The effects of I5AU8I, a chemically stable prostacyclin analog, on the cardiovascular and renin-angiotensin systems of anesthetized dogs [corrected].
15AU81 is a chemically stable tricyclic benzindene analog of prostacyclin. Prostaglandins, PGI2 and PGE2, and their analogs have demonstrated acute hemodynamic benefit in congestive heart failure. The purpose of this study was to evaluate the cardiovascular effects of 15AU81 in anesthetized dogs in order to assess this agent's potential for clinical study in the treatment of congestive heart failure. Four hour intravenous infusions of 15AU81 at 0.1, 0.3, 1.0, or 3.0 micrograms/kg/min produced dose-dependent decreases in mean arterial blood pressure of 10%, 43%, 55% and 68% respectively with associated decreases in total peripheral resistance of 20%, 32%, 56% and 73%, respectively. 15AU81 dilated the pulmonary circulation; however, the effects of 15AU81 on the pulmonary vascular bed were not dose dependent and not stable over time. Maximal decreases in mean pulmonary artery blood pressure achieved were 9%, 23%, 22%, and 18% with an associated decrease in pulmonary vascular resistance of 9%, 33%, 30% and 23%, at doses of 15AU81 of 0.1, 0.3, 1.0 and 3.0 micrograms/kg/min respectively. The onset of vasodilator effects were rapid, reaching a maximum within 5-10 min with an equally rapid recovery when the infusion was discontinued. Cardiac and hormonal effects associated with 15AU81 treatment included decreases in inotropy, and lusitropy and increases in heart rate and plasma angiotensin II concentration. The increase in plasma angiotensin II concentrated correlated significantly with the decrease mean arterial blood pressure. These effects are interpreted to be generally secondary to the potent and profound vasodilator activity of 15AU81 and not likely due to direct cardiac or neurohumoral effects. The hemodynamic profile of 15AU81 suggests that, through its rapid onset and ability to reduce loading conditions of the right and left ventricles and its chemical stability over natural prostacyclin, this prostacyclin analog may have utility in the management of chronic congestive heart failure.
Steffen
R P
RP
Division of Pharmacology, Wellcome Research Laboratories, Research Triangle Park, NC 27709.
de la Mata
M
M
D000804:Angiotensin II / Q000097:blood; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects*; D004285:Dogs; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D012084:Renin-Angiotensin System / Q000187:drug effects*; D014655:Vascular Resistance / Q000187:drug effects
D000804:Angiotensin II