Modulation of vasoconstriction by clopidogrel and ticlopidine.

Clopidogrel is an antiplatelet drug which has undergone extensive clinical trials in the management of stroke and other arterial disorders related to platelet activation. This agent is believed to produce the inhibition of ADP mediated direct and indirect actions leading to platelet adhesion/aggregation and other activation processes. Several other observed pharmacologic actions suggest that this drug may have additional sites of action. Ticlopidine also belongs to the same class of ADP receptor inhibitors and is extensively used for stroke prevention. To study the vasomodulatory action of clopidogrel and ticlopidine, the drugs were administered intravenously into canines at a dose of 10 mg/kg. Thirty minutes later femoral and pulmonary arteries were removed and taken for isolated tissue preparations. The intravenous injection of clopidogrel and ticlopidine caused significant vasomodulatory actions in both femoral and pulmonary ring preparations showing a marked desensitization to serotonin, endothelin-1, serum, and platelet rich plasma/arachidonic acid mixtures. In contrast, when the drugs were added directly to the organ bath containing femoral or pulmonary ring preparations from untreated animals, both clopidogrel and ticlopidine did not produce any effect on contractile response induced by serotonin, endothelin-1, serum, and platelet rich plasma/ arachidonic acid mixtures. These data suggest that endogenous transformation of clopidogrel and ticlopidine plays an important role in producing their vasomodulatory actions. Furthermore, these observations indicate that both clopidogrel and ticlopidine also modulate the vascular sites which may be contributory to the observed clinical effects.