Dihydroergotamine: Pharmacokinetics, Pharmacodynamics, and Mechanism of Venoconstrictor Action in Beagle Dogs

Dihydroergotamine (DHE) elicits selective and long-lasting venoconstrictor activity, although the drug disappears rapidly from the blood. Therefore, a comparative study on the pharmacokinetic and pharmacodynamic properties of DHE was performed in beagle dogs. In addition, the mechanism of the venoconstrictor activity of DHE was investigated in vivo. Changes in the diameter of the saphenous vein and plasma level–time curves of DHE and its metabolites were determined in conscious beagle dogs. After both intravenous and oral administrations of DHE, the venoconstrictor response is of markedly longer duration than would be expected on the basis of the half-life for elimination of DHE from blood. The experimental data support the suggestion that the long duration of the DHE-induced venoconstriction is due (a) to an extremely slow dissociation of the drug from its receptor sites on the venous smooth muscle cell, and (b) to the formation of active metabolites. Using the antagonists ketanserin, pizotifen, and rauwolscine, evidence is presented that the venoconstrictor activity of DHE is mediated through stimulation of 5-HT receptors; there is no evidence of involvement of a-adrenoceptors.