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cGMP signals mainly through cAMP kinase in permeabilized murine aorta

Institut für Pharmakologie und Toxikologie, Technische Universität München, München, Germany

Submitted 19 January 2006 ; accepted in final form 17 August 2006

GMP affects vascular tone by multiple mechanisms, including inhibition of the Rho/Rho kinase-mediated Ca²⁺ sensitization, a process identified as Ca²⁺ desensitization. Ca²⁺ desensitization is mediated probably by both cGMP- and cAMP-dependent protein kinases (cGKI and PKA). We investigate to which extent Ca²⁺ desensitization is initiated by cGKI and PKA. cGMP/cAMP-induced relaxation was studied at constant [Ca²⁺] in permeabilized aortas from wild-type and cGKI-deficient mice. [Ca²⁺] increased aortic tone in the absence and presence of 50 µM GTPS with EC₅₀ values of 160 and 30 nM, respectively. In the absence of GTPS, the EC₅₀ for [Ca²⁺] was shifted rightward from 0.16 µM to 0.43 and 0.82 µM by 1 and 300 µM 8-bromo-cGMP (8-Br-cGMP), and to 8 µM by 10 µM Y-27632. Contractions induced by 300 nM [Ca²⁺] were relaxed by 8-Br-cGMP with an EC₅₀ of 2.6 µM. Surprisingly, [Ca²⁺]-induced contractions were also relaxed by 8-Br-cGMP in aortas from cGKI^–/– mice (EC₅₀ of 19 µM). Western blot analysis of the vasodilator-stimulated phosphoprotein indicated "cross"-activation of PKA by 1 mM 8-Br-cGMP in aortic smooth muscle cells from cGKI^–/– mice. Indeed, the PKA inhibitor peptide (PKI 5–24) completely abolished the relaxant effect of 8-Br-cGMP in muscles from cGKI^–/– mice and to 65% in wild-type aortas. The thromboxane analogue U-46619 induced contraction at constant [Ca²⁺], which was only partially relaxed by 8-Br-cGMP but completely relaxed by Y-27632. The effect of 8-Br-cGMP on U-46619-induced contraction was attenuated by PKI 5–24. These results show that cGKI has only a small inhibitory effect on Ca²⁺ sensitization in murine aortas.

calcium sensitization; Rho kinase; U-46619

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