Activation of prostanoid EP receptors by prostacyclin analogues in the rabbit iliac artery: implications for anti-restenotic potential?

Prostacyclin analogues have the potential to be effective agents in a new generation of drug-eluting stents by virtue of prostanoid IP receptor mediated anti-proliferative effects on smooth muscle cells. However, prostanoid IP receptor mediated vessel relaxation is reduced at elevated analogue concentrations. The mechanisms underlying this loss of activity are unclear, and its influence on the anti-proliferative potential of these compounds remains to be determined. A classical organ bath approach was used to examine the functional response of the rabbit iliac artery to the prostacyclin analogues, AFP-07 and cicaprost. Selective receptor antagonists for prostanoid IP (RO-1138452), EP1 (SC-51322) and EP3 (L-798106) receptors were used to characterise the receptors involved. The effects of these agents on proliferation ([3H]-thymidine incorporation) of rabbit iliac artery smooth muscle cells stimulated by foetal calf serum were then studied. AFP-07 gave a bell-shaped log concentration-response curve consisting of prostanoid IP receptor mediated relaxation followed by reversal at higher concentrations. SC-51322 and L-798106 potentiated this relaxation, although only L-798106 completely removed the contractile element. The prostanoid EP3 receptor agonist, sulprostone, produced constriction, which was attenuated by L-798106. RO-1138452 blocked the inhibitory action of AFP-07 and cicaprost on proliferation, implicating an involvement of prostanoid IP receptors. L-798106 had no effect on the anti-proliferative effect of cicaprost, but reduced the effect of AFP-07. Non-selective activation of prostanoid EP3 receptors (and possibly prostanoid EP1 receptors) compromises the relaxant activity of prostacyclin analogues, although it does not reduce the anti-proliferative capacity of these compounds in the model studied.