Pharmacological actions of the main metabolites of dihydroergotamine

Dihydroergotamine (DHE) and 5 of its main metabolites, namely 8'-hydroxy-dihydroergotamine (8'-OH-DHE), 8',10'-dihydroxy-dihydroergotamine (8',10'-OH-DHE), 2,3seco,N(1)formyl,3-keto,8'-hydroxy-dihydroergotamine (8'-OH,N(1)formyl-DHE), dihydrolysergic acid amide (DH-LSA) and dihydrolysergic acid (DH-LS) were investigated on human and canine veins in vitro, on canine veins in situ, and in the ganglion-blocked rat in vivo. Like DHE, the metabolites 8'-OH-DHE, 8', 10'-OH-DHE and DH-LSA caused constriction of human varicose veins and only weak alpha-adrenoceptor blockade. On canine femoral vein strips the same compounds produced predominantly alpha-adrenoceptor blockade and only negligible stimulation. 8'-OH,N(1)formyl-DHE and DH-LS were largely inactive. The same compounds, which were agonists on human vein strips in vitro, induced dose-dependent reduction of venous compliance when infused locally into the dog saphenous vein in situ. In the ganglion-blocked rat, only 8'-OH-DHE and 8',10'-OH-DHE besides the parent drug produced an increase in diastolic blood pressure when injected intravenously. It is concluded that DHE metabolites with considerable venoconstrictor activity may contribute to the selective therapeutic action of DHE.