Dominant role of cAMP in regulation of microvessel permeability

Am J Physiol Heart Circ Physiol. 2000 Apr;278(4):H1124-33. doi: 10.1152/ajpheart.2000.278.4.H1124.

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 microM). 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 8-Bromo Cyclic Adenosine Monophosphate / pharmacology
  • Adenine / analogs & derivatives
  • Adenine / pharmacology
  • Adenosine Triphosphate / pharmacology
  • Adenylyl Cyclase Inhibitors
  • Adenylyl Cyclases / metabolism
  • Animals
  • Bradykinin / pharmacology
  • Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Capillaries / chemistry
  • Capillaries / enzymology
  • Capillary Permeability / drug effects
  • Capillary Permeability / physiology*
  • Cyclic AMP / physiology*
  • Cyclic GMP / analogs & derivatives
  • Cyclic GMP / pharmacology
  • Cyclic GMP / physiology
  • Dideoxyadenosine / analogs & derivatives
  • Dideoxyadenosine / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Female
  • Isoquinolines / pharmacology
  • Male
  • Mesenteric Veins / physiology
  • Rana pipiens
  • Rats
  • Rats, Sprague-Dawley
  • Receptor Cross-Talk / physiology
  • Sulfonamides*
  • Venules / physiology

Substances

  • Adenylyl Cyclase Inhibitors
  • Enzyme Inhibitors
  • Isoquinolines
  • Sulfonamides
  • 8-Bromo Cyclic Adenosine Monophosphate
  • 8-bromocyclic GMP
  • Dideoxyadenosine
  • 9-(2-hydroxy-3-nonyl)adenine
  • Adenosine Triphosphate
  • 2',5'-dideoxyadenosine
  • Cyclic AMP
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Adenylyl Cyclases
  • Cyclic GMP
  • Adenine
  • N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide
  • Bradykinin