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Regulation of pulmonary venous tone in response to muscarinic receptor activation

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

Submitted 22 June 2004 ; accepted in final form 16 September 2004

We investigated cellular mechanisms that mediate or modulate the vascular response to muscarinic receptor activation (ACh) in pulmonary veins (PV). Isometric tension was measured in isolated canine PV rings with endothelium (E+) and without endothelium (E–). Tension and intracellular Ca²⁺ concentration ([Ca²⁺]_i) were measured simultaneously in fura-2-loaded E– PV strips. In the absence of preconstriction, ACh (0.01–10 µM) caused dose-dependent contraction in E+ and E– rings. ACh contraction was potentiated by removing the endothelium or by nitric oxide (NO) synthase inhibition (N-nitro-L-arginine methyl ester, P = 0.001). Cyclooxygenase inhibition (indomethacin) reduced ACh contraction in both E+ and E– PV rings (P = 0.013 and P = 0.037, respectively). ACh contraction was attenuated by inhibitors of voltage-operated Ca²⁺ channels (nifedipine, P < 0.001), inositol-1,4,5-trisphosphate (IP₃)-mediated Ca²⁺ release (2-aminoethoxydiphenyl borate, P = 0.001), PKC (bisindolylmaleimide I, P = 0.001), Rho-kinase (Y-27632, P = 0.002), and tyrosine kinase (TK; tyrphostin 47, P = 0.015) in E– PV rings. ACh (1 µM) caused a leftward shift in the [Ca²⁺]_i-tension relationship (P = 0.015), i.e., ACh increased myofilament Ca²⁺ sensitivity. Inhibition of PKC, Rho-kinase, and TK attenuated the ACh-induced increase in myofilament Ca²⁺ sensitivity (P < 0.001, P < 0.001, and P = 0.024, respectively). These findings indicate that in canine PV, ACh contraction is modulated by NO and partially mediated by metabolites of the cyclooxygenase pathway and involves Ca²⁺ influx through voltage-operated Ca²⁺ channels and IP₃-mediated Ca²⁺ release. In addition, ACh induces increased myofilament Ca²⁺ sensitivity, which requires the PKC, Rho-kinase, and TK pathways.

endothelium; nitric oxide; myofilament calcium sensitivity; calcium influx and release

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