Md. Okusa et al., Selective A(2A) adenosine receptor activation reduces ischemia-reperfusioninjury in rat kidney, AM J P-REN, 46(3), 1999, pp. F404-F412
A(2A) adenosine receptors (A(2A)-ARs) are known modulators of renal hemodyn
amics and potent inhibitors of inflammation. We sought to determine whether
selective activation of A(2A)-ARs protects kidneys from ischemia-reperfusi
on injury. The ester derivative of DWH-146 (DWH-146e), a selective Aw agoni
st, was found to be more potent and selective for A(2A)-ARs than the protot
ype compound CGS-21680. Osmotic minipumps were implanted subcutaneously to
infuse into rats either vehicle or DWH-146e (0.004 mu g.kg(-1).min(-1)), du
ring and after ischemia-reperfusion injury. Following 24 and 48 h of reperf
usion, the rise in serum creatinine and blood urea nitrogen for vehicle-tre
ated rats was substantially elevated compared with DWH-146e-treated rats. H
istological examination revealed widespread tubular epithelial necrosis and
vascular congestion in the outer medulla of vehicle-treated compared with
DWH-146e-treated animals. ZM-241385, a selective A(2A) antagonist, blocked
the protective effect of DWH-146e. Delaying administration of DWH-146e unti
l the initiation of reperfusion also decreased serum creatinine. We conclud
e that 1) selective A(2A)-AR activation by DWH-146e reduces ischemia-reperf
usion injury in rat kidneys, 2) the effect of DWH-146e is A(2A) receptor me
diated, and 3) the protective effects are mediated by preventing injury dur
ing the reperfusion period.