Influence of systemically given placebo, trapidil and isosorbide dinitrate on norepinephrine-evoked hand vein constriction in healthy subjects.

Since trapidil (CAS 15421-84-8) is able to dilate human hand veins after local intravenous administration, four studies were carried out in healthy male volunteers using the dorsal hand vein compliance technique to test the influence of common systemic single doses of trapidil (200 mg orally, 100 mg intravenously) and isosorbide dinitrate (CAS 87-33-2, 20 mg orally) on norepinephrine (CAS 51-41-2)-evoked hand vein constriction in comparison with oral placebo. Oral placebo and oral trapidil were studied in a randomized double-blind cross-over design in 10 subjects aged 20 to 30 years, and oral isosorbide dinitrate and intravenous trapidil, in a randomized open cross-over design in 8 subjects aged 22 to 29 years. In the three similar studies with oral medications dose-response curves for venoconstriction by locally infused norepinephrine were established before and 1 h, 2 h and 3 h after oral medication and ED50 values of norepinephrine were calculated. The control dose-response curves and ED50 values of norepinephrine did not differ significantly. After oral placebo administration the dose-response curves of norepinephrine did not change significantly, but the ED50 of norepinephrine increased 3 h after placebo (from 12.1 to 31.7 ng/ min), indicating a lessening in norepinephrine effect at this time. After oral trapidil application the dose-response curves of norepinephrine shifted to the left compared with the pre-treatment curve (significantly 2 h after trapidil) and the corresponding curves after placebo with a significant decrease in the ED50 of norepinephrine 3 h after trapidil compared with placebo (from 31.7 to 12.6 ng/ min). After oral isosorbide dinitrate administration the dose-response curves of norepinephrine did not differ significantly from the pre-treatment curve, but they shifted to the left compared with the corresponding curves after placebo (significantly 3 h after isosorbide dinitrate). The ED50 of norephinephrine decreased significantly 2 h after isosorbide dinitrate compared with the pre-treatment value (from 9.4 to 3.3 ng/min) as well as 1 h, 2 h and 3 h after isosorbide dinitrate compared with placebo (from 32.4/21.3/31.7 to 7.3/3.3/6.0 ng/min). Therefore, oral trapidil and isosorbide dinitrate did not weaken norepinephrine-evoked hand vein constriction as expected but strengthened it slightly. Intravenously given trapidil led only to an insignificant short decrease followed by an insignificant increase in permanent venoconstriction due to local norepinephrine infusion. The data suggest that after systemic administration of trapidil or isosorbide dinitrate a hand vein constriction, which could be a reflex consequence of a drug-induced decrease in central venous pressure, exceeds an only discreet direct hand vein dilation.