Pharmacological effects of (+/-)-11-deoxy, 16-phenoxy-prostaglandin E1 derivatives in the cardiovascular system

M&B 28,767 [(+/-)-11-deoxy-16-phenoxy-17,18,19,20-tetranor prostaglandin E1] and a series of close analogues have been compared with U-46619 [(15S)-hydroxy-11 alpha, 9 alpha-(epoxymethano)-prosta-(5Z,13E)-dienoic acid] for prostaglandin endoperoxide-like pharmacological actions in vitro and in vivo. M&B 28,767 caused powerful dose-related contraction of rabbit aorta (EC50: 2.0 microM) and mesenteric artery (EC50: 0.2 microM) strips in vitro, but was less active than U-46619 and/or noradrenaline. M&B 28,767 induced rapid and irreversible aggregation of rat (0.9 times potency of U-46619) and human (0.25 times potency of U-46619) platelets in platelet-rich plasma (PRP) in vitro. Intravenous administration of M&B 28,767 to urethane-allobarbitone anaesthetized rats produced immediate and dose-related thrombocytopoenia (equipotent with U-46619), accompanied in some animals by transient small pressor effects at low doses (1-2 micrograms kg-1) which were not statistically significant and invariably by sharp depressor effects at higher doses (3-10 micrograms kg-1). U-46619 caused moderate, but not dose-related, pressor effects at all doses tested. Considerable variation in potency occurred amongst the thirteen structural analogues of M&B 28,767. Platelet aggregatory activity for those members of the 11-deoxy 16-phenoxy-PGE1 series tested in rat PRP in vitro demonstrated a positive and significant correlation with pro-aggregatory activity in vivo and agonist potency on rabbit aortic strip in vitro.