Asymmetric dimethylarginine (ADMA) inhibits basal but not acetylcholine-induced activity of nitric oxide in rat aorta

Mohammed AL Zobaidy, John Craig, William Martin. University of Glasgow, Glasgow, United Kingdom.

Asymmetric dimethylarginine (NG,NG-dimethyl-L-arginine; ADMA) is recognised as an endogenously produced inhibitor of nitric oxide synthase (NOS; Leiper & Vallance, 2006). We have previously shown that NG-monomethyl-L-arginine (L-NNMA) inhibits basal but not agonist-induced activity of NO in rat aorta (Frew et al., 1993). The aim of this project was to determine if ADMA acts similarly to L-NMMA in rat aorta.

Aortic rings from female rats were mounted under 10 mN resting tension in tissue baths containing Krebs solution at 37°C. Tension was induced using phenylephrine (PE) before obtaining relaxation to acetylcholine (Ach; 1 nM-10 μM). Contractions are expressed in mN and relaxations as % of PE-induced tone (mean ± SEM of n>6 observations), with statistical differences determined by ANOVA followed by the Bonferroni test.

In the presence of low PE-induced tone (2.8±0.4 mN), the addition of 100 μM L-NMMA or ADMA augmented tone further (to 13.3±1.1 and 15.1±2.1 mN, respectively, P<0.001 for both), consistent with inhibition of basal NO activity. Higher concentrations of ADMA (300 and 1000 μM) did not potentiate PE tone further. In the presence of the elevated tone produced by ADMA, Ach-induced relaxation appeared blocked (Emax 22.1±3.1%, P<0.001) when compared with controls (77.5±7.8%) obtained at submaximal PE tone 11.9±2.1 mN). However, if tissues were treated with ADMA (100 μM) and then contracted to submaximal tone with PE, Ach-induced relaxation was not inhibited (Emax 77.3±3.7%). Higher concentrations of ADMA (300 and 1000 μM) also failed to inhibit Ach-induced relaxation in tissues submaximally contracted with PE.

Thus, ADMA, like L-NMMA (Frew et al., 1993), blocks basal but not Ach-induced relaxation in rat aorta. The apparent blockade of Ach-induced relaxation by ADMA seen at maximal levels of tone can be explained by physiological antagonism but not by inhibition of NOS. Further studies are required to determine why ADMA and L-NMMA block basal but not agonist-induced NO-dependent relaxation in rat aorta.

Leiper, J.M. & Vallance, P. 2006. Eur. J. Clin. Pharmacol., 62: 33-38.
Frew, J.D. et al., 1993. Br. J. Pharmacol., 110: 1003-1008.