Characterization of the effects of two new arginine/citrulline analogues on constitutive and inducible nitric oxide synthases in rat aorta.
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 microM), whereas 100 microM 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 microM). 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 microM) significantly potentiated contractile responses to phenylephrine (pEC50: 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.(ABSTRACT TRUNCATED AT 250 WORDS)[1]References
- Characterization of the effects of two new arginine/citrulline analogues on constitutive and inducible nitric oxide synthases in rat aorta. Joly, G.A., Narayanan, K., Griffith, O.W., Kilbourn, R.G. Br. J. Pharmacol. (1995) [Pubmed]
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