Urocortin (UCN) is a peptide related to hypothalamic corticotrophin-releasi
ng hormone and binds with high affinity to corticotrophin-releasing hormone
receptor-2 beta, which is expressed in the heart. In this study, we report
that UCN prevented cell death when administered to primary cardiac myocyte
cultures both prior to simulated hypoxia/ischemia and at the point of reox
ygenation after simulated hypoxia/ischemia. UCN-mediated cell survival was
measured by trypan blue exclusion, 3'-OH end labeling of DNA (TUNEL), annex
in V, and fluorescence-activated cell sorting. To explore the mechanisms th
at could be responsible for this effect, we investigated the involvement of
MAPK-dependent pathways. UCN caused rapid phosphorylation of ERK1/2-p42/44
, and PD98059, which blocks the MEK1-ERK1/2-p42/44 cascade, also inhibited
the survival-promoting effect of UCN. Most important, UCN reduced damage in
isolated rat hearts ex vivo subjected to regional ischemia/reperfusion, wi
th the protective effect being observed when UCN was given either prior to
ischemia or at the time of reperfusion after ischemia. This suggests a nove
l function of UCN as a cardioprotective agent that could act when given aft
er ischemia, at reperfusion.