Novel mechanism of action of a prostacyclin enhancing agent in haemorrhagic shock.
Prostacyclin (PGI2) is a potent vasodilator, an inhibitor of platelet aggregation, and a membrane stabilizing agent with beneficial effects in ischemia and shock. We studied defibrotide, a new agent which enhances PGI2 release from vascular tissue, to determine its effects in a murine model of hemorrhagic shock. Hemorrhaged rats treated with defibrotide maintained post-reinfusion mean arterial blood pressure (MABP) at significantly higher values compared to rats receiving the vehicle (final MABP, 100 +/- 3 vs. 69 +/- 7 mm Hg, p less than 0.01). Defibrotide attenuated the release of the lysosomal hydrolase cathepsin D (p less than 0.02), and the plasma accumulation of free amino-nitrogen groups (p less than 0.02). The plasma activity of a myocardial depressant factor (MDF) was significantly lower in defibrotide treated shocked rats than in the vehicle group (29 +/- 4 vs. 61 +/- 8 U/ml, p less than 0.01). Moreover, plasma i6-keto-PGF1 alpha concentrations increased 3-fold above haemorrhaged rats receiving only the vehicle. This, as well as the improved MABP, was abolished by indomethacin. Additionally, defibrotide exerts an anti-proteolytic action in pancreatic homogenates, and a lysosomal stabilizing effect in large granule fractions of rat liver homogenates. Moreover, defibrotide enhanced the recovery from norepinephrine induced vasoconstriction in rat aortic rings having an intact endothelium (p less than 0.01 from vehicle), and augmented the release of i6-keto-PGF1 alpha, the stable metabolite of PGI2, from isolated rat aortae. Our results indicate that enhancement of endogenous vascular PGI2 release coupled with direct, or PGI2 mediated antiproteolytic and membrane stabilizing actions may be important physiological mechanisms counteracting the deleterious effects of hemorrhagic shock.
Bitterman
H
H
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
Lefer
D J
DJ
Lefer
A M
AM
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D011464:Epoprostenol / Q000502:physiology*; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D008099:Liver / Q000502:physiology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009638:Norepinephrine / Q000494:pharmacology; D010179:Pancreas / Q000502:physiology; D010974:Platelet Aggregation / Q000187:drug effects; D011089:Polydeoxyribonucleotides / Q000627:therapeutic use*; D051381:Rats; D011919:Rats, Inbred Strains; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000503:physiopathology; D013997:Time Factors
D005343:Fibrinolytic Agents; D011089:Polydeoxyribonucleotides; C036901:defibrotide; D000244:Adenosine Diphosphate; D011464:Epoprostenol; D009638:Norepinephrine