Involvement of YC-1 in extracellular signal-regulated kinase action in rat cremasteric muscle

Abstract

Objectives The nitric oxide (NO)-soluble guanylate cyclase (sGC) signalling pathway is attributed to the prevention of ischaemia-reperfusion (I/R)-induced leucocyte-endothelium adhesive interactions. YC-1 (3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole), a NO-independent sGC activator, has been shown to exert cardiovascular benefits, but its action on leucocyte-endothelium interactions remains unknown. In this study, the direct effect and the underlying mechanism of the anti-adhesive action of YC-1 have been examined in cremasteric microcirculation. Methods Rat cremaster muscle was subjected to 4h pudic-epigastric artery ischaemia followed by 2h reperfusion and intravital microscopy was used to observe leucocyte-endothelium interaction and to quantify functional capillaries in rat cremaster muscle flaps. Key findings The values for leucocyte rolling, adhering and transmigrating were 5.5-, 6.9- and 8.8-fold greater, respectively, in I/R than in sham-control animals. YC-1 treatment rescued functional capillary density and reduced leucocyte rolling, adhering and transmigrating in I/R injured cremaster muscles to levels observed in sham-controls. Interestingly, these effects were completely blocked by the MEK (extracellular signal-regulated kinase (ERK) kinase) inhibitor (PD98059) but not by sGC or protein kinase C inhibitors. Cotreatment of PD98059 with YC-1 caused a 3.3-, 7.5- and 8.3-fold increase in the values for leucocyte rolling, adhering and transmigrating, respectively, in postcapillary venules of I/R-injured cremaster muscle. Conclusions This study has indicated that the anti-adhesive and functional capillary density rescue properties of YC-1 were mediated predominantly by the activation of ERK but not sGC, although YC-1 was identified to be a sGC activator. A better understanding of the action of YC-1 on the microvasculature may help shed light on its therapeutic potential for cardiovascular disease. © 2010 The Authors. JPP © 2010 Royal Pharmaceutical Society of Great Britain.