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), EP(1) (SC-51322) and EP(3) (L-798106) receptors were used to characterise the receptors involved. The effects of these agents on proliferation ([(3)H]-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 EP(3) 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 EP(3) receptors (and possibly prostanoid EP(1) receptors) compromises the relaxant activity of prostacyclin analogues, although it does not reduce the anti-proliferative capacity of these compounds in the model studied.

01 Apr 2005·Prostaglandins, Leukotrienes and Essential Fatty AcidsQ3 · MEDICINE

Investigation of the agonist activity of prostacyclin analogues on prostanoid EP4 receptors using GW 627368 and taprostene: Evidence for species differences

Q3 · MEDICINE

Article

Author: K.M. Chan ; R.L. Jones

The possibility that the prostacyclin analogues AFP-07 and cicaprost relax saphenous vein preparations of pig, guinea-pig and rabbit by simultaneously activating prostanoid EP4 and IP (prostacyclin) receptors was investigated using the high-affinity EP4 antagonist GW 627368. The IP receptor system in each preparation was suppressed with the partial agonist taprostene. The results indicate that AFP-07 and cicaprost are moderately potent EP4 agonists on pig saphenous vein, but much weaker EP4 agonists on guinea-pig saphenous vein. GW 627368 did not antagonise AFP-07- and cicaprost-induced relaxation of rabbit saphenous vein, which contrasts with a previous study using the EP4 blocker AH 23848. However, treatment with taprostene was of less value due to poorer antagonism of the rabbit IP system; this may be related to the presence of a sensitive EP2 relaxant system. Relaxation of each preparation induced by the selective EP2 agonist ONO-AE1-259 was unaffected by GW 627368, with and without taprostene.

01 Jun 2004·Journal of Cardiovascular PharmacologyQ4 · MEDICINE

Partial Agonism of Taprostene at Prostanoid IP Receptors in Vascular Preparations from Guinea-Pig, Rat, and Mouse

Q4 · MEDICINE

Article

Author: Robert L Jones ; Kam-ming Chan

This study investigates whether incomplete relaxation of vascular smooth muscle preparations induced by the prostacyclin analogue taprostene is due to partial agonism at prostanoid IP receptors. In the presence of the prostanoid EP4 receptor antagonist AH 23848, 3 microM taprostene induced 45% relaxation of phenylephrine-contracted guinea-pig saphenous vein rings and displaced log concentration-response curves for the prostacyclin analogues AFP-07, TEI-9063, and cicaprost to the right, parallel to their predicted addition curves. In contrast, taprostene interacted additively with prostaglandin E2 (PGE2), ONO-AE1-259 (selective EP2 agonist), and acetylcholine. Similarly, on rat tail artery contracted with phenylephrine, 3 microM taprostene (20% relaxation) opposed AFP-07- but not PGE2-induced relaxation. However, under U-46619-induced tone (AH 23848 absent), taprostene antagonized AFP-07 and cicaprost more than TEI-9063, suggesting that the latter has more than one relaxation mechanism. The presence of a sensitive EP3 contractile system in mouse aorta interfered with IP receptor-mediated relaxation. By generating tone with phenylephrine and the potent EP3 agonist sulprostone, it was possible to show that 3 microM taprostene (15% relaxation) selectively opposed relaxations induced by AFP-07, TEI-9063, and cicaprost. Our experiments indicate that taprostene is a partial agonist at prostanoid IP receptors, and may be a lead to an IP receptor antagonist.

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Indication	Highest Phase	Country/Location	Organization	Date
Arteriosclerosis	Discovery	JP	AGC Biologics, Inc.	-
Myocardial Infarction	Discovery	JP	AGC Biologics, Inc.	-
Thromboembolism	Discovery	JP	AGC Biologics, Inc.	-

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