Peripheral dopamine receptors in the antihypertensive action of dihydroergotoxine in humans.

Abstract

The effect of the intravenous administration of dihydroergotoxine (6 .mu.g/kg) on arterial blood pressure, heart rate, and plasma concentrations of norepinephrine and 3,4-dihydroxyphenylacetic acid (the deaminated dopamine metabolite) was studied in 20 subjects with essential hypertension (8 men and 12 women aged 32-68 years old, World Health Organization Class I-II). In supine resting subjects, dihydroergotoxine significantly decreased systolic blood pressure (from 175 .+-. 5 to 156 .+-. 4 mm Hg; p < 0.001), diastolic blood pressure (from 109 .+-. 4 to 95 .+-. 3 mm Hg; p < 0.001), and heart rate (from 71 .+-. 2 to 63 .+-. 2 beats/min; p < 0.001) as compared with the results of placebo treatment. Moreover, dihydroergotoxine reduced plasma levels of norepinephrine (from 368 .+-. 39 to 238 .+-. 33 pg/ml; p < 0.001) and 3,4-dihydroxyphenylacetic acid (from 1.57 .+-. 0.21 to 1.22 .+-. 0.13 ng/ml; p < 0.01). The time course of the blood pressure decrease paralleled that of plasma norepinephrine concentration. Dihydroergotoxine did not suppress the cardiovascular and plasma norepinephrine response to standing. The effect of domperidone, a peripheral presynaptic dopamine receptor antagonist, on dihydroergotoxine response was studied in six of the 20 subjects (3 men and 3 women 48-64 years old). The intravenous administration of domperidone (0.3 mg/kg) prevented the dihydroergotoxine-induced reduction in blood pressure and heart rate and the fall in plasma norepinephrine and 3,4-dihydroxyphenylacetic acid levels. Domperidone administered alone failed to significantly modify any measured variables. These results suggest that the antihypertensive effect of dihydroergotoxine can be mediated by the inhibition of norepinephrine release from peripheral sympathetic nerves secondary to the activation of presynaptic dopamine receptors.