Investigation of protective effects of Y-27632 as a selective RHO-kinase inhibitor, on organophosphate-induced cardiac toxicity and mortality

This study is designed to examine the effects of Y-27632, a selective Rho-kinase inhibitor, on organophosphate-induced cardiac toxicity and mortality in rats. Rats were randomly divided into four groups as control (corn oil), dichlorvos (30 mg/kg i.p.), 1 and 10 mg/kg Y-27632+dichlorvos groups. All drugs and vehicle were administered by intraperitoneally and after 6h of injection, venous blood samples were collected by direct heart puncture under thiopental anesthesia. Cardiac tissue samples were also obtained. Biochemical and immunohistochemical analysis were performed. Serum cholinesterase levels were suppressed with dichlorvos and these reductions were inhibited with Y-27632 pretreatment. Serum levels of creatine kinase (CK), CK-MB, myoglobin, and N-terminal probrain natriuretic peptide were not markedly affected with poisoning or Y-27632. Cardiac troponin I levels were significantly elevated with dichlorvos, and this increase was not modified with Y-27632. Although serum nitric oxide levels did not change with dichlorvos, cardiac nitric oxide levels were markedly increased with Y-27632 pretreatment. Cardiac glutathione levels also increased with 1 mg/kg Y-27632. There was no staining for apoptosis and immunohistochemical analyses of inducible nitric oxide synthase showed no change in cardiac tissue for all of the groups. Both doses of Y-27632 abolished mortality in rats with acute dichlorvos exposure (100% survival). In conclusion, Rho-kinase pathway is involved in the organophosphate poisoning, and administration of Rho-kinase inhibitor can produce protective effects against dichlorvos intoxication in rats. These findings may provide new possibilities for the treatment of organophosphate poisoning.Keywords: Cardiac toxicity, Poisoning, Dichlorvos, Rho-kinase, Y-27632