In vivo vascular effects of genistein on a rat model of septic shock induced by lipopolysaccharide.
The aim of this study was to investigate the effects of in vivo administration of genistein on rat cardiovascular abnormalities induced by lipopolysaccharide (LPS). Four hours after injection, LPS (10 mg/kg) caused a stable fall in mean arterial pressure (13%) accompanied by ex vivo vascular hyporeactivity to noradrenaline (NA) and relaxation to l-arginine (L-arg), which were inhibited by previous incubation with l-NAME. Endotoxin also caused impairment of aortic relaxant response to acetylcholine, increase nitrite and malonaldehyde plasma levels by 8.6-fold and 2-fold, respectively, and induced aortic expression of inducible nitric-oxide synthase (iNOS) and nitrotyrosine protein. Genistein (1 mg/kg) and daidzein (1 mg/kg) reduced contractile response to NA in vascular tissue, but only genistein was able to inhibit hyporesponsiveness to NA, relaxation to l-arg, increase in nitrite plasma levels, and iNOS expression produced by endotoxin. Moreover, genistein restored impaired aortic relaxation to acetylcholine, lipid peroxidation, and suppressed long-term hypotension. In conclusion, genistein administrated in vivo prevents hypotension and vascular alterations induced by LPS. These protective effects are mediated by both its antioxidant properties and the inhibition of nitric oxide overproduction from de novo synthesis of iNOS due to its tyrosine kinase inhibitor effect.
Bermejo
Almudena
A
Department of Pharmacology, School of Pharmacy, University of Granada, Spain.
Zarzuelo
Antonio
A
Duarte
Juan
J
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D004347:Drug Interactions; D019833:Genistein / Q000627:therapeutic use*; D007022:Hypotension / Q000209:etiology / Q000517:prevention & control*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000633:toxicity; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009638:Norepinephrine / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D012772:Shock, Septic / Q000209:etiology / Q000628:therapy*
D000970:Antineoplastic Agents; D008070:Lipopolysaccharides; D019833:Genistein; D019001:Nitric Oxide Synthase; D011505:Protein-Tyrosine Kinases; D000109:Acetylcholine; D009638:Norepinephrine