Improved survival and reversal of endothelial dysfunction by the 21‐aminosteroid, U‐74389G in splanchnic ischaemia‐reperfusion injury in the rat

Abstract

Anaesthetized rats subjected to total occlusion of the superior mesenteric artery and the coeliac trunk for 45 min developed a severe shock state (splanchnic artery occlusion, SAO shock) resulting in death within 70-90 min after release of the occlusion. Sham-operated animals were used as controls. 2 Survival rate, survival time, serum tumour necrosis factor (TNF-z), white blood cell (WBC) count, mean arterial blood pressure (MAP), plasma malonylaldehyde (MAL), myeloperoxidase activity (MPO) and the responsiveness to acetylcholine (ACh 10 nMm 10 IOM) of aortic rings were investigated. 3 SAO shocked rats had a decreased survival rate and survival time (74 ± 10 min, while sham-shocked rats survived more than 4 h), reduced mean arterial blood pressure, increased serum levels of TNF-a (267 13 u ml-') and plasma levels of MAL (57 ± 7 nmol ml-'), enhanced MPO activity in the ileum (0.23 0.04 u x 1i-3 g-' tissue) and in the lung (2.2 ± 0.8 u x 10-3 g-' tissue), leukopenia and reduced responsiveness to ACh of aortic rings. 4 The 21-aminosteroid U-74389G (30mg kg-', i.v.) increased survival (survival time = 232 ± 15 min), lowered the serum levels of TNF-x and the plasma levels of MAL, reduced leukopenia and MPO activity both in the ileum (0.021 ± 0.004 u x 10-3 g-' tissue) and in the lung (0.23 ± 0.03 u x 10-g-' tissue), improved MAP and restored the responsiveness to ACh of aortic rings. 5 Our data suggest that U-74389G is a potent lipid peroxidation inhibitor and that it has antishock and endothelial protective actions.

The Antioxidant EPC-K1 Attenuates Renal Ischemia-Reperfusion Injury in a Rat Model

“…In this study, we observed that EPC-K1 reduced morphologic changes in renal tissue and mitochondria after renal I/R. We also observed a reduction in the kidney levels of MDA, which is produced when lipids are damaged by ROS and used as an indicator of ROS activity in I/R injury [27]. Furthermore, EPC-K1 significantly suppressed ROS activity in a murine macrophage-like cell line.…”

The 21-Aminosteroid U74389G Enhances Hepatic Blood Flow and Preserves Sinusoidal Endothelial Cell Function and Structure in Endotoxin-Shocked Dogs

“…Oxygen free radicals, in particular the superoxide radical [16], and tumor necrosis factor-␣ (TNF) [17] have been incriminated in this abnormal vasoconstrictive response which may involve an inhibitory effect on nitric oxide (NO). 21-AS, including U74389G, have been shown to inhibit superoxide radical production [18] and to lower TNF levels [19]. U74006F, like superoxide dismutase, was found to restore in vitro endothelium-dependent relaxation of superior mesenteric artery rings in endotoxin-shocked rats [20].…”

Cepharanthine Improves Renal Ischemia-Reperfusion Injury in Rats

“…Upon reaction, hydroxyl radicals themselves instantly disappear, but the reaction damages biomolecules, as well as cell and tissue functions. Malondialdehyde (MDA) is produced when lipids are damaged by ROS [21] and is thus a useful indicator of ROS activity in ischemia-reperfusion injuries [22]. Cepharanthine administration was associated with improvement of ischemia-reperfusion-induced changes in mitochondrial morphology and tissue MDA levels, suggesting that cepharanthine's protective effects may be mediated at least in part by ROS inhibition.…”