5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) improves lipid utilization but not survival following prolonged hemorrhagic shock

Abstract

Hemorrhagic shock induces insulin resistance and cellular ATP depletion, the initial step for cell death and organ injury. AMPK is a fuel-sensing enzyme that maintains ATP production by facilitating glucose and fatty acid uptake and oxidation. Using a previously developed rat model of AKI induced by prolonged hemorrhagic shock, we tested the hypothesis that AICAR, an AMPK activator, can enhance fuel consumption, delay onset of AKI, and increase survival following prolonged hemorrhagic shock. Additionally, we hypothesized that AICAR requires 7.5% polyethylene glycol-20k (PEG) to elicit the catabolism effect, as PEG enhances the capillary perfusion in the absence of resuscitation, and thus, in theory, facilitates AICAR delivery into ischemic tissues. Rats were randomized into 4 groups (n=8/group) based on treatment: saline (vehicle), AICAR, PEG, and AICAR+PEG. Trauma was induced in (Inactin) anesthetized rats with muscle injury and fibula fracture, followed by pressure-controlled hemorrhagic shock (MAP = 55 mmHg) for 45 minutes. Animals then received an intravenous injection of saline (vehicle), AICAR, PEG, or AICAR+PEG. MAP, blood gases, RBF, renal oxygen delivery, capillary perfusion and tissue oxygen levels in the skeletal muscle were monitored for another 2 hours. GFR and mortality were recorded at the end of the experiment. The saline group exhibited impaired tissue perfusion and GFR with 100% mortality. AICAR alone showed no effect on hemodynamics, renal function, or mortality (100%). PEG and AICAR+PEG similarly improved MAP, capillary perfusion in the skeletal muscle, renal blood flow, renal oxygen delivery, and GFR. Compared to PEG, free FA levels were further decreased in AICAR+PEG, which was concomitant with elevated lactate levels and blunted oxygen partial pressure in the skeletal muscle despite the improved capillary perfusion. The mortality was 12.5% in PEG and 50% in AICAR+PEG. Our results suggest that AICAR+PEG does enhance fuel utilization but fails to further improve the tolerance to hemorrhagic shock, possibly due to a shift of oxygen consumption from vital organs to peripheral tissue. Importantly, the catabolism effect of AICAR relies on suffcient tissue perfusion, suggesting that PEG might be potentially considered as a routine therapeutic tool to optimize drug delivery during hemorrhagic shock. DoD disclaimer: The views expressed in this article are those of the author(s) and do not reflect the offcial policy or position of the U.S. Army Medical Department, Department of the Army, DoD, or the U.S. Government. Funding: This study was funded by US Army Medical Research and Development Command. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.