Primate vascular responses to octimibate, a non‐prostanoid agonist at the prostacyclin receptor

• Published in: British journal of pharmacology 1991-01, Vol.102 (1), p.260-266
• Main Authors: Merritt, Janet E., Brown, Anthony M., Bund, Stuart, Cooper, David G., Egan, John W., Hallam, Trevor J., Heagerty, Anthony M., Hickey, Deirdre M.B., Kaumann, Alberto J., Keen, Mary, Kelly, Eamonn, Kenney, Cheryl A., Nichols, Andrew J., Smith, Edward F., Swayne, George T.G., MacDermot, John, Rink, Timothy J.
• Format: Article
• Language: English
• Subjects: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adenosine Diphosphate - pharmacology; Animals; Blood Pressure - drug effects; Dose-Response Relationship, Drug; Heart Rate - drug effects; Hemodynamics - drug effects; Humans; Imidazoles - pharmacology; In Vitro Techniques; Lung - drug effects; Lung - enzymology; Lung - metabolism; Macaca fascicularis; Membranes - drug effects; Membranes - enzymology; Muscle Relaxation - drug effects; Muscle, Smooth, Vascular - drug effects; Prostaglandin Endoperoxides, Synthetic - pharmacology; Receptors, Epoprostenol; Receptors, Prostaglandin - drug effects; Sterol O-Acyltransferase - antagonists & inhibitors
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.1991.tb12163.x

1 Octimibate is a potent inhibitor of human platelet aggregation, and appears to act (at least in part) through the prostacyclin receptor, as described in the preceding paper. Here, the vascular effects, both in vitro and in vivo, of octimibate have been compared to those of the stable prostacyclin (PGI2) mimetic, iloprost. Since octimibate shows extensive species variation and is potent at inhibiting platelet aggregation in primates, all of the experiments reported here have been carried out with primate tissue or in vivo in cynomolgus monkeys. 2 Activation of adenylyl cyclase in human lung membranes appears to involve stimulation of the vascular PGI2 receptor. Octimibate, as well as iloprost, stimulates adenylyl cyclase in this preparation. The EC50 values for iloprost and octimibate are 50 nm and 340 nm respectively. These values are similar to those seen with human platelet membranes. As with platelets, the maximal activation achievable with octimibate is 60% of that seen with iloprost. This result suggests that octimibate is a partial agonist for stimulation of adenylyl cyclase. 3 Iloprost (10–100 nm) relaxes human coronary and mesenteric artery precontracted with KC1, and also relaxes cynomolgus monkey aorta precontracted with phenylephrine. Octimibate appears to be a partial agonist for relaxation of human coronary artery precontracted with KC1; the intrinsic activity of octimibate (10 μm) is 0.15 compared to iloprost, and octimibate surmountably antagonizes the relaxant effects of iloprost with a Kp of 200 nm. Octimibate (up to 10 μm) evokes only weak relaxation of human mesenteric artery (precontracted with KC1) and cynomolgus monkey aorta (precontracted with phenylephrine). 4 The effects of iloprost and octimibate were compared in vivo in cynomolgus monkeys. In addition to inhibiting ex vivo platelet aggregation, both compounds cause hypotension with little effect on heart rate. The dose‐response curves for inhibition of ex vivo platelet aggregation and a fall in mean arterial blood pressure were compared. The dose‐separation (i.e., the relative differences in effective concentrations) for the two responses is similar with both iloprost and octimibate. 5 Since the periberal resistance vessels are intimately involved in regulation of systemic arterial blood pressure, the effects of both agents were tested on human peripheral resistance vessels (150–400 μm diameter) in vitro. These vessels are relaxed by both iloprost and octimibate following preco