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 μM 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 μM 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 μM 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.
From the Department of Pharmacology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.
Received for publication November 19, 2003; accepted February 27, 2004.
This work was supported by a Central Allocation Grant (CA99/00.SC01) from the Research Grants Council of Hong Kong.
Reprints: Professor R.L. Jones, Department of Pharmacology, Basic Medical Sciences Building, Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China (e-mail: firstname.lastname@example.org).