Aminoguanidine effects on nerve blood flow, vascular permeability, electrophysiology, and oxygen free radicals.

Abstract

Since advanced glycosylation end products have been suggested to mediate hyperglycemia-induced microvascular atherogenesis and because aminoguanidine (AG) prevents their generation, we examined whether AG could prevent or ameliorate the physiologic and biochemical indices of streptozotocin (STZ)-induced experimental diabetic neuropathy. Four groups of adult Sprague-Dawley rats were studied: group I received STZ plus AG (25 mg kg'1 day-1), group II received STZ plus AG (50 mg-kg'1day-1), group HI received STZ alone, and group IV was a control. We monitored conduction and action potential amplitudes serially in sciatic-tibial and caudal nerves, nerve blood flow, oxygen free radical activity (conjugated dienes and hydroperoxides), and the product ofthe permeability coefficient and surface area to 125I-labeled albumin. STZ-induced diabetes (group HI) caused a 57% reduction in nerve blood flow and in abnormal nerve conduction and amplitudes and a 60% increase in conjugated dienes. Nerve blood flow was normalized by 8 weeks with AG (groups I and II) and conduction was significantly improved, in a dosedependent manner, by 16 and 24 weeks in sciatic-tibial and caudal nerves, respectively. The permeability coefficient was not impaired, suggesting a normal blood-nerve barrier function for albumin, and the oxygen free-radical indices were not ameliorated by AG. We suggest that AG reverses nerve ischemia and more gradually improves their electrophysiology by an action on nerve microvessels. AG may have potential in the treatment of diabetic neuropathy.In chronic experimental diabetic neuropathy, nerve blood flow (NBF) is reduced and the oxygen tension histogram is shifted into the hypoxic range (1). Nerve biosynthesis of 6-keto-prostaglandin Fia, the stable metabolite of prostacyclin, is significantly reduced in chronic, but not in acute, experimental diabetic neuropathy (2). Platelet thromboxane B2 is increased (3-6), resulting in a reduced prostacyclin/ thromboxane ratio and resultant vasoconstriction. Improvement in blood flow by chemical sympathectomy (7) or an increase in the oxygen supply by supplementation (8) or hyperbaric oxygenation (9) has been shown to improve nerve electrophysiology. Although these findings implicate perturbed microvascular physiology, the mechanism(s) by which chronic hyperglycemia results in a reduction in NBF is uncertain. It has been suggested that advanced glycosylation end products (AGE) may mediate hyperglycemiainduced microvascular atherogenesis (10, 11). Since aminoguanidine (AG) prevents AGE generation and has been reported to prevent basal lamina thickening in diabetic rats (10, 11), we examined whether AG could prevent or ameliorate the physiologic and biochemical indices of streptozotocin (STZ)-induced experimental diabetic neuropathy. METHODS Experimental Diabetic Neuropathy. We used male SpragueDawley rats weighing -250 g. They were separated into four groups of 16 animals each: group I or AG25 received STZ plus AG (25 mg kg-1-day-1), group II or AG50 received STZ plus AG...

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].…”

Medical treatment of diabetic retinopathy

“…There are several published reports on the ability of aminoguanidine to inhibit AGE formation in vivo. [68][69][70][71][72][73][74][75][76][77] A recent report showed the ability of aminoguanidine to prevent the development of diabetic retinopathy in diabetic dogs followed for 5 years. 78 Optimism for the clinical use of aminoguanidine has been tempered by the gradual realisation that aminoguanidine also inhibits a range of other important pathways, most notably generation of nitric oxide by eNOS, which may increase nonspecific and unwanted side effects of the drug.…”