Beneficial attenuating effect of L-threo-3,4-dihydroxy-phenylserine on postural hypotension in anesthetized rats

The effects of L-threo-DOPS (L-threo-3,4-dihydroxyphenylserine), a non-physiologic precursor amino acid of the natural form of norepinephrine, on postural hypotension were assessed in anesthetized rats. Rats were pretreated with DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine), a norepinephrine-decreasing agent acting on central and peripheral tissues, or hexamethonium, a ganglion-blocking agent. Postural hypotension was induced by 60° head-up tilt for 4 min. L-Threo-DOPS (1-10 mg/kg, i.v.) produced an increase in basal blood pressure and attenuation of the postural hypotension, which persisted in a dose-related manner in rats pretreated with DSP-4 (50 mg/kg, i.p. 24 h prior to the tilt-experiment). Hexamethonium (5 mg/kg, i.v.)-induced postural hypotension was also attenuated dose-dependently by i.p. (3-30 mg/kg)- or p.o. (30 and 100 mg/kg)-administered L-threo-DOPS, associated with an increase in basal blood pressure. Neither attenuation of postural hypotension nor increase in basal blood pressure was observed after L-threo-DOPS (30 mg/kg i.p.) in rats pre-injected with carbidopa (20 mg/kg i.v.), a peripheral aromatic L-amino acid decarboxylase inhibitor, under the hexamethonium pretreatment. The effects of L-threo-DOPS administered by cumulative i.v. infusion (12.5-50 μg/kg/min) on the pressor responses to either spinal sympathetic nerve stimulation (1-10 Hz) or i.v. bolus-injected tyramine were also examined. L-Threo-DOPS dose-relatedly potentiated the pressor response to nerve stimulation in rats either untreated or pretreated with DSP-4 and the pressor response to tyramine in rats pretreated with DSP-4. The extent of the potentiation was very slight but statistically significant, associated with a concomitant increase in basal blood pressure. In conclusion, these results suggest that L-threo-DOPS is effectively converted by decarboxylase to norepinephrine, which in turn exerts a beneficial attenuating effect on postural hypotension through a sustained increase in basal blood pressure, and at least in part through an increase in NE release, upon head-up tilt in anesthetized rats.