HUMAN MONOCYTE ADHESION IS MODULATED BY ENDOTHELIN-B RECEPTOR-COUPLEDNITRIC-OXIDE RELEASE

Human monocytes have the capacity to produce both endothelin 1 (ET-1) and nitric oxide (NO), yet the roles of these mediators in monocyte fu nction remain unclear. The relationship of ET-1 and NO release to mono cyte adhesion was explored using peripheral blood monocytes (PBM) and the human monocytic cell lines THP-1 and U937, Specific binding of I-1 25-Iabeled ET-I to THP-I was abrogated by pretreatment with the endoth elin B (ET(B)) receptor antagonist, BQ-788, but not by the endothelin A (ET(A)) receptor antagonist, BQ-123, consistent with predominant ET( B) receptor expression. Direct measurement of NO with an amperometric probe demonstrated the production of nanomolar concentrations of NO by PBM and THP-1 cells upon treatment with ET-1, which was abrogated by BQ-788, but not BQ-123, pretreatment, suggesting functional coupling o f ET(B) receptors to NO release. Indeed, the presence of ET(B) recepto r mRNA transcripts was detected in THP-1 and is consistent with previo us reports that have demonstrated functional coupling of ET(B) recepto rs to constitutive NO synthase activation, In contrast, U937 cells did not release NO in response to ET-I treatment, and mRNA transcripts we re not detected in these cells, consistent their failure to bind I-125 -labeled ET-1, as previously determined. Exposure of PBM to ET-1 marke dly reduced the adhesion of these cells to human saphenous vein, where as PBM adhesion in the presence of BQ-788 was restored to control leve ls, These data demonstrate that PBM interactions with the vascular wal l can be reduced by autocrine production of NO and suggest that ET(B) receptors may attenuate monocyte activity at sites of inflammation.