Volume 14 Supplement 1

6th International Conference on cGMP: Generators, Effectors and Therapeutic Implications

Open Access

Dual actions of ANP on endothelial permeability

  • Wen Chen1,
  • Heike Oberwinkler1,
  • Franziska Werner1,
  • Birgit Gaßner1,
  • Hitoshi Nakagawa1,
  • Robert Feil2,
  • Franz Hofmann3,
  • Jens Schlossmann4,
  • Alexander Dietrich5,
  • Thomas Gudermann5,
  • Motohiro Nishida6,
  • Sabrina Del Galdo7,
  • Thomas Wieland7 and
  • Michaela Kuhn1Email author
BMC Pharmacology and Toxicology201314(Suppl 1):O35

https://doi.org/10.1186/2050-6511-14-S1-O35

Published: 29 August 2013

Atrial natriuretic peptide (ANP), via its cGMP-forming guanylyl cyclase-A (GC-A) receptor, is critically involved in the regulation of arterial blood pressure and intravascular volume. To elucidate the role of the endothelial effects of ANP, we generated mice with conditional, endothelium (EC)-restricted ablation of the GC-A gene. Our observations in these and control mice demonstrated that ANP, via GC-A, mildly stimulates systemic transendothelial albumin transport in the microvasculature of skeletal muscle and skin. These and other studies indicate that concerted renal diuretic/natriuretic and mild endothelial hyperpermeability actions of ANP are essential to adjust intravascular fluid volume.

However, this notion apparently contradicts published in vitro and in vivo studies showing that ANP can strenghen the pulmonary barrier under inflammatory conditions, suggesting that the hormone either acts differently on pulmonary vs systemic endothelium, or it exerts opposite effects on quiescent endothelia (enhanced permeability) and an inflammation-activated endothelium (barrier stabilization). Endothelial hyperpermeability is characteristic of many systemic diseases, such as allergic responses, edema, and sepsis. In particular, histamine markedly and acutely enhances endothelial permeability. Activation of endothelial Gq-coupled H1 receptors activates phospholipase C and elevates intracellular [Ca2+], ultimately leading to actin-myosin contraction and paracellular leakiness.

Here we combined studies in microvascular endothelial cells and intravital microscopy of vascular permeability in the m. cremaster microcirculation to study whether ANP counteracts not only pulmonary but also systemic inflammation, i.e. histamine-induced hyperpermeability. Our observations reveal that transient receptor potential canonical (TRPC) 6 channels mediate the inflammatory effects of histamine. Most importantly, they characterize a regulatory pathway by which histamine-induced activation of TRPC6 channels and subsequent calcium-dependent acute endothelial hyperpermeability are prevented by ANP/GC-A-induced, cGMP-dependent protein kinase I (cGKI) - mediated inhibitory phosphorylation of these channels.

Declarations

Acknowledgement

This work was supported by SFB 688.

Authors’ Affiliations

(1)
Institute of Physiology, University of Würzburg
(2)
Interfakultäres Institut für Biochemie, University of Tübingen
(3)
FOR 923, Technical University München
(4)
Institute of Pharmacology and Toxicology, University of Regensburg
(5)
Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University München
(6)
Department of Drug Discovery and Evolution, Graduate School of Pharmaceutical Sciences, Kyushu University
(7)
Institute of Experimental Pharmacology and Toxicology, Medical Faculty Mannheim, Heidelberg University

Copyright

© Chen et al; licensee BioMed Central Ltd. 2013

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://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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