Screening for novel inhibitors of the Rho-Kinase-mediated Ca²⁺-independent contraction of vascular smooth muscle

Abstract

Rho-Kinase (ROK)-mediated Ca²⁺-independent contraction of vascular smooth muscle (VSM) plays a pivotal role in the pathophysiology of vasospasm. We previously identified sphingosylphosphorylcholine (SPC) and Fyn as upstream signaling molecules of ROK-mediated Ca²⁺-independent abnormal contraction of VSM. In addition, we found that eicosapentaenoic acid (EPA) can selectively inhibit the SPC-induced Ca²⁺-independent contraction without affecting the [Ca²⁺]_i elevation and contraction induced by high K⁺-depolarization. Moreover, we reported that EPA was clinically and highly effective in preventing vasospasm after subarachnoid hemorrhage. However, EPA is limited to oral administration and thus unsuitable for clinically serious patients unable to ingest orally. We therefore screened for novel compounds which could inhibit Ca²⁺-independent abnormal VSM contraction induced by SPC, and substitute for EPA. Tension study of VSM showed that several compounds inhibited the SPC-induced abnormal VSM contraction, to an extent comparable to the effects of EPA. These results suggest that the newly found compounds would be the candidates for novel therapeutic drugs for vasospasm and substitute for EPA. [J Physiol Sci. 2007;57 Suppl:S124]