To investigate the mechanism of smooth muscle contraction induced by emptying of intracellular Ca2⁢ stores, we measured isometric contraction and 45Ca2⁢ influx. CaCl2 increased Ca2⁢ store emptying- induced contraction in dose-dependent manner, but phospholipase C activity was not affected by the Ca2⁢ store emptying-induced contraction. The contraction was inhibited by voltage-dependent Ca2⁢ channel antagonists dose dependently, but not by TMB-8 (intracellular Ca2⁢ release blocker). Both PKC inhibitors (H-7 and staurosporine) and tyrosine kinase inhibitors (genistein and methyl 2,5-dihydroxycinnamic acid) significantly inhibited the contraction, but calmodulin antagonists (W-7 and trifluoperazine) had no inhibitory effect on the contraction. The combined inhibitory effects of protein kinase inhibitors, H-7 and genistein, together with verapamil were greater than that of each one alone. In Ca2⁢ store-emptied condition, 45Ca2⁢ influx was significantly inhibited by verapamil, H-7 or genistein but not by trifluoperazine. However combined inhibitory effects of protein kinase inhibitors, H-7 and genistein, together with verapamil were not observed. Therefore, this kinase pathway may modulate the sensitivity of contractile protein. These results suggest that contraction induced by emptying of intracellular Ca2⁢ stores was mediated by influx of extracellular Ca2⁢ through voltage-dependent Ca2⁢ channel, also protein kinase C and/or tyrosine kinase pathway modulates the Ca2⁢ sensitivity of contractile protein.