Epinephrine (E) is synthesized in the adrenal by the enzyme phenylethanolamine-N-methyltransferase (PNMT). PNMT is also present in many other tissues along with another N-methyltransferase (NMT) that can also synthesize E. E can raise blood pressure and cause insulin resistance. Both spontaneously hypertensive rats and diabetic rats have elevated tissue levels of PNMT, NMT and E. The rat kidney can synthesize E and excrete that E into urine. Preliminary studies show that hyperinsulinemic human hypertensives have excess urinary E of renal origin. Studies will define how extra-adrenal E synthesis affects plasma and urinary E levels, glucose metabolism and blood pressure control. Rats will have their adrenal medullae removed and be made diabetic. One group will receive SKF7698 to inhibit extra-adrenal E and epinine synthesis. A second group will receive the beta2 adrenergic blocker ICI 118,551. A third group will receive placebo. Animals will be tested for insulin sensitivity to determine if E stimulation of B2 receptors causes insulin resistance. Normal human subjects and hypertensives will undergo 3 H-E infusion and have plasma and urine 3HE and E levels measured to determine plasma E kinetics, urinary E clearance, and to determine the amount of urinary E synthesized by the kidney. Subjects with hyperinsulinemic hypertension will have E levels measured and undergo insulin clamp studies to define the site of insulin resistance at both normal insulin levels and when a normal rate of glucose flux is driven by hyperinsulinemia and hyperglycemia.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL035924-05
Application #
3350380
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1991-07-01
Project End
1994-06-30
Budget Start
1992-07-01
Budget End
1993-06-30
Support Year
5
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Type
Schools of Medicine
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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Kennedy, B; Elayan, H; Ziegler, M G (1993) Glucocorticoid elevation of mRNA encoding epinephrine-forming enzyme in lung. Am J Physiol 265:L117-20

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