Funds are requested to continue support of a study of the specificity and mechanism of action of a variety of Na+, Ca++ and K+ -antagonists in enzymatically dispersed single myocytes from frog and guinea-pig hearts. In comparison to multicellular cardiac preparations, isolated single cells offer a number of important advantages for quantitative voltage-clamp and pharmacological studies: (i) the ability to study possible mechanisms of pharmacological modulation of ion channel function both at the level of whole-cell ionic currents as well as single channel currents, and (ii) the ability to carefully assess the specificity of pharmacological agents on each component of ionic current under conditions in which contamination by other currents is minimal. Considerable recent progress has been made in understanding the interactions of several organic Ca++ channel antagonists with Ca++ and K+ channels in single frog atrial myocytes. We propose to continue these experiments in isolated single guinea-pig myocytes to include an analysis of the mechanism of action and specificity of several Na+ and K+ channel antagonists. Since many of the compounds to be studied are important therapeutic agents used clinically to treat a variety of cardiovascular conditions, the proposed experiments will provide new information with regard to the cellular actions of these compounds. This information will contribute to a better understanding of cardiac arrhythmias in general and may lead to the development of newer and more effective antiarrhythmic agents.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL030143-04
Application #
3341188
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1982-09-01
Project End
1989-08-31
Budget Start
1985-09-01
Budget End
1986-08-31
Support Year
4
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Michigan State University
Department
Type
Schools of Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Hume, J R; Horowitz, B (1995) A plethora of cardiac chloride conductances: molecular diversity or a related gene family. J Cardiovasc Electrophysiol 6:325-31
Collier, M L; Hume, J R (1995) Unitary chloride channels activated by protein kinase C in guinea pig ventricular myocytes. Circ Res 76:317-24
Levesque, P C; Leblanc, N; Hume, J R (1994) Release of calcium from guinea pig cardiac sarcoplasmic reticulum induced by sodium-calcium exchange. Cardiovasc Res 28:370-8
Hume, J R; Hart, P; Levesque, P C et al. (1994) Molecular physiology of CFTR Cl- channels in heart. Jpn J Physiol 44 Suppl 2:S177-82
Levesque, P C; Clark, C D; Zakarov, S I et al. (1993) Anion and cation modulation of the guinea-pig ventricular action potential during beta-adrenoceptor stimulation. Pflugers Arch 424:54-62
Horowitz, B; Tsung, S S; Hart, P et al. (1993) Alternative splicing of CFTR Cl- channels in heart. Am J Physiol 264:H2214-20
Levesque, P C; Hart, P J; Hume, J R et al. (1992) Expression of cystic fibrosis transmembrane regulator Cl- channels in heart. Circ Res 71:1002-7
Harvey, R D; Jurevicius, J A; Hume, J R (1991) Intracellular Na+ modulates the cAMP-dependent regulation of ion channels in the heart. Proc Natl Acad Sci U S A 88:6946-50
Levesque, P C; Leblanc, N; Hume, J R (1991) Role of reverse-mode Na(+)-Ca2+ exchange in excitation-contraction coupling in the heart. Ann N Y Acad Sci 639:386-97
Hume, J R; Harvey, R D (1991) Chloride conductance pathways in heart. Am J Physiol 261:C399-412

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