NO-dependent Smooth Muscle Vasodilatation is Reduced in NIDDM Patients with Peripheral Sensory Neuropathy

Abstract

In order to determine the involvement of denervation in endothelium‐independent, nitric oxide (NO)‐dependent smooth muscle vasodilatation, we have measured vascular endothelial and smooth muscle function in three groups of age‐ and sex‐matched patients: 8 patients with non‐insulin‐dependent (Type 2) diabetes mellitus (NIDDM) with neuropathy; 7 NIDDM patients without neuropathy; and 10 non‐diabetic control subjects. Laser Doppler probes were used to measure blood flow in the dorsum of the left foot. Vascular endothelial response was assessed by measuring vasodilatory responses to iontophoretic application of acetylcholine to the dorsum of the foot. Vascular smooth muscle activity was assessed by the response to iontophoresis of sodium nitroprusside (SNP)—a NO donor and direct vasodilator. The vasodilator response to acetylcholine, expressed as the ratio of peak to basal blood flow, was significantly reduced in both diabetic groups when compared to non‐diabetic controls (geometric mean ×/÷ anti‐logged SD 9.81 ×/÷ 1.65 versus patients with neuropathy 3.50 ×/÷ 2.03, p < 0.005 and diabetic non‐neuropathic subjects 3.49 ×/÷ 1.67, p < 0.005). The difference between the two groups of diabetic patients was not significant. In contrast, the vasodilatation to nitroprusside was significantly reduced only in the diabetic neuropathic patients, significantly lower than in either the non‐neuropathic diabetic controls or the non‐diabetic controls (2.1 ×/÷ 2.0 versus 6.42 ×/÷ 1.56 and 7.02 ×/÷ 2.05, p < 0.005). This indicates that neuropathy is important in abnormalities of endothelium‐independent vasodilatation. © 1997 by John Wiley & Sons, Ltd.

Treatment of Chronic Painful Diabetic Neuropathy With Isosorbide Dinitrate Spray

“…Recent data suggest that impaired nitric oxide (NO) synthesis plays an important role in the pathogenesis of painful diabetic neuropathy. Sasaki et al (5) and Rodella et al (6) demonstrated that impaired neuronal NO generation in diabetic rats induced hyperalgesia, whereas Pitei et al (7) showed that decreased NO production contributed to a reduction in endoneurial blood flow in type 2 diabetic patients with peripheral sensory neuropathy. The preservation of endothelialdependent vasodilatory responses to nitroglycerin (8), which directly releases NO, further implicates a defect or defects in endoneurial NO synthesis as the cause of impaired vascular responses in diabetes.…”

Repeated Dosing with NCX1404, a Nitric Oxide-Donating Pregabalin, Re-establishes Normal Nociceptive Responses in Mice with Streptozotocin-Induced Painful Diabetic Neuropathy

“…Different investigators (Sasaki et al, 1998;Rodella et al, 2000) have demonstrated that impaired NO generation in diabetic rats results in hyperalgesia, and that the administration of L-arginine, known to enhance the circulating NO concentration, is antinociceptive in diabetic mice. Pitei et al (1997) showed that decreased NO production contributes to reduced endoneuronal blood flow in diabetic patients and causes pain, whereas the local application of NO donors such as isosorbide dinitrate (Yuen et al, 2002) or nitroglycerin (Francis et al, 1977;Agrawal et al, 2007) relieves pain and burning sensations in patients with PDN.…”

“…The pathophysiology of PDN remains unclear, but neurogenic and vascular components have been described (Yorek, 2003). For instance, peripheral demyelination, reduction in nerve conductance, and progressive degeneration of peripheral sensory fibers (Watkins, 1984) along with microvascular and macrovascular abnormalities dependent on dysfunctional endothelium, the innermost layer of the blood vessel, have long been established in experimental animal models and in diabetic patients (Pieper and Gross, 1988;Pitei et al, 1997) as well as in individuals who will later develop diabetes (Cosentino and Luscher, 1998).…”

Conservative Treatment of Peripheral Neuropathy and Neuropathic Pain

“…Impaired or reduced endoneurial nitric oxide synthethase has been implicated in the pathogenesis of painful neuropathies such as those found in diabetes [52]. Yuen and colleagues [53] have demonstrated a 50% reduction of painful burning sensations recalcitrant to other therapies in a small, well-controlled study.…”