It is becoming increasingly apparent that the effects of a variety of neurotransmitters, hormones and mediators derived from either blood or brain can be positively or negatively influenced by the simultaneous activation of other neurotransmitter/neuromodulator systems. These interactions can subsequently modulate the function of various central nervous system (CNS) constituents, such as neuronal excitability, blood- brain barrier (BBB) permeability, vasomotor responses, etc., during both physiologic and pathophysiologic conditions. An important aspect of these intercommunications occurs at the level of cellular second messenger systems. However, little is known about the existence and possible intracellular mechanisms of interactions between histamine with other neurotransmitters and their influence on endothelial function. This study demonstrates the presence of histaminergic (H1 and H2) and purinergic (A1 and A2) receptors on endothelial cells derived from human brain microvessels. Histamine dose-dependently increased both inositol triphosphate (IP3) (EC50=10.2+/-0.9 micromoles) and cyclic adenosine monophosphate (cAMP) (EC50=5.2 +/- 0.9 micromoles) formation in human brain endothelial cells (HBEC). IP3 generation was completely abolished by the H1 receptor antagonists mepyramine maleate and chlorpheniramine, but not by the H2 receptor antagonist cimetidine, whereas cAMP production was only efficiently inhibited by cimetidine. Selective A1 receptor agonists decreased, whereas selective A2 receptor agonists increased cAMP production by HBEC. Concomitant treatment of HBEC with histamine and A1- or A2-receptor agonists resulted in inhibition of histamine-induced IP3 stimulation. This effect was reversed in the presence of specific A1 and A2 receptor antagonists, respectively. Marked augmentation of histamine~induced cAMP production by HBEC was observed in the presence of an A2 agonist; this response was diminished by H1 antagonists. Overnight pretreatment of HBEC with pertussis toxin abolished both histamine- and adenosine analog-induced changes of second messengers as well as their interactions, indicating an essential role for G-proteins in these responses. It is suggested that the interaction between histamine and adenosine which modulates induction of second messengers in HBEC may influence endothelium-mediated responses of the brain microvascular compartment.
