The long range goals of the proposed research are to elucidate the molecular mechanisms by which agonists linked to phosphoinositide metabolism alter contractility of the mammalian heart. A key hypothesis to be tested is that alpha-adrenergic, Kappa-opioid and endothelin-1 receptors are coupled to pathways in which specific diacylglycerols become elevated, leading to selective activation of protein kinase C isoforms and phosphorylation of specific proteins associated with the contractile apparatus. The effects of phosphorylation on rates of activation and relaxation, as well as on the kinetics of product release steps during the cross-bridge cycle will be examined using the novel method of pulse photolysis of caged compounds to rapidly alter Ca2+, inorganic phosphate and ADP in single cardiac myocytes. Information obtained will provide a basis for understanding changes in cardiac performance during heart failure, ischemic/reperfusion injury or during chronic diseased states such as hypertension or diabetes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Modified Research Career Development Award (K04)
Project #
5K04HL003119-03
Application #
2027033
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Project Start
1995-01-01
Project End
1999-12-31
Budget Start
1997-01-01
Budget End
1997-12-31
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Physiology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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Pi, Y; Walker, J W (2000) Diacylglycerol and fatty acids synergistically increase cardiomyocyte contraction via activation of PKC. Am J Physiol Heart Circ Physiol 279:H26-34
Huang, X; Pi, Y; Lee, K J et al. (1999) Cardiac troponin I gene knockout: a mouse model of myocardial troponin I deficiency. Circ Res 84:1-8
Sreekumar, R; Ikebe, M; Fay, F S et al. (1998) Biologically active peptides caged on tyrosine. Methods Enzymol 291:78-94
Pi, Y; Walker, J W (1998) Role of intracellular Ca2+ and pH in positive inotropic response of cardiomyocytes to diacylglycerol. Am J Physiol 275:H1473-81
Pi, Y; Sreekumar, R; Huang, X et al. (1997) Positive inotropy mediated by diacylglycerol in rat ventricular myocytes. Circ Res 81:92-100
Huang, X P; Pi, Y; Lokuta, A J et al. (1997) Arachidonic acid stimulates protein kinase C-epsilon redistribution in heart cells. J Cell Sci 110 ( Pt 14):1625-34