The human adrenal synthesizes and secretes a variety of important regulatory hormones. We have shown that the adrenal cortex is a tissue rich in endogenous digoxin-like immunoreactive factor (DLIF) and that is secretes DLIF into the circulation. We have also purified DLIF to homogeneity, determined its molecular weight and chemical composition. The chemical composition of endogenous DLIF is remarkably similar to that of the cardioactive cardenolides. Several studies have demonstrated elevated levels of endogenous DLIF in serum from patients with essential hypertension (EH), pregnancy induced hypertension (PIH), and during cardiovascular dysfunction. DLIF may regulate the enzymatic activity of ouabain-sensitive sodium-potassium ATPase. Na/K-ATPase (sodium pump) is an important modulator of vascular smooth muscle tone in arterioles as well as other cardiovascular events. Inhibition of the sodium pump causes vasoconstriction which leads to systemic hypertension. Therefore, DLIF from the adrenal cortex may play a role in the etiology of EH and PIH. We propose a working hypothesis: DLIF from human adrenal cortex are endogenous inhibitors of ouabain-sensitive sodium-potassium ATPase and by this mechanism they affect blood pressure in mammals.
The aim of this project is to define the detailed molecular structure of DLIF and characterize the biological activity of this factor obtained from adrenal tissues. Characterization will be done using four independent assays of digitalis-like activity; immunoreactivity, receptor binding, sodium-potassium ATPase enzymatic activity, and sodium pump activity. This research will provide the much needed biochemical identification of DLIF from adrenal cortex, compare these factors to DLIF from plasma, and test the hypothesis that DLIF from adrenals are endogenous inhibitors of sodium-potassium ATPase. These factors may prove useful in elucidating the mechanism responsible for EH or PIH and provide much needed diagnostic markers for these diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL036172-05A1
Application #
3350918
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1987-09-01
Project End
1995-03-31
Budget Start
1992-04-17
Budget End
1993-03-31
Support Year
5
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Louisville
Department
Type
Schools of Medicine
DUNS #
City
Louisville
State
KY
Country
United States
Zip Code
40292
el-Masri, M Adnan; Clark, Barbara J; Qazzaz, Hassan M et al. (2002) Human adrenal cells in culture produce both ouabain-like and dihydroouabain-like factors. Clin Chem 48:1720-30
Rose, A M; Qazzaz, H M; Zolotarjova, N et al. (2000) Sodium pump isoforms in xenotransplantation: importance of biochemical compatibility. Clin Chem 46:234-41
Qazzaz, H M; El-Masri, M A; Valdes Jr, R (2000) Secretion of a lactone-hydrogenated ouabain-like effector of sodium, potassium-adenosine triphosphatase activity by adrenal cells. Endocrinology 141:3200-9
Grider, G; El-Mallakh, R S; Huff, M O et al. (1999) Endogenous digoxin-like immunoreactive factor (DLIF) serum concentrations are decreased in manic bipolar patients compared to normal controls. J Affect Disord 54:261-7
Rose, A M; Mellett, B J; Valdes Jr, R et al. (1998) Alpha 2 isoform of the Na,K-adenosine triphosphatase is reduced in temporal cortex of bipolar individuals. Biol Psychiatry 44:892-7
Linder, M W; Prough, R A; Valdes Jr, R (1997) Pharmacogenetics: a laboratory tool for optimizing therapeutic efficiency. Clin Chem 43:254-66
Qazzaz, H M; Jortani, S A; Poole, J M et al. (1996) Evidence for presence of a reduced form of digoxin-like immunoreactive factor (dihydro-DLIF) in mammalian tissues. Clin Chem 42:1092-9
Qazzaz, H M; Goudy, S L; Valdes Jr, R (1996) Deglycosylated products of endogenous digoxin-like immunoreactive factor in mammalian tissue. J Biol Chem 271:8731-7
Miller, J J; Straub Jr, R W; Valdes Jr, R (1996) Analytical performance of a monoclonal digoxin assay with increased specificity on the ACS:180. Ther Drug Monit 18:65-72
Qazzaz, H M; Valdes Jr, R (1996) Simultaneous isolation of endogenous digoxin-like immunoreactive factor, ouabain-like factor, and deglycosylated congeners from mammalian tissues. Arch Biochem Biophys 328:193-200

Showing the most recent 10 out of 14 publications