Effects of Some Guanidino Compounds on Human Cerebral Arteries

Abstract

Background and Purpose —Accumulation of endogenous guanidino-substituted analogues of l -arginine in chronic renal failure might contribute to some of the vascular and neurological disorders of this pathology. We tested the hypothesis that in human cerebral arteries, some guanidino compounds may increase vascular tone, through nitric oxide (NO) synthase inhibition, and impair endothelium-dependent relaxation. Methods —Rings of human middle cerebral artery were obtained during autopsy of 26 patients who had died 3 to 12 hours before. The rings were suspended in organ baths for isometric recording of tension. We then studied the responses to N G -monomethyl- l -arginine (L-NMMA), N G , N G -dimethyl- l -arginine (asymmetrical dimethylarginine; ADMA), aminoguanidine (AG), and methylguanidine (MG). Results —L-NMMA (10 −6 to 3×10 −4 mol/L) and ADMA (10 −6 to 3×10 −4 mol/L) caused concentration- and endothelium-dependent contractions (median effective concentrations [EC 50 ]=1.1×10 −5 and 1.6×10 −5 mol/L, respectively; E max =35.5±7.9% and 43.9±5.9% of the response to 100 mmol/L KCl). AG (10 −5 to 3×10 −3 mol/L) and MG (10 −5 to 3×10 −3 mol/L) produced endothelium-independent contractions (E max =44.3±8.8% and 45.7±5.8% of the response to 100 mmol/L KCl, respectively). l -Arginine (10 −3 mol/L) prevented the contractions by L-NMMA and ADMA but did not change contractions induced by AG and MG. L-NMMA and ADMA inhibited endothelium-dependent relaxation induced by acetylcholine in a concentration-dependent manner; AG and MG were without effect. Conclusions —The results suggest that the contractions induced by L-NMMA and ADMA are due to inhibition of endothelial NO synthase activity, whereas AG and MG do not affect the synthesis of NO. An increase in the plasma concentration of L-NMMA and ADMA associated with uremia is likely to represent a diminished release or effect of NO, and consequently, an increased cerebrovascular tone in uremic patients is highly conceivable.