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(The FASEB Journal. 2007;21:979.11)
© 2007 FASEB
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979.11

cGMP-mediated calcium desensitisation of pulmonary artery does not involve Rho kinase or PKG: role for PKA

Jeremy PT Ward, Anushika De Silva and Philip I Aaronson

Asthma, Allergy and Lung Biology, King’s College London, 2nd floor Thomas Guy House, Guy’s Campus, London, SE1 9RT, United Kingdom

ABSTRACT

Vasodilators that increase cGMP reduce Ca2+ sensitivity as well as Ca2+, and may inhibit the RhoA/Rho kinase pathway. We examined cGMP-mediated Ca2+ desensitisation using 8-Br-cGMP, in rat {alpha}-toxin permeabilized intrapulmonary arteries (IPA). In IPA contracted by raising Ca2+, 8-Br-cGMP relaxed IPA with an EC50 of ~25nM. Surprisingly, the Rho kinase inhibitor Y-27632 (10µM) had no significant effect. Consistent with this, 100nM 8-Br-cGMP caused a significant shift in the Ca2+ response curve (EC50 Control: 157 ± 23 nM; 8-Br-cGMP: 252 ± 47 nM); although Y-27632 also increased the EC50 (204 ± 26 nM), in its presence 8-Br-cGMP still caused a further increase (306 ± 45nM). Similar results were obtained with PGF2{alpha}, which activates Rho kinase. The effects of 8-Br-cGMP were not inhibited by KT5823, a PKG inhibitor, but were by H89, a PKA inhibitor. Similarly, Rp-8-Br-cAMP (25 µM) depressed 8-Br-cGMP-mediated relaxation at pCa 6.8 from 76.9 ± 2.5% to 43.1 ± 4.5%. 8-Br-cGMP had a greater effect on MLC phosphorylation than on that of MYPT1. This suggests 8-Br-cGMP reduces Ca2+ sensitivity in IPA via PKA, possibly involving its target teleokin which affects myosin phosphatase.

Supported by MRC and Wellcome Trust.





This Article
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