Involvement of YC-1 in extracellular signal-regulated kinase action in rat cremasteric muscle.
OBJECTIVE
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 4 h pudic-epigastric artery ischaemia followed by 2 h reperfusion and intravital microscopy was used to observe leucocyte-endothelium interaction and to quantify functional capillaries in rat cremaster muscle flaps.


RESULTS
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.
Department of Life Science and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.
Yu-Hsuan
YH
Hsieh
Shiang-Suo
SS
Huang
Yuan-Ji
YJ
Day
Fu-Chan
FC
Wei
Li-Man
LM
Hung
D000818:Animals; D002196:Capillaries / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006162:Guanylate Cyclase / Q000378:metabolism; D007191:Indazoles / Q000494:pharmacology*; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D008833:Microcirculation; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018482:Muscle, Skeletal / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism*; D015398:Signal Transduction; D000071756:Soluble Guanylyl Cyclase; D014699:Venules / Q000378:metabolism
D007191:Indazoles; D018160:Receptors, Cytoplasmic and Nuclear; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D009569:Nitric Oxide; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase