Effect of tyrosine kinase inhibition on sepsis-induced vascular hyporesponsiveness, iNOS mRNA expression and NF-kappa B nuclear translocation in rats

The dependence of the critical steps in the sepsis cascade on the transcrip tion factor NF-kappaB and its relation to nitric oxide (NO) production are controversial. Tyrosine kinase (TK) is involved in several of the steps, an d TK inhibitors (TKI) inhibit lipopolysaccharide (LPS)-induced vascular hyp oresponsiveness in septic animals. We studied the relationship of TK inhibi tion, hemodynamics, vascular contraction, iNOS mRNA expression and NF-kappa B translocation in anesthetized endotoxic rats. The TKI AG556 (2.5 mg/kg i. p.), given 1 h before i.v. endotoxin (LPS) resulted in attenuation of early (<60 min) and late (60-120 min) hypotension, improved contraction of mesen teric arteries to norepinephrine 4 h after LPS, and attenuated tissue iNOS mRNA expression. LPS-induced NF-<kappa>B translocation was unaffected. The observed dissociation between NF-kappaB translocation and the salutary effe ct of TKI in vivo and ex vivo and its effect on iNOS mRNA expression sugges t that although NF-kappaB may be involved in the sepsis cascade, it may not be essential for some of the molecular and vascular consequences of septic shock.