Effects of a false neurotransmitter, p-hydroxynorephedrine, on the function of adrenergic neurons in hypertensive patients

Abstract

Previous studies have shown that amphetamine and p-hydroxyamphetamine impair adrenergic transmission, and it has been suggested that this effect is mediated by an active metabolite, p-hydroxynorephedrine (PHN). Studies in experimental animals have shown that PHN can deplete and substitute for norepinephrine (NE) in the transmitter pool, thus meeting the criteria of a false neurotransmitter. The pharmacologic effects of PHN on adrenergic function and NE synthesis were studied in eight hypertensive patients and compared with placebo. Mean erect and supine blood pressure (BP) decreased 22/14 and 9/6 mm Hg, respectively, during PHN 600 mg daily. The post-Valsalva diastolic overshoot was abolished. The pressor sensitivity to tyramine decreased whereas the pressor response to NE was enhanced. A mild natriuresis occurred. The 24 h urinary excretion of catecholamines and catecholamine metabolites during the administration of PHN compared with placebo changed as follows: vanillylmandelic acid (VMA), 42% decrease; NE. 42% decrease; normetanephrine (NM), 400% increase: metanephrine, unchanged; dopamine, 40% decrease; while homovanillic acid was unchanged. The sum of VMA, NE, and NM decreased 23%. The posttreatment urinary excretion of PHN was biexponential with first and second phase half-lives of 13 and 55 h. respectively. The time of the second phase closely approximated the recovery of the changes in BP and excretion of VMA. No effects of PHN on the central nervous system were observed. These studies show that PHN acts peripherally to interfere with adrenergic function and NE synthesis in hypertensive patients with a resultant decrease in BP.