The beneficial effects of protein tyrosine kinase inhibition on the circulatory failure induced by endotoxin in the rat.
Implication of enhanced activity of tyrosine kinases has been established in the pathophysiology of many diseases associated with local (e.g., atherosclerosis) or systemic (e.g., septic shock) inflammation. The main objective of this study was to elucidate whether tyrosine kinase and nitric oxide were involved in endotoxin-induced impairment of vascular responses to sympathetic nerve stimulation (SNS) in rat isolated mesenteric bed. Therefore, the effects of genistein, an inhibitor of protein tyrosine kinase, and L-NAME (N-nitro-L-arginine methyl ester), an inhibitor of nitric oxide synthase, on endotoxin-induced shock were investigated in the thiopental-anesthetized rats. We also studied the effects of endotoxin on the vasoconstrictor responses to SNS in the rat isolated perfused mesenteric bed. Endotoxin injection (10 mg kg(-1), i.p.) produced a marked hypotension and a reduction of the pressor responses elicited by phenylephrine (0.1, 0.3, and 3 microg kg(-1), i.v.). Pretreatment of the rats with either genistein (10 mg kg(-1) i.p., 2 h before endotoxin injection), L-NAME (0.1 mg kg(-1), i.p., 30 min before endotoxin injection), or a combination of both attenuated the hypotension caused by endotoxin. SNS in the rat isolated perfused mesenteric bed caused a frequency-dependent vasoconstrictor response, which was abolished by tetrodotoxin (10(-7) M), prazoscin (10(-7) M), and guanethidine (10(-7)M). In mesenteric vascular beds removed from rats injected with endotoxin, the vasoconstrictor responses to SNS were markedly impaired. Although genistein and L-NAME pretreatment attenuated the vascular hyporeactivity to phenylephrine, they did not improve the impaired SNS response of the isolated vascular bed of endotoxin-treated animals. These results indicate that genistein and L-NAME pretreatment prevent the hypotension and the delayed hyporeactivity to phenylephrine induced by endotoxin, but they failed to restore the vascular hyporeactivity to SNS.
Fatehi
Mohammad
M
Department of Physiology and Pharmacology, Faculty of Medicine, Mashhad University of Medical Sciences, Iran.
Anvari
Khaleda
K
Fatehi-Hassanabad
Zahra
Z
D000818:Animals; D004347:Drug Interactions; D004731:Endotoxins / Q000633:toxicity; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D019833:Genistein / Q000008:administration & dosage / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage / Q000494:pharmacology; D010656:Phenylephrine / Q000008:administration & dosage / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012772:Shock, Septic / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology*; D013152:Splanchnic Circulation / Q000187:drug effects / Q000502:physiology; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000503:physiopathology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology
D004731:Endotoxins; D004791:Enzyme Inhibitors; D010656:Phenylephrine; C044101:endotoxin, Escherichia coli; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D019331:NG-Nitroarginine Methyl Ester