Improved survival and reversal of endothelial dysfunction by the 21-aminosteroid, U-74389G in splanchnic ischaemia-reperfusion injury in the rat.
1. 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-alpha), white blood cell (WBC) count, mean arterial blood pressure (MAP), plasma malonyladehyde (MAL); myeloperoxidase activity (MPO) and the responsiveness to acetylcholine (ACh 10 nM-10 microM) 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-alpha (267 +/- 13 u ml-1) and plasma levels of MAL (57 +/- 7 nmol ml-1), enhanced MPO activity in the ileum (0.23 +/- 0.04 u x 10(-3) g-1 tissue) and in the lung (2.2 +/- 0.8 u x 10(-3) g-1 tissue), leukopenia and reduced responsiveness to ACh of aortic rings. 4. The 21-aminosteroid U-74389G (30 mg kg-1, i.v.) increased survival (survival time = 232 +/- 15 min), lowered the serum levels of TNF-alpha and the plasma levels of MAL, reduced leukopenia and MPO activity both in the ileum (0.021 +/- 0.004 u x 10(-3) g-1 tissue) and in the lung (0.23 +/- 0.03 u x 10(-3) g-1 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.
Squadrito
F
F
Institute of Pharmacology, School of Medicine, University of Messina, Italy.
Altavilla
D
D
Ammendolia
L
L
Squadrito
G
G
Campo
G M
GM
Sperandeo
A
A
Canale
P
P
Ioculano
M
M
Saitta
A
A
Caputi
A P
AP
D000109:Acetylcholine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D007958:Leukocyte Count; D007970:Leukopenia / Q000503:physiopathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008315:Malondialdehyde / Q000097:blood; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology; D008641:Mesenteric Vascular Occlusion / Q000188:drug therapy / Q000401:mortality; D009599:Nitroprusside / Q000494:pharmacology; D009195:Peroxidase / Q000378:metabolism; D011281:Pregnatrienes; D051381:Rats; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000401:mortality; D013152:Splanchnic Circulation / Q000187:drug effects / Q000502:physiology; D013260:Steroids, Heterocyclic / Q000494:pharmacology / Q000627:therapeutic use*; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000975:Antioxidants; D011281:Pregnatrienes; D013260:Steroids, Heterocyclic; D014409:Tumor Necrosis Factor-alpha; C074965:U 74389F; D009599:Nitroprusside; D008315:Malondialdehyde; D009195:Peroxidase; D000109:Acetylcholine