Effect of hypoxia and intravenous anesthetics on calcium sensitization of contraction in cerebral vascular smooth muscle

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To study the effect of intravenous anesthetics on the calcium sensitization of contraction in porcine cerebral arterial smooth muscle,1) isometric force was measured in permeabilized smooth muscle at constant (clamped) intracellular calcium concentration. Smooth muscles were stimulated with PGF2α, endothelin, U46619, or GTPγS.2) To see the participation of one of small GTP binding protein, RhoA, and its downstream effecor, Rho-kinase (Rock II) in the calcium sensitization, the inhibitor for RhoA, exoenzyme C3, for Rho-kinase, Y-27632 were used. Intravenous anesthetics, which have a vasodilating effect, were applied to see the potential therapeutic effect on the cerebral vasospasm.We found that1) RhoA/Rho-kinase may be responsible for the mechanism of calcium sensitization of contraction induced by PGF2α, endothelin, U-46619, or GTPγS in the cerebral artery.2) Intravenous anesthetics, ketamine, thiamylal, propofol had little effect on the calcium sensitization of contraction induced by PGF2α, endothelin, U-46619, or GTPγS in the cerebral artery.3) Ketamine at higher concentration, potentiated the myosin phosphatase activity when relaxation was induced at pCa 4.5, with myosin kinase inhibitor, ML-9.4) Western blotting analysis showed the presence of RhoA, Rho-kinase (Rock II), RhoGDI in the cerebral artery.The mechanism of potentiation by ketamine of the myosin phosphatase activity remained to be clarified. Another mechanism of calcium sensitization of contraction, by PKC, with specification of isoenzyme, awaits for further investigation.In summary, it is suggested that the suppression of the calcium sensitization of contraction through RhoA/Rho-kinase in cerebral artery may be useful as one of potential pharmacological intervention for the vasospasm after subarachnoid hemorrhage in human.