This proposal involves two major areas of investigation: 1) To further study a new mechanism of smoking related vascular disease, the effect of cigarettes and nicotine on the balance between thromboxane A2(TXA2) and prostacyclin (PGI2) will be studied using validated radioimmunoassay (RIA) and gas chromatography mass spectrometry (GCMS) techniques. These studies will extend our initial observations showing that tobacco inhibits PGI2 production in chronic smokers. Chronic smokers and nonsmokers will inhale varying nicotine containing cigarettes and receive nicotine directly in a gum. PGI2 and TXA2 changes will be correlated with plasma nicotine and cotinine levels. Specific adrenergic agonists and antagonists will be studied to determine the role of adrenergic nervous system in smoking related prostaglandin (PG) changes. To study renal and extrarenal PGI2 generation, 6 keto PGF1 alpha and 2,3 dinor 6 keto PGF1 alpha will be assayed in urine using RIA and GCMS. TXB2 exvivo in serum and TXB2 in urine will be measured via GCMS validated RIA to determine systemic and renal TXA2 generation after nicotine and smoking. PGI2 and PGE2 play important roles in maintaining renal blood flow (RBF) and may be important in Bp regulation. Therefore, the effect of smoking on PG levels, RBF, and Bp will be determined in certain disease states such as congestive heart failure where PG's may play an important role in vascular homeostasis. 2) In the second area of investigation, the effect of calcium (Ca+2) and Ca+2 channel blockade on PGE2 and PGI2 production, systemic and renal hemodynamics, and aldosterone synthesis will be studied in normal and hypertensive man to evaluate the role of Ca+2 in 1) vascular regulation, 2) vasodilatory PG production, and 3) aldosterone synthesis. Approaches will include giving normal subjects nonpressor or pressor Ca+2 infusions either alone or with PG inhibitors, adrenergic antagonists, or slow Ca+2 channel blockers. Noninvasive determinations of systemic and renal hemodynamics will be obtained and correlated with PG levels. Subjects with primary aldosteronism will receive Ca+2 blockers and hemodynamics and aldosterone levels determined. Preliminary data suggests that PGI2 plays a key role in modulating Ca+2's vasoconstrictive action and Ca+2 blockers lower Bp and markedly reduce aldosterone levels in subjects with primary aldosteronism.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL001496-05
Application #
3081864
Study Section
Research Manpower Review Committee (MR)
Project Start
1985-07-01
Project End
1990-06-30
Budget Start
1989-07-01
Budget End
1990-06-30
Support Year
5
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Southern California
Department
Type
Schools of Medicine
DUNS #
041544081
City
Los Angeles
State
CA
Country
United States
Zip Code
90033
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Manoogian, C; Nadler, J; Ehrlich, L et al. (1988) The renal vasodilating effect of dopamine is mediated by calcium flux and prostacyclin release in man. J Clin Endocrinol Metab 66:678-83
Natarajan, R; Stern, N; Nadler, J (1988) Diacylglycerol provides arachidonic acid for lipoxygenase products that mediate angiotensin II-induced aldosterone synthesis. Biochem Biophys Res Commun 156:717-24

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