This project concerns the cellular electrophysiology of cardiac muscle, with emphasis on the membrane electrical properties and nature of the voltage-dependent cation channels. The changes in membrane electrical properties that occur during development of chick and rat hearts and in cell culture will be studied. The parameters examined include K ions permeability, and ultrastructure. We are attempting to learn what factors control membrane differentiation in situ, e.g., whether neurotrophic factors are involved. In answering these questions, young embryonic hearts will be placed in organ culture to determine what factors control membrane electrical differentiation in vitro. In addition, we will trypsin-disperse young and old embryonic hearts and prepare cell cultures (denervated, as monolayers and as spherical reaggregates. We will attempt to define what factors cause some cultured myocardial cells to revert back (partially dedifferentiate) towards the some cultured myocardial cells to revert back (partially dedifferentiate) towards the young embryonic state, whereas other cell cultures retain (or regain) their highly differentiated state. Spherical reaggregate cultures will be characterized with respect to their electrophysiological properties, degree of electrical coupling, and presence of pharmacological receptors. We will also continue to elucidate the properties of myocardial slow channels, including their ionic specificity, activation energy, etc. A search will be made for other agents which either block the slow channels or which make more slow channels become available for voltage activation, and how this is brought about. We will test our hypothesis that phorphorylation of protein constituent of the slow channel, by a cyclic AMP-dependent protein kinase, makes the channel available for voltage activation, and that this is one of the mechanisms by which some positive inotropic agents and neurotransmitters act. We will test whether the peculiar property of myocaridal slow channels, namely energy dependence, serves to protect the heart under adverse conditions of hypoxia or regional ischemia.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL031942-03
Application #
3343115
Study Section
Cardiovascular Study Section (CVA)
Project Start
1983-07-01
Project End
1986-11-30
Budget Start
1984-12-01
Budget End
1985-11-30
Support Year
3
Fiscal Year
1985
Total Cost
Indirect Cost
Name
University of Cincinnati
Department
Type
Schools of Medicine
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Zhu, L; Marvin, M J; Gardiner, A et al. (1999) Cerberus regulates left-right asymmetry of the embryonic head and heart. Curr Biol 9:931-8
Katsube, Y; Yokoshiki, H; Nguyen, L et al. (1998) Inhibition of Ca2+ current in neonatal and adult rat ventricular myocytes by the tyrosine kinase inhibitor, genistein. Eur J Pharmacol 345:309-14
Sumii, K; Imazu, M; Yamakido, M et al. (1997) Cyclic GMP-dependent protein kinase regulates the L-type calcium current in rat ventricular myocytes. Heart Vessels Suppl 12:62-5
Katsube, Y; Sperelakis, N (1996) Na+/Ca2+ exchange current: lack of effect of taurine. Eur J Pharmacol 316:97-103
Masuda, H; Sumii, K; Sperelakis, N (1996) Developmental changes in beta-adrenergic and muscarinic modulations of Ca2+ currents in fetal and neonatal ventricular cardiomyocytes of the rat. Reprod Fertil Dev 8:129-35
Yokoshiki, H; Sumii, K; Sperelakis, N (1996) Inhibition of L-type calcium current in rat ventricular cells by the tyrosine kinase inhibitor, genistein and its inactive analog, daidzein. J Mol Cell Cardiol 28:807-14
Masuda, H; Sumii, K; Sperelakis, N (1995) Long openings of calcium channels in fetal rat ventricular cardiomyocytes. Pflugers Arch 429:595-7
Conforti, L; Sumii, K; Sperelakis, N (1995) Dioctanoyl-glycerol inhibits L-type calcium current in embryonic chick cardiomyocytes independent of protein kinase C activation. J Mol Cell Cardiol 27:1219-24
Sumii, K; Sperelakis, N (1995) cGMP-dependent protein kinase regulation of the L-type Ca2+ current in rat ventricular myocytes. Circ Res 77:803-12
Haddad, G E; Sperelakis, N; Bkaily, G (1995) Regulation of the calcium slow channel by cyclic GMP dependent protein kinase in chick heart cells. Mol Cell Biochem 148:89-94

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