Ex vivo studies after oral treatment of the beagle with dihydroergotamine

Abstract

Plasma concentrations of unchanged dihydroergotamine (DHE) were measured in beagle dogs on days 1 and 7 of a 1 week treatment with daily oral doses of DHE. Responses to both 5-HT and noradrenaline were monitored isometrically on spiral strips from saphenous arteries and femoral veins removed 24 and 72 h after the last oral dosage of DHE. Femoral vein strips were removed from dogs treated for 1 week with daily doses of 0.60 mg/kg DHE p.o. and suspended in organ baths. When stretched to an initial tension of 500 mg, such strips relaxed significantly less than strips taken from control beagles. Furthermore, the vasoconstrictor potencies of both 5-HT and noradrenaline were significantly increased on strips from femoral veins but not on strips from saphenous arteries removed from DHE-treated beagles. About 210 min after suspension in organ baths, femoral vein strips from DHE-treated dogs developed spontaneously an increase in basal tone, a phenomenon which was not observed with saphenous arteries. It is suggested that sensitization of venous smooth muscle to the constrictor activities of endogenous catecholamines and 5-HT contributes to the venoconstrictor activity of DHE. Moreover, the pharmacologic action of orally administered DHE, as assessed by the ex vivo measured changes in sensitivity of vein strips, requires peak plasma levels of more than 0.30 ng/ml. However, the duration and maintenance of the venoconstrictor response is largely independent from continuously elevated plasma DHE levels.