Partial agonist activity of the prostacyclin analogue taprostene on vascular preparation from guinea-pig, rat and mouse R .L. Jones & K.M. Chan. Department of Pharmacology, The Chinese University of Hong Kong, Hong Kong SAR, China.	Print Abstract Search PubMed for: Jones RL Chan KM

The prostacyclin analogue taprostene (Schneider et al., 1993) may be a partial agonist at prostanoid IP receptors in blood vessel preparations from pig and rabbit. However, it is difficult to analyse its interactions with putative full agonists (AFP-07, TEI-9063 and cicaprost) owing to the actions of these agents on highly sensitive EP₃ (constrictor) and EP₄ (dilator) systems present in the preparations (Jones & Chan, 2001). We now report attempts to resolve this issue.

Ring preparations of saphenous vein, tail artery and thoracic aorta from male guinea-pigs (Dunkin-Hartley, 450 g), rats (Sprague-Dawley, 200g) and mice (BALB/c, 30 g) respectively were suspended in Krebs-Henseleit solution (95% O₂/5% CO₂) at 37°C in a Mulvaney-style myograph. Tone was induced with 3 µM phenylephrine on saphenous vein and 0.1 µM U-46619 (0.1 µM nifedipine) on tail artery, while 0.05 µM phenylephrine/0.3 µM sulprostone was used to activate the EP₃ contractile system in mouse aorta. The EP₄ antagonist AH 23848 (30 µM) (Coleman et al., 1994) was present for guinea-pig saphenous vein and the TP antagonist GR 32191(Lumley et al., 1989) for saphenous vein (0.2 µM) and aorta (1.0 µM). DP, EP₁, EP₃ (except mouse aorta) and FP prostanoid receptor systems were not identified in the preparations. The potency ranking for relaxation was AFP-07 > TEI-9063 > cicaprost > taprostene on each preparation. Taprostene had IC₅₀ values of 0.10, 0.27 and 0.40 µM and Emax values of 40, 33 and 33% on saphenous vein, tail artery and aorta respectively. With 3 µM taprostene present, log concentration-response curves for the prostacyclin analogues, but not PGE₂, were right-shifted (Table 1). The antagonisms were surmountable, except for TEI-9063 on mouse aorta; dose ratios are given in Table 1.

Table 1 Antagonism of vasorelaxant effects by taprostene.

* Experimental curve versus theoretical addition curveRelaxations induced by the selective EP₂ agonist ONO-AE1-259 (Cao et al., 2002) on saphenous vein (IC₅₀ = 15 nM) and isoprenaline on tail artery (IC₂₅ = 150 nM) and aorta (IC₅₀ = 360 nM) were unopposed by 3 µM taprostene.

Our experiments support taprostene acting as a partial agonist at IP receptors in vascular preparations from several species. Further structure-activity studies are in progress.

Cao J et al (2002). Eur J Pharmacol., 442, 115-123.
Coleman RA et al (1994). Prostaglandins, 47, 151-168.
Jones RL & Chan KM (2001). Br J Pharmacol., 134, 313-324.
Lumley P et al (1989). Br J Pharmacol., 97, 783-794.
Schneider J et al(1993). Cardiovasc Drug Rev 11, 479-500.

Gifts of taprostene frpm Grünenthal GmbH, TEI-9063 from Teijin Ltd., AFP-07 from Asahi Glass Co., cicaprost from Schering AG, and ONO-AE1-259 from ONO Pharmaceutical Co. are appreciated. Supported by a Central Allocation Grant: CA 99/000.SC01.