1 New potent inhibitors of nitric oxide synthase (NOS) may be useful in the treatment of septic shock, a disorder characterized by a vascular hyporeactivity to catecholamines caused by an overproduction of nitric oxide (NO-). We examined the effects of L-thiocitrulline (L-TC) and S-methyl-L-thiocitrulline (L-SMTC), novel NOS inhibitors, on the constitutive and inducible NOS in rat aorta and compared those effects with inhibition due to NG-methyl-L-arginine (L-NMA). 2 Phenylephrine evoked similar concentration-contraction curves in the control rings and in the rings treated with these different NOS inhibitors (10 gM), whereas 100 MM of L-NMA, L-TC or L-SMTC increased significantly, and to a similar extent, contractions evoked by phenylephrine in aortic rings with endothelium without significantly affecting the maximal responses. 3 Relaxations evoked by acetylcholine, adenosine triphosphate, or calcium ionophore were significantly inhibited in a dose-dependent manner by L-NMA, L-SMTC, or L-TC (10-100 gM). The potencies of these inhibitors in reducing the relaxations of these vasodilators were not significantly different. 4 In endotoxin-treated preparations with endothelium, the three L-arginine analogues (10 MM) significantly potentiated contractile responses to phenylephrine (pEC5o: 6.73 ± 0.12 and 7.3 + 0.12, 7.34 + 0.13, or 7.22 ± 0.14; in the absence and the presence of L-NMA, L-TC, or L-SMTC respectively) and increased maximal contractions from 1.53 +0.15 g to 1.95 +0.13 g, 2.08 ±0.12 g, and 2.03 ±0.13 g with L-NMA, L-TC, and L-SMTC respectively. A higher concentration of these NOS inhibitors (100 MM) further increased contractions evoked by this a,-agonist without further enhancing the maximal contractions; however, contractions evoked by 10 nM phenylephrine were significantly greater in the presence of L-SMTC or L-TC than in the presence of L-NMA (100 gM) (L-NMA: 0.4 + 0.11 g; L-TC: 0.78 +0.14 g and L-SMTC: 0.82+±0.17 g). The effects of these inhibitors on NO-synthesis induced by endotoxin were significantly reversed by addition of L-arginine (1 mM) but not by L-citrulline (1 mM). In LPS-treated rings with endothelium, all three NOS inhibitors (100 FM) shifted the concentrationcontraction curves evoked by phenylephrine significantly to the left (pEC5o: 7.19 + 0.03 and 7.79 + 0.08, 8.01 + 0.07, or 8.02 + 0.07, in the absence and the presence of L-NMA, L-TC, or L-SMTC, respectively) and increased significantly maximal contractions from 2.05 + 0.05 g to 2.38 + 0.14 g, 2
