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Abstract We reported previously that increasing cAMP levels in endothelial cells attenuated ATP-induced increases in hydraulic conductivity ( L p ), and that the activation of cGMP-dependent pathways was a necessary step to increase L p in response to inflammatory mediators. The aim of the present study was to evaluate the role of basal levels of cAMP in microvessel permeability under resting conditions and to evaluate the cross talk between cAMP- and cGMP-dependent signaling mechanisms in regulation of microvessel permeability under stimulated conditions, using individually perfused microvessels from frog and rat mesenteries. We found that reducing cAMP levels by inhibition of adenylate cyclase or inhibiting cAMP-dependent protein kinase through the use of H-89 increased basal L p in both frog and rat mesenteric venular microvessels. We also found that 8-bromocAMP (8-BrcAMP, 0.2 and 2 mM) was sufficient to attenuate or abolish the increases in L p due to exposure of frog mesenteric venular microvessels to 8-BrcGMP (2 mM) and ATP (10 μM). Similarly, in rat mesenteric venular microvessels, application of 8-BrcAMP (2 mM) abolished the increases in L p due to exposure to 8-BrcGMP alone (2 mM) or with the combination of bradykinin (1 nM). In addition, application of erythro-9-(2-hydroxy-3-nonyl)adenine, an inhibitor of cGMP-stimulated phosphodiesterase, significantly attenuated both 8-BrcGMP- and bradykinin-induced increases in L p . These results demonstrate that basal levels of cAMP are critical to maintaining normal permeability under resting conditions, and that increased levels of cAMP are capable of overcoming the activation of cGMP-dependent pathways, therefore preventing increases in microvessel permeability. The balance between endothelial concentrations of these two opposing cyclic nucleotides controls microvessel permeability, and cAMP levels play a dominant role. hydraulic conductivity adenosine 3′,5′-cyclic monophosphate analog guanosine 3′,5′-cyclic monophosphate analog erythro-9-(2-hydroxy-3-nonyl)adenine-phosphodiesterase inhibitor adenylate cyclase inhibitor Footnotes Address for reprint requests and other correspondence: P. He, Dept. of Human Physiology, School of Medicine, Univ. of California Davis, One Shields Ave., Davis, CA 95616-8644 (E-mail: pnhe@ucdavis.edu ). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “ advertisement ” in accordance with 18 U.S.C. §1734 solely to indicate this fact. Copyright © 2000 the American Physiological Society
AJP - Heart and Circulatory Physiology – The American Physiological Society
Published: Apr 1, 2000
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