The Rho/Rho-kinase pathway plays an important role in many cardiovascular diseases such as hypertension, atherosclerosis, heart failure, and myocardial infarction. Although previous studies have shown that Rho-kinase inhibitors reduce ischemia/reperfusion (I/R) injury and cytokine production, the role of Rho-kinase in leukocytes during I/R injury is not well understood. Mice were subjected to 30-min ischemia and reperfusion. Rho-kinase activity was significantly greater in leukocytes subjected to myocardial I/R compared to the sham-operated mice. Administration of fasudil, a Rho-kinase inhibitor, significantly reduced the I/R-induced expression of the proinflammatory cytokines interleukin (IL)-6, C-C motif chemoattractant ligand 2 (CCL2), and tumor necrosis factor (TNF)-α, in leukocytes, compared with saline as the vehicle. Furthermore, fasudil decreased I/R-induced myocardial infarction/area at risk (IA) and I/R-induced leukocyte infiltration in the myocardium. Interestingly, IA in fasudil-administered mice with leukocyte depletion was similar to that in fasudil-administered mice. I/R also resulted in remarkable increases in the mRNA expression levels of the proinflammatory cytokines TNF-α, IL-6, and CCL2 in the heart. Inhibition of Rho-kinase activation in leukocytes has an important role in fasudil-induced cardioprotective effects. Hence, inhibition of Rho-kinase may be an additional therapeutic intervention for the treatment of acute coronary syndrome.

No abstract

Introduction: The Rho/Rho‐kinase pathway has been related to various physiological responses of the cardiovascular system. Previous reports have suggested a significant effect of Rho signals on the electrophysiological characteristics of the heart. We hypothesized that the Rho/Rho‐kinase system would contribute to the rapid pacing‐related change of atrial effective refractory period (AERP).Methods and Results: In 17 dogs, AERP was measured at the right atrial appendage (RAA) and posterior left atrium (LA) before, during, and after 6‐hours rapid atrial pacing at 500 bpm. Saline control (n = 5), verapamil (n = 5), or fasudil (n = 7) were infused throughout the protocol. The shortening of AERP after rapid pacing was abrogated by the administration of verapamil, as reported in previous studies. Furthermore, fasudil (Rho/Rho‐kinase inhibitor) influenced the change of AERP in a manner similar to the infusion of verapamil throughout the experiments.Conclusions: Since the AERP was attenuated by fasudil, rapid pacing‐related atrial electrophysiological changes might involve the Rho/Rho‐kinase pathway.