NITRIC-OXIDE REDUCES TUMOR-CELL ADHESION TO ISOLATED RAT POSTCAPILLARY VENULES

Adhesion of circulating tumor cells to microvascular endothelium plays an important role in tumor metastasis to distant organs. The purpose of this study was to determine whether nitric oxide (NO) would attenua te tumor cell adhesion (TCA) to naive or Lipopolysaccharide (LPS)-trea ted postcapillary venules. A melanoma cell line, RPMI 1846, was shown to be much more adhesive to postcapillary venules isolated from rat me sentery than to corresponding precapillary arterioles, Although venule s exposed to LPS for 4 h demonstrated an increased adhesivity for the melanoma cells, TCA to LPS-treated arterioles was not altered. Isolate d venules exposed to DETA/NO (1 mM), an NO donor, for 30 min prior to tumor cell perfusion prevented the increment in adhesion induced by LP S and attenuated TCA to naive postcapillary venules. While L-arginine (100 mu M), an NO precursor, failed to decrease TCA to naive postcapil lary venules, this treatment abolished LPS-stimulated TCA to postcapil lary venules. The effect of L-arginine was reversed by administration of N-omega-nitro-L-arginine methyl ester (L-NAME, 100 mu M), an NO syn thase (NOS) inhibitor. These observations indicate that both exogenous and endogenous NO modulate TCA to postcapillary venules. To assess th e role of NO-induced activation of cGMP in the reduction in TCA produc ed by DETA/NO, two additional series of experiments were conducted. In the first series, LY-83583 (10 mu M), a guanylyl cyclase inhibitor, w as shown to completely reverse the effect of DETA/NO on TCA to both na ive and LPS-activated postcapillary venules. On the other hand, admini stration of 8-bromoguanosine 3',5'-cyclic monophosphate (8-B-cGMP) (1 mM), a cell permeant cGMP analog, mimicked the effect of DETA/NO and r educed TCA to LPS-stimulated postcapillary venules. These data suggest that (a) tumor cells are more likely to adhere to postcapillary venul es than to corresponding precapillary arterioles, (b) LPS enhances TCA to postcapillary venules, (c) both exogenously applied (DETA/NO) and endogenously generated (L-arginine) NO attenuate the enhanced adhesion induced by LPS, but only DETA/NO reduced TCA to naive postcapillary v enules, and (d) the NO-induced reduction in TCA to LPS-activated postc apillary venules occurs by a cGMP-dependent mechanism.