Naloxone treatment of endotoxin shock: stereospecificity of physiologic and pharmacologic effects in the rat

Abstract

Endogenous opiates (endorphins) like exogenous opiates can, even in small doses, profoundly depress blood pressure and heart rate. Since endorphins are released in response to stressors, it appeared possible that endorphins might be released during shock and serve to further reduce blood pressure. We used the specific opiate-antagonist naloxone to block there anticipated effects of endorphins in a conscious rat endotoxin-shock model. Naloxone treatment resulted in a rapid increase in mean arterial pressure (MAP) in animals made hypotensive by endotoxin administration. Naloxone was effective in reversing this hypotension at a dose as small as 0.1 mg/kg. This therapeutic effect of naloxone was stereospecific: (-)-naloxone reversed the hypotension, although its stereoisomer (+)-naloxone did not. A single 10 mg/kg i.v. bolus injection of naloxone significantly improved MAP for a period of 30 min, and MAP remained elevated as compared to saline controls for approximately 2 hr. Bolus injections of naloxone followed by continuous i.v. infusion produced similar changes in MAP. Despite the rapid effect of naloxone in restoring MAP toward base-line levels, 24 hr survival was not significantly improved by this narcotic antagonist. This suggests that factors other than hypotension are critical determinants of survival in this rat model. Collectively, these findings support the hypothesis that endorphins are hypotensive factors in endotoxin shock and suggest that the therapeutic effects of naloxone are specific and are mediated by the opiate receptor.