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...

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The receptor pharmacology of the human sweat gland was studied in vivo. The axon-reflex response was mediated by nicotinic receptors which were activated by nicotine and acetylcholine, but not pilocarpine, and inhibited by hexamethonium. The direct response was mainly muscarinic, responding to pilocarpine and acetylcholine. A component of the direct response was nicotinic, since it was activated by nicotine and blocked by hexamethonium in a dose-dependent manner. The axon-reflex response to nicotine and acetylcholine was partially blocked by pilocarpine, especially when application of pilocarpine preceded the procedure. The inhibition of the nicotinic response may be secondary to M1 antagonism since pilocarpine is an M2 agonist and M1 antagonist and pirenzepine, a specific M1 antagonist, caused similar effects as pilocarpine.

Insulin administration can cause or worsen experimental and human diabetic neuropathy ("insulin neuritis"). In this study, we tested the hypothesis that insulin administration impairs tissue oxygenation. We infused insulin under nonhypoglycemic conditions and evaluated its effect on endoneurial oxygen tension, nerve blood flow, and the oxyhemoglobin dissociation curve of peripheral nerve in normal and diabetic rats. Intravenous insulin infusion resulted in a dose-dependent reduction in endoneurial oxygen tension in normal nerves (from 26% at 0.04 U/kg insulin to 55% at 32 U/kg). The nerves of rats with streptozotocin-induced diabetes were resistant, but with control of hyperglycemia this susceptibility to the endoneurial hypoxic effect of insulin returned. The reduction in endoneurial oxygen tension regressed with glycosylated hemoglobin (Y = 53.8-2.7X, where Y = %reduction in endoneurial oxygen tension and X = HbA1; r = 0.87; P = < 0.001). Diabetes or insulin administration resulted in only minimal and physiologically insignificant alterations in the oxygen dissociation curve and 2,3-diphosphoglycerate of sciatic nerve. Instead, insulin administration resulted in a reduction in nerve nutritive blood flow and an increase in arteriovenous shunt flow. When the latter was eliminated by the closure of arteriovenous shunts (infusion of 5-hydroxytryptamine), endoneurial oxygen reverted to normal. These findings indicate a deleterious vasoactive effect of insulin and may explain the development of insulin neuritis.

SUMMARY1. Transperineurial arterioles connect the extrinsic (epineurial) and the intrinsic (endoneurial) microvasculatures. Our goal was to determine whether the extrinsic system regulated nerve blood flow locally and whether subperineurial and centrifascicular endoneurial nerve blood flows were regulated differentially.2. The local application of noradrenaline resulted in a dose-dependent reduction of nerve blood flow in subjacent endoneurium. Asymptotes of 78-8 and 763 % vasoconstriction were recorded for subperineurial and centrifascicular endoneurial nerve blood flow, respectively, indicating near-complete closure of capillaries.3. Near-identical concentrations required to generate 50 % vasoconstriction (EC,50) and asymptotes are suggestive of the fact that the two areas are not differentially regulated.4. Local vasoconstriction cannot be due to a systemic effect of noradrenaline since a significant decrease in nerve blood flow occurs despite undetectable increases in plasma noradrenaline and mean blood pressure, or decrease in contralateral sciatic nerve blood flow.5. There are small and statistically non-significant reductions of the compound muscle action potential and conduction velocity in the sciatic-tibial nerve following nerve ischaemia.6. These findings suggest that epineurial arterioles control regional nerve blood flow and are primarily responsible for its regulation in subjacent endoneurial tissue.