Hypoxia and sympathetic activation are main factors in the pathogenesis of acute kidney injury.

The hypothesis was tested that norepinephrine (NE) in hypoxia/re-oxygenation (H/R) model enhances the vasoreactivity of mouse interlobar arteries.The vessels were exposed for 60 min either to control conditions or to hypoxia in the absence or presence of NE (10^-9), followed by 10 minutes of re-oxygenation.

The subsequent response to Ang II (10^-10 to 3*10^-7 mol/l) was reduced after hypoxia compared with normoxia. However, incubation of the vessels with NE during hypoxia increased the contraction to Ang II to values larger than during normoxia. The above-mentioned effect of NE was abolished in the combined presence of the a1-antagonist prazosin and the a2-antagonist yohimbine, but was unaffected in the presence of prazosin or yohimbine alone. Propranolol (b1,2-receptor antagonist) inhibited the effect of NE during hypoxia on Ang II-induced contractions completely, without affecting the Ang II responses under normoxia. But after simultaneous inhibition of a1,2- and b1,2-receptors the NE effect was still presented. Phosphorylation of p38 MAPK and MLC(20) was increased after H/R compared to normoxia both with NE and Ang II treatment. The selective p38 MAPK inhibitor SB202190 blocked the NE effect on Ang II-induced contractions during hypoxia. In contrast, the latter effect was maintained in mice deficient for the p38 MAPK downstream target MK-2.

Thus, the data show that the enhancing effect of NE on Ang II-induced contractions during hypoxia is mediated by several adrenergic receptors and requires p38 MAPK activation.