POST-TREATMENT WITH THE NOVEL DELTORPHIN E, A δ2-OPIOID RECEPTOR AGONIST, INCREASES RECOVERY AND SURVIVAL AFTER SEVERE HEMORRHAGIC SHOCK IN BEHAVING RATS

Abstract

Deltorphin E was investigated as a pharmaceutical intervention in the ischemic hemorrhagic model. To monitor the hemodynamic biomarkers mean arterial pressure (MAP) and heart rate (HR) and to facilitate i.v. injections, rats were surgically fitted with femoral artery and vein catheters under anesthesia. After removal of 48% of total blood volume (range, 12-15 mL), posthemorrhage i.v. injections of 5.5-mg/kg deltorphin E were found to significantly (P < 0.05) increase maximum MAP, pulse pressure, and survival after hemorrhage, whereas lactic acid concentration was decreased when compared with saline injections. The results for the 5.5-mg/kg deltorphin E-treated animals versus saline controls showed the following values (expressed as mean +/- SEM): maximum MAP, 58 +/- 7 vs. 35 +/- 9 mmHg, respectively; lactic acid, 6.5 +/- 1.25 vs. 8.9 +/- 0.12 mmol/L, respectively; pulse pressure, 47.9 +/- 0.55 vs. 38.3 +/- 0.44 mmHg, respectively; and at least a fourfold increase in survival, 331 +/- 18 vs. 50 +/- 8 min, respectively. Heart rate in deltorphin E-treated groups was not significantly different from that in saline-treated groups (maximum HR, 396 +/- 40 vs. 425 +/- 94 bpm, respectively). Using logistic analysis, deltorphin E did not significantly alter the baroreflex sensitivity. However, a significant deltorphin E dose-dependent correlation was found between survival time and lactic acid production. Increased pulse pressure was also correlated with survival. Glibenclamide, a potassium-sensitive adenosine triphosphate-sensitive channel blocker, did not interfere with the positive effects of deltorphin E. Only the antagonists tested, known to affect delta(2)-opioid receptors, interfered with the deltorphin E survival benefit after hemorrhage. As a conclusion, deltorphin E is an effective pharmaceutical intervention in severe hemorrhagic shock and, perhaps, in other ischemic shock scenarios when administered after the onset of stress. Therefore, deltorphin E may have clinical potential.