CA2-INHIBITABLE ADENYLYL-CYCLASE AND PULMONARY MICROVASCULAR PERMEABILITY()

Intracellular mechanisms responsible for endothelial cell disruption a re unknown, although either elevated cytosolic Ca2+ ([Ca2+](i)) or dec reased adenosine 3',5'-cyclic monophosphate (cAMP) promotes permeabili ty. Recent identification that Ca2+-inhibitable adenylyl cyclase estab lishes an inverse relationship between [Ca2+](i) and cAMP in macrovasc ular 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 Ca2+-inhibitable adenylyl cy clase in pulmonary microvascular endothelium and 2) Ca2+ inhibition of adenylyl cyclase and cAMP content as a paradigm for inflammatory medi ator-induced permeability in the intact circulation. We therefore addr essed these issues in microvascular endothelial cells derived from rat lung and in an isolated perfused rat lung preparation. Results demons trate expression of a Ca2+-inhibitable adenylyl cyclase in microvascul ar endothelial cells. Furthermore, data suggest that Ca2+ inhibition o f adenylyl cyclase is necessary for development of microvascular perme ability in the intact circulation. We conclude Ca2+ inhibition of cAMP represents a critical step in genesis of microvascular permeability i n the intact pulmonary circulation.