Kk. Mcdonald et al., INHIBITION OF ENDOTHELIAL-CELL AMINO-ACID-TRANSPORT SYSTEM Y(-OXIDE SYNTHASE() BY ARGININE ANALOGS THAT INHIBIT NITRIC), Biochimica et biophysica acta. Biomembranes, 1324(1), 1997, pp. 133-141
A variety of N-omega-monosubstituted L-arginine analogs are establishe
d inhibitors of nitric oxide synthase; in all cases, initial binding i
s competitive with the substrate L-arginine. The efficacy of such comp
ounds in vivo will depend on their transport into the relevant nitric
oxide synthase-containing cells; in fact, inhibition may actually be a
ugmented if cellular uptake of L-arginine is also blocked by the analo
gs, Because vascular endothelial cells synthesize vasoactive nitric ox
ide under both physiological and pathophysiological conditions, we hav
e performed inhibition analyses with novel arginine analogs to determi
ne the substrate specificity of the primary L-arginine transport syste
m, Na+-independent System y(+), present in porcine pulmonary artery en
dothelial cells. As reported by others, no Na+-independent System b(o,
+) activity was detectable, For System y(+), Dixon plots suggest compe
titive inhibition and apparent K-i values, which ranged between 0.1 an
d 0.8 mM, were estimated for each inhibitor, Some influence of amino a
cid side chain structure could be detected, but in general, the data e
stablish that this transport system accepts a broad range of arginine
derivatives, Loading the cells with individual arginine analogs result
ed in trans-stimulation of arginine uptake suggesting that they serve
as substrates of System y(+) as well as inhibitors. These results indi
cate that plasma membrane transport is unlikely to be a limiting facto
r in drug development for nitric oxide synthase inhibitors.