TRANSPORT OF NITRIC-OXIDE SYNTHASE INHIBITORS THROUGH CATIONIC AMINO-ACID CARRIERS IN HUMAN ERYTHROCYTES

The interaction of arginine analogues, which are known to inhibit nitr ic oxide synthase, with two cationic amino acid transporters of human erythrocytes (systems y(+) and y(+)L) was studied. Arginine and releva nt analogues [N-G-monomethyl-L-arginine (L-NMMA); N-G-monomethyl-D-arg inine (D-NMMA) and N-G-nitro-L-arginine (L-NOARG)] were found to inhib it labeled lysine influx into intact erythrocytes. As expected, the pa ttern of inhibition reflected the contribution of the two distinct tra nsport systems. All analogues showed a higher affinity for system y(+) L than for system y(+). The half-saturation; (inhibition) constants es timated for systems y(+) and y(+)L (+/-SEM) were (mu M): L-arginine, 5 5.7 +/- 5.4 and 2.4 +/- 0.1; L-NMMA, 151 +/- 13 and 7.5 +/- 0.5; D-NMM A, 2660 +/- 404 and 269 +/- 25; L-NOARG, 9414 +/- 169 and 594 +/- 35. The transport properties of the analogues were investigated using an a ssay based on the trans-stimulation of lysine efflux. The addition of saturating concentrations of unlabeled analogues to the external mediu m stimulated efflux of labeled lysine through systems y(+)L and y(+), showing that the analogues can enter the cell through these pathways.