Ca(2+)-inhibitable adenylyl cyclase and pulmonary microvascular permeability.
Intracellular mechanisms responsible for endothelial cell disruption are unknown, although either elevated cytosolic Ca2+ ([Ca2+]i) or decreased adenosine 3',5'-cyclic monophosphate (cAMP) promotes permeability. Recent identification that Ca(2+)-inhibitable adenylyl cyclase establishes an inverse relationship between [Ca2+]i and cAMP in macrovascular endothelial cells provided a possible mechanism of development of permeability. However, these data utilized an in vitro model; lacking was evidence supporting 1) expression of Ca(2+)-inhibitable adenylyl cyclase in pulmonary microvascular endothelium and 2) Ca2+ inhibition of adenylyl cyclase and cAMP content as a paradigm for inflammatory mediator-induced permeability in the intact circulation. We therefore addressed these issues in microvascular endothelial cells derived from rat lung and in an isolated perfused rat lung preparation. Results demonstrate expression of a Ca(2+)-inhibitable adenylyl cyclase in microvascular endothelial cells. Furthermore, data suggest that Ca2+ inhibition of adenylyl cyclase is necessary for development of microvascular permeability in the intact circulation. We conclude Ca2+ inhibition of cAMP represents a critical step in genesis of microvascular permeability in the intact pulmonary circulation.
Chetham
P M
PM
Department of Anesthesiology, University of Colorado-Health Sciences Center, Denver 80262, USA.
Guldemeester
H A
HA
Mons
N
N
Brough
G H
GH
Bridges
J P
JP
Thompson
W J
WJ
Stevens
T
T
D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000096:biosynthesis* / Q000737:chemistry; D000595:Amino Acid Sequence; D000818:Animals; D000918:Antibody Specificity; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000494:pharmacology*; D002196:Capillaries / Q000187:drug effects / Q000502:physiology; D002199:Capillary Permeability / Q000187:drug effects; D002478:Cells, Cultured; D017931:DNA Primers; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology* / Q000293:injuries; D008297:Male; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology; D016133:Polymerase Chain Reaction; D011652:Pulmonary Circulation / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019284:Thapsigargin / Q000494:pharmacology
D000067956:Adenylyl Cyclase Inhibitors; D017931:DNA Primers; D010446:Peptide Fragments; D019284:Thapsigargin; D000262:Adenylyl Cyclases; D002118:Calcium