The authors' previous study speculated that YC-1, a guanylate cyclase (GC) activator,
ameliorated ischemia-reperfusion (I/R)-induced microcirculatory disturbance; however,
its underlying mechanism remains largely unknown. This study aimed to investigate
the role of the GC, protein kinase C (PKC), and MAP kinase in YC-1's ability to ameliorate
I/R-induced microcirculatory disturbances in rat cremaster muscle flaps.
Male Sprague Dawley (SD) rats were randomized (n = 5–8 per group) into seven groups:
Group 1, sham-operated control; Group 2, I/R (4 hr of pudic epigastric artery ischemia
followed by 1 hr of reperfusion); Group 3, YC-1 (0.2 mg/kg) + I/R; Group 4, YC-1 (0.2
mg/kg) + ODQ (GC − inhibitor, 5 mg/kg) + I/R; Group 5, YC-1 (0.1 mg/kg) + I/R; Group
6, YC-1 (0.1 mg/kg) + ODQ (5 mg/kg) + I/R; Group 7, YC-1 (0.2 mg/kg) + Chelerythrine
(PKC-inhibitor, 5 mg/kg) + I/R. Intravital microscopy was used to observe leukocyte/endothelial
cell interactions and quantify functional capillaries in cremaster muscles.
Microscopically, they observed that I/R markedly increased the number of rolling,
adhering, and transmigrating leukocytes. I/R also markedly decreased the number of
functional capillaries. In contrast, pretreatment of YC-1 can ameliorate I/R-induced
leukocyte-endothelium adhesive interaction. Compared to the YC-1 treated group, both
GC inhibitor (ODQ) and PKC inhibitor (Chelerythrine) antagonized the microcirculatory
beneficial effects of YC-1. In addition, YC-1 downregulated I/R-induced E-selectin,
L-selectin, TNF-alpha, and IL-1 beta protein expression in rat cremaster muscle were
also blocked by ODQ and Chelerythrine.
These results suggest that YC-1 ameliorated I/R-induced microcirculatory disturbance
and inhibited pro-inflammatory cytokines protein may occur through both GC and PKC-dependent
mechanisms.
