Dexmedetomidine-induced contraction involves tyrosine kinase-mediated calcium sensitization in isolated rat aortae

Abstract

The goal of this study was to investigate the role of tyrosine kinase in contraction induced by the highly selective alpha-2 adrenoceptor agonist dexmedetomidine, which has been widely used for sedation in various procedures in isolated endothelium-denuded rat aortae and the tyrosine kinase-mediated pathway. The effects of genistein, tyrphostin 23, sodium orthovanadate, 1-butanol and 2-butanol on dexmedetomidine-induced contraction were examined. The effect of genistein on the simultaneous intracellular calcium level ([Ca2+](i))-tension curves induced by dexmedetomidine in fura-2-loaded aortic strips was also investigated. Additionally, the effects of rauwolscine and genistein on dexmedetomidine-induced phosphorylation of protein tyrosine, c-Jun NH2-terminal kinase (JNK), and caldesmon in rat aortic vascular smooth muscle cells were examined using Western blotting. The effects of rauwolscine, genistein, and 1-butanol on dexmedetomidine-induced phospholipase D (PLD) activity in rat aortic vascular smooth muscle cells were also investigated. Genistein, tyrphostin 23 and 1-butanol attenuated the dexmedetomidine-induced contraction whereas sodium orthovanadate enhanced it. Both 1-butanol (0.05%) and its inactive congener 2-butanol (0.05%) attenuated dexmedetomidine (10(-6) M)-induced contraction. However, 1-butanol attenuated dexmedetomidine (10(-6) M)-induced contraction to a greater extent compared to 2-butanol. Rauwolscine and genistein attenuated dexmedetomidine-induced phosphorylation of protein tyrosine, JNK, and caldesmon and genistein shifted the slope of the [Ca2+](i)-tension curves induced by dexmedetomidine downward. Rauwolscine, genistein, and 1-butanol attenuated dexmedetomidine-induced PLD activity. Taken together, these results suggest that dexmedetomidine-induced contraction involves tyrosine kinase-induced calcium sensitization, which seems to be mediated by either JNK and caldesmon or PLD.