Reduction of endothelial monolayer hyperpermeability by cgmp -dependent mechanisms: special role of nitric oxide and phosphodiesterase isoenzyme ii. Suttorp, Norbert, Stefan Hippenstiel, Martin Fuhrmann, Matthias Kr[umlaut]ull, and Thomas Podzuweit. Department of Internal Medicine, Justus Liebig-University of Giessen, Klinikstrasse 36, 35392 Giessen, Germany, Max Planck Institute for Physiology, Benekestrasse 2, 61231 Bad Nauheim, Germany
APStracts 2:0339C, 1995.
Regulation of endothelial permeability is poorly understood. Previous studies had shown that endothelial cells contain phosphodiesterase (PDE) isoenzymes II-IV and that simul taneous adenylate cyclase activation/PDE-inhibition blocked endothelial hyperpermeability (J. Clin. Invest.91:1421-1428,1993). Now we focused on a possible role of cGMP-dependent mechanisms and studied hydrogen peroxide (H202) -exposed porcine pulmonary artery endothelial cell monolayers. Pretreatment of cells with different NO donors or atrial natriuretic peptide (ANP) increased endothelial cGMP-content severalfold and blocked H202-related effects on permeability; opposite results were obtained with a NO-synthase inhibitor. Determination of cGMP degradation in nitroprusside exposed endothelial cells identified PDE II as the major cGMP metabolizing pathway, while PDE III and IV contributed little or nothing. Inhibition of PDE II reduced H202 -related endothelial hyperpermeability, an effect that could be enhanced synergistically by simultaneous guanylate cyclase activation. In summary, these studies indicate that cGMP-dependent mechanisms (NO-donors, ANP, dibutyryl-cGMP) blocked H202-related increases in endothelial permeability. The major cGMP degrading pathway in endothelial cells was PDE II, thereby substituting the missing PDE V in these cells. Simultaneous guanylate cyclase activation/PDE II inhi bition may be a valuable approach to treat endothelial hyperpermeability. 

Received 31 October 1994; accepted in final form 6 September
1995.
APS Manuscript Number C647-4.
Article publication pending Am. J. Physiol. (Cell Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 23 September 1995.