Atrial Natriuretic Peptide–Mediated Inhibition of Microcirculatory Endothelial Ca <sup>2+</sup> and Permeability Response to Histamine Involves cGMP-Dependent Protein Kinase I and TRPC6 Channels

DOI Web Site 3 Citations 42 References
  • Wen Chen
    From the Institute of Physiology, University of Würzburg, Würzburg, Germany (W.C., H.O., F.W., B.G., H.N., M.K.); Interfakultäres Institut für Biochemie, University of Tübingen, Tübingen, Germany (R.F.); FOR 923, Technical University München, Garching, Germany (F.H.); Institute of Pharmacology and Toxicology, University of Regensburg, Regensburg, Germany (J.S.); Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University München, Munich, Germany (A.D., T.G.); Department...
  • Heike Oberwinkler
    From the Institute of Physiology, University of Würzburg, Würzburg, Germany (W.C., H.O., F.W., B.G., H.N., M.K.); Interfakultäres Institut für Biochemie, University of Tübingen, Tübingen, Germany (R.F.); FOR 923, Technical University München, Garching, Germany (F.H.); Institute of Pharmacology and Toxicology, University of Regensburg, Regensburg, Germany (J.S.); Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University München, Munich, Germany (A.D., T.G.); Department...
  • Franziska Werner
    From the Institute of Physiology, University of Würzburg, Würzburg, Germany (W.C., H.O., F.W., B.G., H.N., M.K.); Interfakultäres Institut für Biochemie, University of Tübingen, Tübingen, Germany (R.F.); FOR 923, Technical University München, Garching, Germany (F.H.); Institute of Pharmacology and Toxicology, University of Regensburg, Regensburg, Germany (J.S.); Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University München, Munich, Germany (A.D., T.G.); Department...
  • Birgit Gaßner
    From the Institute of Physiology, University of Würzburg, Würzburg, Germany (W.C., H.O., F.W., B.G., H.N., M.K.); Interfakultäres Institut für Biochemie, University of Tübingen, Tübingen, Germany (R.F.); FOR 923, Technical University München, Garching, Germany (F.H.); Institute of Pharmacology and Toxicology, University of Regensburg, Regensburg, Germany (J.S.); Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University München, Munich, Germany (A.D., T.G.); Department...
  • Hitoshi Nakagawa
    From the Institute of Physiology, University of Würzburg, Würzburg, Germany (W.C., H.O., F.W., B.G., H.N., M.K.); Interfakultäres Institut für Biochemie, University of Tübingen, Tübingen, Germany (R.F.); FOR 923, Technical University München, Garching, Germany (F.H.); Institute of Pharmacology and Toxicology, University of Regensburg, Regensburg, Germany (J.S.); Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University München, Munich, Germany (A.D., T.G.); Department...
  • Robert Feil
    From the Institute of Physiology, University of Würzburg, Würzburg, Germany (W.C., H.O., F.W., B.G., H.N., M.K.); Interfakultäres Institut für Biochemie, University of Tübingen, Tübingen, Germany (R.F.); FOR 923, Technical University München, Garching, Germany (F.H.); Institute of Pharmacology and Toxicology, University of Regensburg, Regensburg, Germany (J.S.); Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University München, Munich, Germany (A.D., T.G.); Department...
  • Franz Hofmann
    From the Institute of Physiology, University of Würzburg, Würzburg, Germany (W.C., H.O., F.W., B.G., H.N., M.K.); Interfakultäres Institut für Biochemie, University of Tübingen, Tübingen, Germany (R.F.); FOR 923, Technical University München, Garching, Germany (F.H.); Institute of Pharmacology and Toxicology, University of Regensburg, Regensburg, Germany (J.S.); Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University München, Munich, Germany (A.D., T.G.); Department...
  • Jens Schlossmann
    From the Institute of Physiology, University of Würzburg, Würzburg, Germany (W.C., H.O., F.W., B.G., H.N., M.K.); Interfakultäres Institut für Biochemie, University of Tübingen, Tübingen, Germany (R.F.); FOR 923, Technical University München, Garching, Germany (F.H.); Institute of Pharmacology and Toxicology, University of Regensburg, Regensburg, Germany (J.S.); Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University München, Munich, Germany (A.D., T.G.); Department...
  • Alexander Dietrich
    From the Institute of Physiology, University of Würzburg, Würzburg, Germany (W.C., H.O., F.W., B.G., H.N., M.K.); Interfakultäres Institut für Biochemie, University of Tübingen, Tübingen, Germany (R.F.); FOR 923, Technical University München, Garching, Germany (F.H.); Institute of Pharmacology and Toxicology, University of Regensburg, Regensburg, Germany (J.S.); Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University München, Munich, Germany (A.D., T.G.); Department...
  • Thomas Gudermann
    From the Institute of Physiology, University of Würzburg, Würzburg, Germany (W.C., H.O., F.W., B.G., H.N., M.K.); Interfakultäres Institut für Biochemie, University of Tübingen, Tübingen, Germany (R.F.); FOR 923, Technical University München, Garching, Germany (F.H.); Institute of Pharmacology and Toxicology, University of Regensburg, Regensburg, Germany (J.S.); Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University München, Munich, Germany (A.D., T.G.); Department...
  • Motohiro Nishida
    From the Institute of Physiology, University of Würzburg, Würzburg, Germany (W.C., H.O., F.W., B.G., H.N., M.K.); Interfakultäres Institut für Biochemie, University of Tübingen, Tübingen, Germany (R.F.); FOR 923, Technical University München, Garching, Germany (F.H.); Institute of Pharmacology and Toxicology, University of Regensburg, Regensburg, Germany (J.S.); Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University München, Munich, Germany (A.D., T.G.); Department...
  • Sabrina Del Galdo
    From the Institute of Physiology, University of Würzburg, Würzburg, Germany (W.C., H.O., F.W., B.G., H.N., M.K.); Interfakultäres Institut für Biochemie, University of Tübingen, Tübingen, Germany (R.F.); FOR 923, Technical University München, Garching, Germany (F.H.); Institute of Pharmacology and Toxicology, University of Regensburg, Regensburg, Germany (J.S.); Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University München, Munich, Germany (A.D., T.G.); Department...
  • Thomas Wieland
    From the Institute of Physiology, University of Würzburg, Würzburg, Germany (W.C., H.O., F.W., B.G., H.N., M.K.); Interfakultäres Institut für Biochemie, University of Tübingen, Tübingen, Germany (R.F.); FOR 923, Technical University München, Garching, Germany (F.H.); Institute of Pharmacology and Toxicology, University of Regensburg, Regensburg, Germany (J.S.); Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University München, Munich, Germany (A.D., T.G.); Department...
  • Michaela Kuhn
    From the Institute of Physiology, University of Würzburg, Würzburg, Germany (W.C., H.O., F.W., B.G., H.N., M.K.); Interfakultäres Institut für Biochemie, University of Tübingen, Tübingen, Germany (R.F.); FOR 923, Technical University München, Garching, Germany (F.H.); Institute of Pharmacology and Toxicology, University of Regensburg, Regensburg, Germany (J.S.); Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University München, Munich, Germany (A.D., T.G.); Department...

