--- - |2 Summary We have previously demonstrated that the activation of the spleen tyrosine kinase (Syk)/inhibitory‐κB (IκB)‐α/nuclear factor‐κB (NF‐κB) p65 signalling pathway contributes to hypotension and inflammatory response in a rat models of zymosan (ZYM)‐induced non‐septic shock. The purpose of this study was to further examine the possible mechanism underlying the effect of inhibition of Syk by BAY61‐3606 via NF‐κB activity at the level of nuclear translocation regarding the production of vasodilator and proinflammatory mediators in lipopolysaccharide (LPS) (septic)‐ and ZYM (non‐septic)‐induced shock. Administration of LPS (10 mg/kg, i.p.) or ZYM (500 mg/kg, i.p.) to male Wistar rats decreased mean arterial pressure and increased heart rate that was associated with an increase in the activities of cyclooxygenase and nitric oxide synthase, tumor necrosis factor‐α, and interleukin‐8 levels, and NF‐κB activation and nuclear translocation in sera and/or cardiovascular and renal tissues. BAY61‐3606 (3 mg/kg, i.p.), the selective Syk inhibitor, given 1 h after LPS‐ or ZYM injection reversed all the above mentioned effects. These results suggest that, Syk contributes to the LPS‐ or ZYM‐induced hypotension and inflammation associated with transactivation of NF‐κB in septic and non‐septic shock. This article is protected by copyright. All rights reserved. - 'Clinical and Experimental Pharmacology and Physiology, Volume 0, Issue ja, -Not available-. '