INTERACTION BETWEEN HISTAMINE AND ADENOSINE IN HUMAN CEREBROMICROVASCULAR ENDOTHELIAL-CELLS - MODULATION OF 2ND MESSENGERS

This study demonstrates the presence of histamine H-1 and H-2 receptors and purinoreceptors A(1) and A(2) on endothelial cells derived from human brain microvessels (HBEC). Histamine induced formation of both inositol triphosphate (IP3) (EC(50) = 10.2 +/- 0.9 mu M) and cyclic adenosine monophosphate (cAMP) (EC(50) = 5.2 +/- 0.9 mu M) in HBEC in a concentration-dependent fashion. IP3 formation was inhibited by H-1 receptor antagonists mepyramine maleate and chlorphenyramine, but not by H-2 receptor antagonist cimetidine. Production of cAMP was efficiently inhibited by cimetidine. Selective A(1) receptor agonists decreased, whereas A(2) receptor agonists increased cAMP production in HBEC. When added together with histamine to HBEC cultures, both A(1) and A(2) receptor agonists diminished histamine-induced IP3 stimulation. This effect was reversed in the presence of specific A(1) and A(2) receptor antagonists, respectively. Marked augmentation of histamine-induced cAMP production by HBEC was observed in the presence of A(2) agonist. This response was dependent on H-1 receptors, since it was reduced in the presence of H-1-receptor antagonist. It is suggested that interaction between histamine and adenosine modulating induction of second messengers in HBEC may influence endothelium-dependent responses of brain microvascular compartments.