a p38 MAPK- and ERK-mediated pathway. However, SP600125 is not a specific inhibitor of JNK because it also inhibits other protein kinases including MLCK (Bain et al., 2007). Therefore, taking the previous study into consideration (Bain et al., 2007), we should be PARP Inhibitors very cautious to interpret data that may be associated with non-specific inhibitory actions of the high concentrations of protein kinase inhibitors used in the current in vitro study. In addition, there are several crosstalk points among the signal transduction pathways of protein kinasemediated contraction associated with increased Ca2+ sensitivity (Abdel-Latif, 2001; Akata, 2007b; Hirano, 2007).

For example, the interrelationship between the tyrosine kinase pathway and MLCK asenapine pathway has been reported in vascular smooth muscle (Jin et al., 1996). The increase in   sends cross-signals for activation of either the RhoA/Rho-kinase pathway or the PKC pathway, leading to an increase in Ca2+ sensitivity (Hirano, 2007). Bupivacaine inhibits Nmethyl- D-aspartate receptor signaling by inhibiting PKC (Hahnenkamp et al., 2006). Taking the previous reports into consideration (Abdel-Latif, 2001; Akata, 2007b; Hahnenkamp et al., 2006; Hirano, 2007; Hughes andWijetunge, 1998; Jin et al., 1996; Khalil et al., 1995), it is very difficult to fully elucidate the signaling pathways involving Rho-kinase, PKC, and JNK activation that are mainly responsible for levobupivacaine-induced contraction.

Therefore, further investigation regardingwhether levobupivacaine stimulates the buy Glycyrrhizic acid aforementioned protein kinases directly or through activation of the upstreamreceptor or amixture of bothmechanisms is needed. Reinforced with the results from isometric tension measurements, pretreatmentwith GF 109203X and Y-27632 inhibited levobupivacaine (10 4 M)-induced PKC phosphorylation and ROCK-2membrane translocation, respectively. Levobupivacaine (10 4 M) induced ERK and JNK phosphorylation in VSMCs, which were inhibited by PD 98059 and SP600125, respectively. Differences in specimens and incubation periods may explain the difference in magnitude between the inhibition of levobupivacaine-induced phosphorylation and contraction by PD 98059.

Taken together, these results suggest that levobupivacaine contracts rat aortic smooth muscle through the primary involvement of PKC-, Rho-kinase-, and JNK-mediated purchase Staurosporine pathways. Levobupivacaine is clinically used at concentrations of 0.25 to 0.75% (equivalent to approximately 8.7×10 3 to 2.6×10 2 M). The maximumplasma concentration following scalp blockwith levobupivacaine is 5.4×10 6 M (Costello et al., 2005), whereas the local tissue concentration of levobupivacaine encountered in the clinical setting with 95% protein binding ranges from 0.27×10 6 M to 1.3×10 3 M, which workforce includes the range of concentrations producing vasoconstriction observed in the current in vitro study. The clinical relevance of protein kinase-mediated .