Location, development, control, and function of extraadrenal phenylethanolamine N-methyltransferase.

Phenylethanolamine N-methyltransferase (PNMT) methylates norepinephrine (NE) to form epinephrine (E). It is present in a high concentration in the adrenal medula but occurs in many other tissues throughout the body. In the brain stem and retina PNMT is present in specific neurons. Cardiac PNMT develops early in the fetal heart and is found in relatively high levels in the adult left atrium. Intrinsic cardiac adrenergic cells are distributed throughout the adult myocardium and contain all the enzymes necessary for E synthesis. The PNMT gene promoter region contains a glucocorticoid response element; however, the initial development of brain and cardiac fetal PNMT is glucocorticoid independent. Rat fetal heart PNMT peaks at embryonic day 11 and becomes sensitive to glucocorticoid induction by day 12. PNMT-containing cells are concentrated in the atrioventricular canal and interventricular septum during cardiac development, areas important in the development of the cardiac conduction system. In the adult rat, cardiac PNMT is inducible by glucocorticoids and synthesizes E. Glucocorticoids are essential for development of the high levels of PNMT in the adrenal, but are less important outside the adrenal. The PNMT gene contains 3 exons and 2 introns. Adrenal PNMT mRNA exists as a single type, but in the heart PNMT mRNA is present as both an intronless and an intron-containing type. In some cardiac tissues, glucocorticoids decrease levels of intron-containing PNMT mRNA and increase intronless PNMT mRNA and PNMT activity. Studies in adrenalectomized animals suggest that extraadrenal PNMT increases blood pressure, blood glucose, and lymphocyte cytokine production. PNMT may also play a role in the regulation of fetal heart rate prior to development of the adrenal medulla.