Salutary effects of CG-4203, a novel, stable prostacyclin analog, in hemorrhagic shock.
Prostacyclin (PGI2) is a potent vasodilator, an inhibitor of platelet aggregation, and a membrane-stabilizing agent that has been shown to exert beneficial effects in a variety of models of ischemia and circulatory shock. However, the use of PGI2 is limited by its instability and rapid biodegradation. We studied the effects of a novel, stable prostacyclin analog, CG-4203, in a murine model of hemorrhagic shock. Hemorrhaged rats treated with CG-4203 maintained postreinfusion mean arterial blood pressure (MABP) at significantly higher values than rats receiving only the vehicle (final MABP 101 +/- 3 vs. 75 +/- 5 mm Hg, p less than 0.01). CG-4203 was also found to attenuate the increase in plasma cathepsin D activity (p less than 0.01), as well as the plasma accumulation of free amino-nitrogen compounds (p less than 0.05). Furthermore, the plasma activity of a myocardial depressant factor (MDF) was significantly lower in CG-4203-treated hemorrhaged rats than in rats receiving the vehicle (25 +/- 2 vs. 54 +/- 7 U/ml, p less than 0.01). In addition, CG-4203 exerted an anti-proteolytic action in pancreatic homogenates and inhibited platelet aggregation in platelet-rich plasma. However, CG-4203, at concentrations expected during treatment of shock, failed to have an immediate or delayed vasodilator effect in rat aortic rings, and thus vasodilation is not an important aspect of the antishock effects of CG-4203. Our results suggest that inhibition of platelet aggregation, as well as the antiproteolytic and membrane-stabilizing actions, could mediate the beneficial effects of CG-4203 in hemorrhagic shock.
Bitterman
H
H
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Smith
B A
BA
Lefer
D J
DJ
Lefer
A M
AM
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002415:Cats; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D066298:In Vitro Techniques; D008297:Male; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D011480:Protease Inhibitors; D051381:Rats; D011919:Rats, Inbred Strains; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000503:physiopathology; D013152:Splanchnic Circulation / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
D011480:Protease Inhibitors; C039188:taprostene; D011464:Epoprostenol