Aminoguanidine‐effects on endoneurial vasoactive nitric oxide and on motor nerve conduction velocity in control and streptozotocin‐diabetic rats

Abstract

1 The e ects of aminoguanidine (AG) treatment on reductions in motor nerve conduction velocity (MNCV) and sciatic nerve blood¯ow, indexed by laser Doppler¯ux (LDF), were investigated in rats with experimental diabetes (streptozotocin-induced; 8 ± 10 weeks duration). The contribution of endoneurial vasoactive nitric oxide to the LDF of these animals was also investigated by the direct micro-injection of N G -nitro-L-arginine methyl ester (L-NAME; 1 nmol in 1 ml), followed by L-arginine (100 nmol in 1 ml), into the sciatic nerve endoneurium. 2 The MNCV (m s 71 , mean+1 s.d.) of diabetic rats (38.2+1.5) was lower (P50.01) than that of agematched controls (47.2+4.2). AG treatment (50 mg kg 71 day 71 , i.p.) attenuated the diabetes-induced de®cits in MNCV (43.4+5.9; P50.01), but had no e ect in controls (48.8+3.8) or, if administered via drinking water (1 g l 71 ), diabetics (37.4+4.1). 3 L-NAME markedly reduced the resting LDF (arbitrary units; mean+s.e.mean) of controls (209+13 to 120+18; P50.005), an e ect reversed by subsequent L-arginine (to 206+27). In diabetic rats the LDF reduction following L-NAME was much smaller (111+11 to 84+6; P50.05), but the change with Larginine was signi®cantly increased (to 145+12; P50.001). 4 AG treatment increased the resting LDF of control (265+34) and diabetic rats (133+14 for daily injection and 119+13 for drinking water). The responses to L-NAME and L-arginine were not changed markedly by AG treatment. However, L-arginine appeared to be less e ective. 5 In conclusion, these data suggest that AG treatment may a ect nitric oxide production in the vasa nervorum of peripheral nerves. However, the e ects of AG-treatment are not consistent with the prevention of a diabetes-associated reduction in endoneurial nitric oxide production. The mechanisms by which AG attenuates nerve conduction slowing in streptozotocin-diabetic rats therefore remain unclear.

Effect of Treating Streptozotocin‐Induced Diabetic Rats With Sorbinil, Myo‐Inositol or Aminoguanidine on Endoneurial Blood Flow, Motor Nerve Conduction Velocity and Vascular Function of Epineurial Arterioles of the Sciatic Nerve

“…As has been previously reported, we demonstrate that treating streptozotocin-induced diabetic rats with sorbinil or aminoguanidine significantly improves the reduction in EBF and slowing of MNCV [3][4][5][6][7][8][9][10][11][12][24][25][26][27][28]. In sorbinil treated diabetic rats EBF and MNCV remained suppressed by 15 and 18%, respectively compared to controls, whereas in aminoguanidine treated rats EBF and MNCV, compared to controls, was decreased by 6 and 16%, respectively.…”

“…We have previously shown that endothelialdependent vascular relaxation of arterioles that provide circulation to the region of the sciatic nerve is impaired by diabetes [35,36]. In the present study we sought to determine the effect treatment of diabetic rats with sorbinil, an aldose reductase inhibitor, aminoguanidine, an inhibitor of nonenzymatic glycation, or myoinositol supplementation has on EBF, MNCV as well as vascular relaxation of arterioles that provide circulation to the region of the sciatic nerve.As has been previously reported, we demonstrate that treating streptozotocin-induced diabetic rats with sorbinil or aminoguanidine significantly improves the reduction in EBF and slowing of MNCV [3][4][5][6][7][8][9][10][11][12][24][25][26][27][28]. In sorbinil treated diabetic rats EBF and MNCV remained suppressed by 15 and 18%, respectively compared to controls, whereas in aminoguanidine treated rats EBF and MNCV, compared to controls, was decreased by 6 and 16%, respectively.…”

“…Based on these studies pharmacological compounds, like aldose reductase inhibitors and anti-glycation agents, have been developed for the treatment of diabetic neuropathy [59]. In diabetic animal models these agents have been shown to improve nerve function and endoneurial blood flow [3][4][5][6][7][8][9][10][11][12][24][25][26][27][28]. However, studies on the effect these agents may have on vascular function of vessels that provide circulation to nerves have been limited.…”

“…Treatment of diabetic rats with aminoguanidine, an inhibitor of the formation of advanced glycosylation end products [23], ameliorates the slowing of motor nerve conduction velocity and reduction of endoneurial blood flow [24][25][26][27][28]. This suggests that the formation of advanced glycation end products in the nerve or vascular tissue perturbs neural function [29][30][31][32].…”

Functional and structural abnormalities in the nerves of Type I diabetic baboons: aminoguanidine treatment does not improve nerve function

“…Its effects on nerve morphometry have not been assessed at this stage because aminoguanidine treated animals have not reached the duration of diabetes for nerve biopsies electrophysiological results lead us, however, to believe that aminoguanidine will have little it any effect on structural changes. The inability of aminoguanidine to restore nerve function in baboons differs from some of the studies in rats that showed treatment to be beneficial although the results are conflicting [18,19,22,41,42]. One study found that diabetic rats given 50 mg/kg aminoguanidine in the drinking water for 16 weeks had NCV restored although doses of 10 and 25 mg/ kg were ineffective [19].…”