Catecholamine biosynthesis and blood pressure

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We found that phenylethanolamine N-methyltransferase (PNMT), the enzyme that synthesizes epinephrine, is involved in many functions outside the adrenal. PNMT is expressed early in cardiac development, and can be induced in the heart by glucocorticoids. PNMT is also present in specific nerve cells of the brain which participate in blood pressure control and temper activation of the sympathetic nervous system. The investigators have developed a PNMT knockout mouse. This mouse provides excellent histologic localization of PNMT expressing cells in both heart and brain. This mouse will be used to map the fetal expression of PNMT during ontogeny and to define the cardiac cells that express PNMT during development. The mouse will be cross-bred to develop a conditional knock-out of catecholamine production in PNMT expressing cells. This conditional knockout animal will be studied to determine if cardiac expression of catecholamines in these cells is essential for fetal cardiac development, since animals that cannot make any catecholamines die with abnormal hearts. Initial studies find the PNMT knockout mouse to be hypertensive. Studies will define chronic and stress blood pressures of these mice and will investigate the hypothesis that a failure of epinephrine production in the brain disinhibits sympathetic nerve activity leading to hypertension. Initial studies find increased sympathetic nervous activity in human subjects who carry a polymorphism of the PNMT promoter that leads to low levels of expression of the gene. Human studies will define basal and stressed levels of autonomic acitivity in subjects with high and low expressing polymorphisms of the PNMT gene and measure basal blood pressures and blood pressure responses to stressors in these subjects. The parallel human and animal studies should provide a complementary understanding of the important role of the PNMT gene in autonomic and cardiovascular physiology.