Inhibition of Dopamine β-Hydroxylase in Blood Vessels by Picolinic Acid Derivatives in vivo and their Antihypertensive Effects

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Abstract
The effect of picolinic acid derivatives, 5-butylpicolinic (fusaric) acid (FA), 5-(3'',4''-dibromobutyl)picolinic acid(Br2FA) and 5-(N.cntdot.N-dimethyldithiocarbamoylmethyl)picolinic acid (YP-279) on dopamine .beta.-hydroxylase in blood vessels in vivo was studied. Maximum inhibition of the conversion of 14C-dopamine (14C-DA) to 14C-norepinephrine (14C-NE) in rat aorta, mesenteric artery and renal artery was detected 30 min after FA and Br2FA (75 mg/kg) and 60 min after YP-279 (75 mg/kg). NE synthesis from 14C-DA returned to near control values by 6 h in the blood vessels. NE levels of the aorta and mesenteric artery were significantly reduced by 30-50% at 4 h after Br2FA or FA (75 mg/kg). Dopamine .beta.-hydroxylase (DBH) activity, using tyramine as substrate, in heart, aorta, mesenteric artery and renal artery was markedly reduced. The concentrations of FA, Br2FA and YP-279 in rat blood following a single i.p. injection of each drug increase rapidly, reaching highest values in 0-30 min and decreasing slowly to 0 after 6 h. These compounds did not affect the uptake of 3H-NE into the rat heart. These 3 compounds lowered blood pressure effectively in normal Wistar rats (above 25 mg/kg).