ABSTRACT
The authors hypothesized that augmenting skeletal muscle adenosine 3′,5′-cyclic monophosphate
(cAMP) levels could reduce tissue inflammation and improve muscle survival in response
to ischemia/reperfusion (I/R) injury. Gracilis muscle flaps in male Wistar rats were
subject to 4 hr of ischemia followed by 3 hr of reperfusion, to assess neutrophil
accumulation and microvessel tone, or by 24 hr to evaluate percentage of muscle survival.
Animals were grouped as follows: positive (saline) or negative (sham) control, or
with infused cAMP elevating agents (8 Bromo-cAMP (8 Br-cAMP) or forskolin). Radioimmunoassay
demonstrated significant increases in tissue cAMP levels throughout 3 hr of reperfusion
with forskolin, while the 8 Br-cAMP-treated group showed only a temporary increase.
Compared with vehicle-infused controls, forskolin administered 5 min prior to reperfusion
and repeated as an infusion during the first 45 min of reperfusion, resulted in reduced
neutrophil adherence and transmigration, and muscle edema with sustained vasodilatation.
The percentage of muscle survival using nitro-blue tetrazolium staining demonstrated
enhanced muscle-flap preservation with forskolin. There was no beneficial change in
the presence of 8 Br-cAMP. These observations suggested that sustained elevation of
the cAMP pathway may reduce ischemia-reperfusion injury by decreasing neutrophil-mediated
injury and improving vessel tone. Elucidation of the cAMP pathway may provide novel
opportunities to modulate ischemia/reperfusion injury.
