Ischemia-reperfusion (I/R) injury is a complex process involving the generation and
release of inflammatory cytokines, accumulation and infiltration of neutrophils and
macrophages, that disturb the microcirculatory hemodynamics. It has been reported
that NO-donor induced elevation of intracellular cGMP alleviates I/R injury. An activator
of soluble guanylyl cyclase (sGC), YC-1 [3-(5′-hydroxymethyl-2′-furyl)-1-benzyl indazole]
could potentially increase intracellular cGMP levels and thus protect the tissue against
I/R injury. Therefore this study aimed to assess the effects of YC-1 on I/R-injured
cremaster muscles and further elucidate its underlying mechanisms.
Male Sprague Dawley (SD) rats were randomized (n = 5–8 per group) into five 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 (10 min before I/R, 0.05 mg/kg i.v.) + I/R;
Group 4, YC-1 (0.1 mg/kg) + I/R; and Group 5, YC-1 (0.2 mg/kg) + I/R. Intravital microscopy
was used to observe leukocyte/endothelial cell interactions and quantify functional
capillaries in cremaster muscles. ELISA was used to examine intracellular cGMP levels.
In the control group (Group 2), I/R markedly increased the number of rolling, adhering,
and transmigrating leukocytes, and also markedly decreased the number of functional
capillaries. In contrast, pretreatment of YC-1 reduced I/R-induced leukocyte rolling,
adhesion, transmigration in a dose-dependent manner as well as reserved capillary
function. Furthermore, compared to the I/R group, pretreatment of YC-1 significantly
downregulated I/R-induced E-selectin, L-selectin, TNF-alpha, Il-1 beta proteins expression
in rat cremaster muscle. The intracellular cGMP levels were also evaluated in cremaster
muscle.
These results suggest that YC-1, a GC-activator, ameliorated I/R-induced microcirculatory
disturbance and downregulated I/R-induced pro-inflammatory mediator proteins expression
possibly through a GC/cGMP/PKG signaling pathway.
