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Cellular mechanisms of thromboxane A₂-mediated contraction in pulmonary veins

Center for Anesthesiology Research, The Cleveland Clinic Foundation, Cleveland, Ohio

Submitted 20 April 2005 ; accepted in final form 15 June 2005

Our objectives were to identify the relative contributions of [Ca²⁺]_i and myofilament Ca²⁺ sensitivity in the pulmonary venous smooth muscle (PVSM) contractile response to the thromboxane A₂ mimetic U-46619 and to assess the roles of PKC, tyrosine kinases (TK), and Rho-kinase (ROK) in that response. We tested the hypothesis that U-46619-induced contraction in PVSM is mediated by both increases in [Ca²⁺]_i and myofilament Ca²⁺ sensitivity and that the PKC, TK, and ROK signaling pathways are involved. Isometric tension was measured in isolated endothelium-denuded (E–) canine pulmonary venous (PV) rings. In addition, [Ca²⁺]_i and tension were simultaneously measured in fura-2-loaded E– PVSM strips. U-46619 (0.1 nM–1 µM) caused dose-dependent (P < 0.001) contraction in PV rings. U-46619 contraction was attenuated by inhibitors of L-type voltage-operated Ca²⁺ channels (nifedipine, P < 0.001), inositol 1,4,5-trisphosphate-mediated Ca²⁺ release (2-aminoethoxydiphenylborate, P < 0.001), PKC (bisindolylmaleimide I, P < 0.001), TK (tyrphostin A-47, P = 0.014), and ROK (Y-27632, P = 0.008). In PV strips, U-46619 contraction was associated with increases in [Ca²⁺]_i and myofilament Ca²⁺ sensitivity. Both Ca²⁺ influx and release mediated the early transient increase in [Ca²⁺]_i, whereas the late sustained increase in [Ca²⁺]_i only involved Ca²⁺ influx. Inhibition of both PKC and ROK (P = 0.006 and P = 0.002, respectively), but not TK, attenuated the U-46619-induced increase in myofilament Ca²⁺ sensitivity. These results suggest that U-46619 contraction is mediated by Ca²⁺ influx, Ca²⁺ release, and increased myofilament Ca²⁺ sensitivity. The PKC, TK, and ROK signaling pathways are involved in U-46619 contraction.

pulmonary vein; Ca²⁺ homeostasis; myofilament Ca²⁺ sensitivity

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