Volume 7 Supplement 1

3rd International Conference on cGMP Generators, Effectors and Therapeutic Implications

Open Access

Relaxation of vascular smooth muscle by the cGMP-kinase substrate IRAG

BMC Pharmacology20077(Suppl 1):P8

DOI: 10.1186/1471-2210-7-S1-P8

Published: 25 July 2007

Intracellular signalling by NO/cGMP-dependent protein kinase type I (cGKI) relaxes smooth muscles thereby modulating e.g. vascular tone. An important mediator of this signalling cascade is the inositol 1,4,5,-trisphosphate receptor I (IP3 RI) associated protein cGMP kinase substrate (IRAG). This protein forms a trimeric complex together with the cGMP kinase Iβ and the IP3 RI. Recently, it was shown that the relaxation of hormone-contracted aortic smooth muscle by cGMP was abolished in IRAG Δ12/Δ12 mutant mice with a disrupted IRAG-IP3 RI interaction site [1]. Now we investigated whether IRAG might regulate the vascular tone in small vessels. NO-mediated relaxation of isolated arteria tibialis was nearly absent in the IRAG mutant. Moreover, the relaxing effect of IRAG on NO-mediated dilation of resistance vessels in perfused hind limbs of mutant mice was abolished.

To analyze the in vivio function of IRAG/IP3 RI interaction, we finally recorded blood pressure in conscious, freely moving animals via implanted radiotelemetric devices. After application of NO-donors blood pressure decrease was clearly diminished in IRAGΔ12/Δ12 mutants compared to control mice.

These data suggest that IRAG is essential for NO/cGMP-dependent relaxation of vascular smooth muscle.

Authors’ Affiliations

(1)
Institut für Pharmakologie und Toxikologie
(2)
Institut für Pharmakologie und Toxikologie, Universität Regensburg

References

  1. Geiselhoringer A, Werner M, Sigl K, Smital P, Worner R, Acheo L, Stieber J, Weinmeister P, Feil R, Feil S, Wegener J, Hofmann F, Schlossmann J: IRAG is essential for relaxation of receptor-triggered smooth muscle contraction by cGMP kinase. EMBO J. 2007, 23: 4222-4231. 10.1038/sj.emboj.7600440.View ArticleGoogle Scholar

Copyright

© Bernhard et al; licensee BioMed Central Ltd. 2007

This article is published under license to BioMed Central Ltd.

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