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

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.

References

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    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.

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Correspondence to Dominik Bernhard.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Bernhard, D., Hofmann, F. & Schlossmann, J. Relaxation of vascular smooth muscle by the cGMP-kinase substrate IRAG. BMC Pharmacol 7, P8 (2007). https://doi.org/10.1186/1471-2210-7-S1-P8

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Keywords

  • Vascular Smooth Muscle
  • Inositol
  • Mutant Mouse
  • Hind Limb
  • Vascular Tone