 86Rb efflux. J Pharmacol Exp Ther 252:51-9
Cox, R H (1990) K(+)-channel activators in vascular smooth muscle. Prog Clin Biol Res 334:171-85
Bialecki, R A; Tulenko, T N (1989) Excess membrane cholesterol alters calcium channels in arterial smooth muscle. Am J Physiol 257:C306-14
Cox, R H; Tulenko, T N (1989) Effects of aging on agonist-activated 86Rb efflux in arteries of Fischer 344 rats. Am J Physiol 257:H494-501
Broderick, R; Bialecki, R; Tulenko, T N (1989) Cholesterol-induced changes in rabbit arterial smooth muscle sensitivity to adrenergic stimulation. Am J Physiol 257:H170-8
Cox, R H; Detweiler, D K (1988) Comparison of arterial wall properties in young and old racing greyhounds. Mech Ageing Dev 44:51-67
Tulenko, T N; Rabinowitz, J L; Cox, R H et al. (1988) Altered Na+-K+-ATPase, cell Na+ and lipid profiles in canine arterial wall with chronic cigarette smoking. Int J Biochem 20:285-9

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