Abstract

Administration of 5-dimethyldithiocarbamylpicolinic acid (YP-279), an inhibitor of dopamine- β-hydroxylase, caused selective reduction of peripheral norepinephrine (NE) biosynthesis and reduced the blood pressure of spontaneously hypertensive rats, as well as normotensive rats, but had no effect on brain NE biosynthesis. YP-279, which does not appear to cross the blood-brain barrier, did not affect either stress-induced gastric ulcer or ethanol-induced sleeping time, both of which are thought to he mediated through the central nervous system. Evidence that YP-279 is a selective inhibitor of the peripheral dopamine-β-hydroxylase is 1) that the conversion of ³H-dopamine into ³H-NE in rat brains was not inhibited by intraperitoneal injection of this compound, but the conversion of ³H-dopamine into ³H-NE in rat hearts was effectively inhibited and 2) that this inhibitor could not be detected in the brain after its intraperitoneal administration, but could be detected in other tissues. In contrast, 5-butylpicolinic acid and its derivatives (analog of YP-279), which also inhibit dopamine-β-hydroxylase, that do pass the bloodbrain barrier exhibited all of the positive effects indicated above as well as abilities to prevent stress-induced gastric ulcers and to prolong ethanol-induced sleep. 5-Butylpicolinic acid and its derivatives, except for YP-279, were found in brain and peripheral tissues. They also inhibited the conversion of ³H-dopamine into ³H-NE in the brain as well as in other tissues.