The orally active thia-imino-prostacyclin Hoe 892: antiaggregatory and cardiovascular activities.
The short chemical half-life limits the potential therapeutic value of Prostacyclin (PGI2). Replacement of the acid-labile enolether structure of PGI2 by a beta-thia-imino group resulted in the orally active and chemically stable analogue Hoe 892. Incubation of rabbit platelet rich plasma with PGI2 and Hoe 892 caused a dose dependent inhibition of collagen and arachidonic acid (AA) induced platelet aggregation with ID50 of 4.2 and 20.1 ng/ml for PGI2 respectively 43.3 and 170.2 ng/ml for Hoe 892. These effects could be potentiated by the phosphodiesterase inhibitor theophylline. Single oral administration of Hoe 892 in conscious rabbits inhibited platelet aggregation for more than 3 hrs with an ID50 of 0.2 mg/kg using collagen and 1.5 mg/kg using AA. These doses were without influence on systemic blood pressure (BP) in conscious rabbits. Intravenous injection of Hoe 892 induced a dose dependent decrease of systemic BP in anesthetized rats (ED25 of 2.2 micrograms/kg) and in the rats with acute renal hypertension. Hoe 892 stimulated renin release in anesthetized rats. The hemodynamic profile in anesthetized dogs (0.5 micrograms/kg/min i.v.) was characterized by a decrease of systemic BP, left ventricular pressure, pulmonary artery pressure, total peripheral resistance and in increase in heart rate, cardiac output and dp/dt max, thus demonstrating arteriolar vasodilation. In conscious dogs with two kidney, two wrapped hypertension oral treatment for 1 or 5 days resulted in a marked reduction of BP.
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D003094:Collagen / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D011464:Epoprostenol / Q000494:pharmacology* / Q000031:analogs & derivatives; D005260:Female; D006439:Hemodynamics / Q000187:drug effects*; D006977:Hypertension, Renal / Q000503:physiopathology; D007700:Kinetics; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects*; D011453:Prostaglandins / Q000494:pharmacology*; D011817:Rabbits; D012083:Renin / Q000097:blood
D001095:Arachidonic Acids; D011453:Prostaglandins; D016718:Arachidonic Acid; C037638:HOE 892; D003094:Collagen; D011464:Epoprostenol; D012083:Renin