Figure 9.

Schematic diagram of the signalling pathway activated by B₁ receptor agonists leading to the formation of ONOO¯ upon post‐translational activation of iNOS and NADPH oxidase. Activation of the B₁ receptor through Gαi and βγ‐dependent activation of Src, Ras, Raf and MEK leads to ERK‐dependent phosphorylation of iNOS on Ser⁷⁴⁵ that causes high NO output (Brovkovych et al., 2011). Simultaneously, B₁ receptor agonists can activate NADPH oxidase to generate O₂ ^●¯ (Dias et al., 2010) that can rapidly react with NO to form ONOO¯. The latter exerts a positive feedback loop to enhance the expression of B₁ receptors. Blockade of iNOS with 1400W prevents this vicious cycle and the pro‐inflammatory effects of B₁ receptors.