Effects of guanidino compounds on the endothelium-derived relaxing factor inhibitor NG-monomethyl L-arginine

Abstract

The vasoconstrictor effect of NG-monomethyl L-arginine (L-NMMA) is believed to be due to the inhibition of the synthesis of endothelium-derived relaxing factor (EDRF) from L-arginine. Here, we tested a series of guanidino compounds other than L-arginine on the rat aorta preparation with and without endothelium present. None of the compounds promoted vascular relaxation like N alpha-benzoyl L-arginine ethyl ester or elicited vasoconstriction like L-NMMA. We discovered that the two guanidino compounds, L-homoarginine (L-HA) and L-amino-tau-guanidino butyric acid (L-AGBA), behave like L-arginine and reversed the vasoconstrictor effect of L-NMMA. This effect was stereospecific and concentration-dependent. The order of potency to overcome the effects of L-NMMA was L-HA, followed by L-AGBA. This was the same order of potency for overcoming the inhibitory effects of L-NMMA on cyclic GMP formation. Two related compounds, L-amino guanidino propionic acid and guanidine, were ineffective. Furthermore, high performance liquid chromatography analysis showed that rat aortic vessels contain the same amount of L-arginine in the presence or absence of endothelium, and no detectable amount of L-citruline is formed during endothelium-dependent relaxation. We conclude that the reversal of the effects of L-NMMA by L-HA and L-AGBA is due to their structural similarities to L-NMMA and not to synthesis of an EDRF-like material from these guanidines. We suggest that some of the inhibition of L-NMMA by L-arginine may have a similar basis of structural antagonism.