The applicant's laboratory has made significant contributions to understanding the cellular basis of the phenomenon of postjunctional supersensitivity. This phenomenon is the expression of a cellular homeostatic mechanism by which cells compensate for chronic changes in the net stimulus the cells receive, generally via their innervation. Our long term goals have been and continue to be to understand the cellular and molecular bases of these changes in sensitivity and their biological significance. The proposed work is directly in line with these goals. There are three components to the proposal. (1) Identify the cellular bases of supersensitivity in the heart. (2) Determine if sensitivity changes in vascular smooth muscle contribute to renal hypertension in rats. (3) Determine if sensitivity changes in discrete regions of the brain contribute to the seizure state in rat models of epilepsy. The broad goals of this proposal necessitate the use of a wide range of methodologies. Most of the methods to be employed are established in the laboratory of the responsible investigator and include pharmacological techniques (e.g. construction and interpretation of concentration-response curves), biochemical procedures (e.g. radioactive ligand binding, rubidium uptake, assay of adenylate cyclase activity and cyclic AMP levels and measurement of Na+, K+ -ATPase activity). A major portion of the proposal also involves various electrophysiological techniques (e.g. intracellular recording from cardiac and smooth muscle cells; extracellular recording of individual neuronal activity in situ and microiontophoretic application of drugs to individual neurons). Studies of the proteins involved in the coupling of cardiac receptors to adenylate cyclase will be undertaken in collaboration with Dr. Theodore Torphy and Jeffrey Stadel of Smith, Kline, Beckman as a consultant.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM029840-18A2
Application #
3277539
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1982-01-01
Project End
1992-03-31
Budget Start
1987-04-01
Budget End
1988-03-31
Support Year
18
Fiscal Year
1987
Total Cost
Indirect Cost
Name
West Virginia University
Department
Type
School of Medicine & Dentistry
DUNS #
191510239
City
Morgantown
State
WV
Country
United States
Zip Code
26506
Caveney, S W; Taylor, D A; Fleming, W W (1997) Examination by radioligand binding of the alpha1 adrenoceptors in the mesenteric arterial vasculature during the development of salt-sensitive hypertension. Naunyn Schmiedebergs Arch Pharmacol 356:374-82
Roberts, M I; Stadel, J M; Torphy, T J et al. (1997) Mechanisms of adaptive supersensitivity: correlation of guinea pig atrial supersensitivity with modifications in adenylyl cyclase activity. Biochem Pharmacol 53:347-56
Kong, J Q; Taylor, D A; Fleming, W W (1995) Sustained hypertension in Dahl rats. Negative correlation of agonist response to blood pressure. Hypertension 25:139-45
Hershman, K M; Taylor, D A; Fleming, W W (1995) Adaptive supersensitivity and the Na+/K+ pump in the guinea pig vas deferens: time course of the decline in the alpha 2 subunit. Mol Pharmacol 47:726-9
Gould, E M; Curto, K A; Craig, C R et al. (1995) The role of GABAA receptors in the subsensitivity of Purkinje neurons to GABA in genetic epilepsy prone rats. Brain Res 698:62-8
Kong, J Q; Taylor, D A; Fleming, W W (1994) Functional distribution and role of alpha-1 adrenoceptor subtypes in the mesenteric vasculature of the rat. J Pharmacol Exp Ther 268:1153-9
Bexis, S; Lungershausen, Y K; Mano, M T et al. (1994) Dietary fish oil administration retards blood pressure development and influences vascular properties in the spontaneously hypertensive rat (SHR) but not in the stroke prone-spontaneously hypertensive rat (SHR-SP). Blood Press 3:120-6
Hershman, K M; Fleming, W W; Taylor, D A (1993) A quantitative method for assessing protein abundance using enhanced chemiluminescence. Biotechniques 15:790, 792, 794 passim
Hershman, K M; Taylor, D A; Fleming, W W (1993) Adaptive supersensitivity in the guinea pig vas deferens is associated with a reduction in the abundance of the alpha 2 subunit isoform of Na+/K(+)-ATPase. Mol Pharmacol 43:833-7
Roberts, M I; Biser, P S; Stadel, J M et al. (1992) Adenylyl cyclase and guanine nucleotide-binding proteins in supersensitive guinea pig ventricles. Mol Pharmacol 42:784-91

Showing the most recent 10 out of 26 publications