Accelerated intimal hyperplasia and increased endogenous inhibitors for NOsynthesis in rabbits with alloxan-induced hyperglycaemia

1 We examined whether endogenous inhibitors of NO synthesis are involved in the augmentation of intimal hyperplasia in rabbits with hyperglycaemia ind uced by alloxan. 2 Four weeks after the endothelial denudation of carotid artery which had b een performed 12 weeks after alloxan, the intimal hyperplasia was greatly a ugmented with hyperglycaemia. The degree of hyperplasia was assessed using three different parameters of histopathological findings as well as changes in luminal area and intima:media ratio. 3 There were positive and significant correlations between intima:media rat io, plasma glucose, and concentrations of N-G-monomethyl-L-arginine (L-NMMA ) and N-G, N-G-dimethyl-L-arginine (ADMA) in endothelial cells, that is, th e intima:media ratio became greater as plasma glucose and endothelial L-NMM A and ADMA were increased. Furthermore, endothelial L-NMMA and ADMA were in creased in proportion to the increase in plasma glucose. 4 In contrast, there were inverse and significant correlations between cycl ic GMP production by carotid artery strips with endothelium and plasma gluc ose, between cyclic GMP production and endothelial L-NMMA and ADMA, and bet ween the intima:media ratio and cyclic GMP production. 5 Exogenously applied L-NMMA;and ADMA inhibited cyclic GMP production in co ncentration-dependent manner. IC50 values were determined to be 12.1 mu M f or the former and 26.2 mu M for the latter. The cyclic GMP production was a bolished after the deliberate removal of endothelium from the artery strips . 6 These results suggest that the augmentation of intimal hyperplasia with h yperglycaemia is closely related to increased accumulation of L-NMMA and AD MA with hyperglycaemia, which would result in an accelerated reduction in N O production/release by endothelial cells.