It has been suggested that ticlopidine may act to sensitize platelets to the effects of anti-aggregatory prostaglandins ( I2, E1, D2) or enhance endogenous production of such PG’s. Rats (male, Sprague Dawley, 280-575g, Simonsen, Gilroy, CA) or guinea pigs, (male, Hartley strain, 330-410g, Simonsen) were dosed o rally with ticlopidine hydrochloride (RS 99847) at 100 mg/kg for 3 days. At 2h following the final dose, platelet function (ADP-induced aggregation, retention by glass beads) was examined within 5 min of blood withdrawal via the abdominal aorta. In rats chronically maintained on a fat-free diet, there is a deficiency in tissue levels of essential fatty acid (EFA) precursors for PG biosynthesis. Consequently, a marked (∼90%) reduction in platelet PG production and vascular PGI2 production was seen. Under such conditions, administration of ticlopidine hydrochloride inhibited platelet function in a manner indistinguishable from that in control animals. Similarly, in both guinea pig and rat, intraperitoneal administration of indcmethacin (100 mg/kg) lh before the final dose of ticlopidine failed to interfere with the anti-plate let effects of ticlopidine, even though vascular PGI2 production (in thoracic aorta) was shown to be virtually abolished. It is concluded that EFA’s and their PG metabolites are not necessary for the platelet inhibitory effects of ticlopidine to be exerted.
Dilator actions of endothelin in coronary resistance vessels and the abdominal aorta of the guinea pig