Background: Prostacyclin (PGI₂) analogues may have potential for use in a novel drug-eluting stent by virtue of an IP receptor mediated, anti-proliferative effect on smooth muscle cells (SMC). We examined the functional response of the pig coronary (PCA) and rabbit iliac artery (RIA) to PGI₂ analogues, and assessed the anti-proliferative potential of these compounds. Methods and Results: 3-4mm length artery rings were precontracted with PGF_2-α (2μM, PCA) or phenylephrine (0.2μM, RIA). Dose response curves were generated by cumulative addition of the PGI₂ analogues, AFP-07 or cicaprost (1nM-1μM), alone or in the presence of the EP₁ or EP₃ receptor antagonists SC51322, and L-798106 respectively (1μM). In PCA, AFP-07 produced a weak biphasic response consisting of a maximum relaxation of 18 ± 3.5% (30nM), followed by a reversal of the initial relaxation. SC51322 and L-798106 potentiated the relaxation response. In RIA, AFP-07 produced a maximum relaxation of 70 ±7% (30nM), followed by partial reversal. The reversal was fully blocked by L-798106, and partially by SC51322. Cicaprost produced near complete relaxation in RIA. SMC proliferation was assessed by [³H]-thymidine incorporation, following 24-hour incubation in 10% or 2% foetal calf serum (FCS). AFP-07 (0.01-1μM) and cicaprost (0.1-1μM) significantly inhibited RIASMC proliferation following 2%FCS stimulation. A reduced anti-proliferative effect was observed in RIASMC stimulated with 10%FCS, and no anti-proliferative effect of cicaprost or iloprost was observed in PCASMC stimulated with 10%FCS. Conclusions: IP receptor agonists have significant actions on EP receptor subtypes in the coronary artery. The rabbit iliac artery is more sensitive to the relaxant, and anti-proliferative effects of PGI₂ analogues, compared to the pig coronary artery. This may, in part, be due to differences in the distribution of the prostanoid IP, EP₁ and EP₃ receptor types within each tissue.