Effects of guanidino compounds on the endothelium-derived relaxing factor inhibitor NG-monomethyl L-arginine.
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.
Thomas
G
G
Department of Physiology and Biophysics, Georgetown University Medical Center, Washington, DC.
Ramwell
P W
PW
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D001120:Arginine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D006152:Cyclic GMP / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D006146:Guanidines / Q000494:pharmacology*; D006709:Homoarginine / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D051381:Rats; D011919:Rats, Inbred Strains; D019323:omega-N-Methylarginine
D006146:Guanidines; D006709:Homoarginine; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine; D006152:Cyclic GMP