Inhibitors of endogenously‐formed carbon monoxide arrest bleeding and confer protection in a model of severe hepatic injury

Uncontrolled bleeding contributes to morbidity and mortality after massive soft tissue trauma. As endogenously formed carbon monoxide (CO) promotes relaxation of vascular smooth muscle, but inhibits the NOSs, we wanted to examine the possibility that CO blockade might preferentially constrict vessels with endothelial damage and limit blood loss during massive hepatic trauma. Experiments used adult male SD rats. To determine the isolated effects of the endothelium on CO blockade, experiments were conducted in isolated gracilis arterioles (60 mmHg). In intact vessels (n=6) with a 1.5 mmHg gradient (36±4 μL/min), introduction of CrMP (chromium mesoporphyrin, 15μmol/L) ‐to block CO production‐ produced a 19±1 μm dilation, but caused a 50% decrease in vascular diameter in vessels denuded of endothelium. In addition, anesthetized intact animals were treated for 20 min with vehicle (3mL/Kg) or 45μmol/Kg ZnDPBG (zinc deuteroporphyrin bis‐glycol) to inhibit CO production. Six corkscrew tears were made through the liver and MAP was monitored for 2 hours. In vehicle treated animals, the hepatic injury reduced MAP to 15±10mmHg, but only lowered the MAP to 73±7 mmHg in the ZnDPBG treated animals. The findings suggest that inhibition of CO can promote vasoconstriction preferentially in vessels denuded of endothelium to arrest wound bleeding and confer protection during severe soft tissue injury. (Support: NIH/DOD)