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<jats:sec> <jats:title>Objective—</jats:title> <jats:p>Histamine increases microvascular endothelial leakage by activation of complex calcium-dependent and -independent signaling pathways. Atrial natriuretic peptide (ANP) via its cGMP-forming guanylyl cyclase-A (GC-A) receptor counteracts this response. Here, we characterized the molecular mechanisms underlying this interaction, especially the role of cGMP-dependent protein kinase I (cGKI).</jats:p> </jats:sec> <jats:sec> <jats:title>Approach and Results—</jats:title> <jats:p> We combined intravital microscopy studies of the mouse cremaster microcirculation with experiments in cultured microvascular human dermal endothelial cells. In wild-type mice, ANP had no direct effect on the extravasation of fluorescent dextran from postcapillary venules, but strongly reduced the histamine-provoked vascular leakage. This anti-inflammatory effect of ANP was abolished in mice with endothelial-restricted inactivation of GC-A or cGKI. Histamine-induced increases in endothelial [Ca <jats:sup>2+</jats:sup> ] <jats:sub>i</jats:sub> in vitro and of vascular leakage in vivo were markedly attenuated by the Ca <jats:sup>2+</jats:sup> -entry inhibitor SKF96365 and in mice with ablated transient receptor potential canonical (TRPC) 6 channels. Conversely, direct activation of TRPC6 with hyperforin replicated the hyperpermeability responses to histamine. ANP, via cGKI, stimulated the inhibitory phosphorylation of TRPC6 at position Thr <jats:sub>69</jats:sub> and prevented the hyperpermeability responses to hyperforin. Moreover, inhibition of cGMP degradation by the phosphodiesterase 5 inhibitor sildenafil prevented the edematic actions of histamine in wild types but not in mice with endothelial GC-A or cGKI deletion. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions—</jats:title> <jats:p>ANP attenuates the inflammatory actions of histamine via endothelial GC-A/cGMP/cGKI signaling and inhibitory phosphorylation of TRPC6 channels. The therapeutic potential of this novel regulatory pathway is indicated by the observation that sildenafil improves systemic endothelial barrier functions by enhancing the endothelial effects of endogenous ANP.</jats:p> </jats:sec>

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