THE METABOLISM OF CIRCULATING NOREPINEPHRINE BY HUMAN SUBJECTS

Seven physically healthy young men were infused continuously with dl -norepinephrine-7- 3 H (specific activity = 8.521 ± 0.319 c/mM) at a rate of 1.92 µ/hr for a 48-hour period which for the average subject was the equivalent of L838 µg/48 hr. Urine specimens were collected at periodic intervals during the infusion and for 48 hours after its cessation. Data are presented which indicate that somewhere between 12 and 24 hours after the beginning of the infusion the system was very near an isotopic steady state and that approximately 15 hours after cessation of the infusion the 3 H-norepinephrine (NE) had mixed homogeneously with the endogenous circulating NE and those pools with which this compartment is in equilibrium. It was found that even though homogeneous mixing, as defined above, had occurred the specific activities of both urinary 3-methoxy-4-hydroxymandelic acid (VMA) and 3-methoxy-4-hydroxyphenolglycol (MHPG) were lower by at least a factor of 10 than the specific activities of urinary NE and normetanephrine (NM). Estimates taken from earlier work and parameter values obtained from data presented in this report were used to calculate the expected quantifies of urinary metabolites due to circulating NE and those pools with which it is in equilibrium. It was found that all of the endogenous urinary free NE, conjugated NE and NM could be accounted for by metabolism of the circulating NE and those pools with which it is in equilibrium. In contreat, most of the endogenous urinary VMA and MHPG appear to originate in pools which, relative to their total rates of norepinephrine synthesis or size, are penetrated poorly or not at all by circulating NE. Possible candidates for these poorly penetrated compartments are brain (articularly as a potential source of MHPG), adrenal medulla and intraaxonal NE. Given the correctness of the assumption that almost all of the circulating NE is derived from NE released at sympathetic nerve endings it is suggested that assays of urinary total NE + total NM should give a good, albeit indirect, measure of sympathetic nerve activity.