Impaired vasoreactivity to nitric oxide in experimental diabetic neuropathy

doi:10.1016/0014-4886(95)90023-3

Experimental Neurology

Volume 132, Issue 2, April 1995, Pages 180-185

https://doi.org/10.1016/0014-4886(95)90023-3 Get rights and content

Abstract

Nerve blood flow (NBF) is reduced in experimental diabetic neuropathy (EDN), but the mechanism of its reduction is uncertain. We tested the hypothesis that reduced NBF might be due to alterations of nitric oxide synthase (NOS) and endothelin of microvascular endothelial cells of sciatic nerve. We evaluated epineurial arteriolar vasoreactivity in response to superfused test agents. NBF was measured using microelectrode H₂ polarography. Vasoconstrictor responses to endothelin-1 (ET-1; 10⁻¹, 10⁻⁷, 10⁻⁸, 10⁻⁹, 10⁻¹⁰ M showed dose-response curves with similar EC₅₀ values, indicating no change in potency. We applied the NOS inhibitor N^G-nitro-l-arginine and observed reduced inhibition of NBF in EDN, correctable with insulin treatment and also with infused L-arginine. We conclude that vasoreactivity is disturbed in EDN, and is due to a combination of an impairment of NOS activity with reduced NO and increased endothelin effect (normal receptor sensitivity and increased plasma values) in EDN. Hyperglycemia is likely to be the mechanism of NOS inhibition since insulin treatment reversed this abnormality.

References (46)

O. Appenzeller et al.
The nerves to blood vessels supplying blood to nerves: the innervation of vasa nervorum
Brain Res.
(1984)
P.A. Low et al.
Nerve blood flow and oxygen delivery in normal, diabetic, and ischemic neuropathy
Int. Rev. Neurobiol.
(1989)
S. Moncada et al.
A lipid peroxide inhibits the enzyme in blood vessel microsomes that generates from prostaglandin endoperoxides the substance (prostaglandin X) which prevents platelet aggregation
Prostaglandins
(1976)
Y. Oyama et al.
Attenuation of endothelium-dependent relaxation in aorta from diabetic rats
Eur. J. Pharmacol.
(1986)
H. Shindo et al.
Clinical efficacy of a stable prostacyclin analog, iloprost, in diabetic neuropathy
Prostaglandins
(1991)
Y. Takeda et al.
Production of endothelin-1 from the mesenteric arteries of streptozotocin-induced diabetic rats
Life Sci.
(1991)
B. Tesfamariam
Free radicals in diabetic endothelial cell dysfunction
Free Rad. Biol. Med.
(1994)
D.R. Tomlinson et al.
Aldose reductase inhibitors and diabetic complications
Pharmacol. Ther.
(1992)
T. Yamauchi et al.
Enhanced secretion of endothelin-1 by elevated glucose levels from cultured bovine aortic endothelial cells
FEBS Lett.
(1990)
D.W. Zochodne et al.
Adrenergic control of nerve blood flow
Exp. Neurol.
(1990)

W. Abebe et al.

Enhanced arterial contractility to noradrenaline in diabetic rats is associated with increased phosphoinositide metabolism

Can. J. Physiol. Pharmacol.

(1991)

R. Andriantsitohaina et al.

Acetylcholine released from guinea-pig submucosal neurones dilates arterioles by releasing nitric oxide from endothelium

J. Physiol.

(1992)

G.J. Blackwell et al.

Inhibition of phospholipase

Br. Med. Bull.

(1983)

R. Bucala et al.

Advanced glycosylation products quench nitric oxide and mediate defective endothelium-dependent vasodilatation in experimental diabetes

J. Clin. Invest.

(1991)

N.E. Cameron et al.

Nerve blood flow in early experimental diabetes in rats: Relation to conduction deficits

Am. J. Physiol.

(1991)

A. Collier et al.

Plasma endothelin-like immunoreactivity levels in IDM patients with microalbuminuria

Diabetes Care

(1992)

T.J. Day et al.

Analysis of Hz clearance curves used to measure blood flow in rat sciatic nerve

J. Physiol. (London)

(1989)

W. Durante et al.

Impairment of endothelium-dependent relaxation in aortae from spontaneously diabetic rats

Br. J. Pharmacol.

(1988)

D. Dvornik

Aldose Reductase Inhibition. An Approach to the Prevention of Diabetic Complications

(1987)

T. Haak et al.

Increased plasma levels of endothelin in diabetic patients with hypertension

Am. J. Hypertens.

(1992)

D. Horrobin

Omega-6 Essential Fatty Acids

(1990)

D.F. Horrobin

The use of gamma-linolenic acid in diabetic neuropathy

Agents Actions Suppl.

(1992)

M. Kihara et al.

Regulation of rat nerve blood flow: Role of epineurial alpha-receptors

J. Physiol.

(1990)

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Diabetes is also associated with increased circulating levels of endothelium-derived adhesion molecules and plasminogen activator inhibitor 1, reflecting a proinflammatory and prothrombotic endothelial phenotype (Tabit et al., 2010). In experimental diabetic neuropathy, impaired vasodilation to NO has been demonstrated (Kihara and Low, 1995). Diabetic neuropathy might also be associated with altered NO synthase isoforms (NOS) enzyme activity (Zochodne et al., 2000), unresponsiveness to peptide vasodilatation (Zochodne and Ho, 1993), loss of perivascular peptidergic axons innervating vasa nervorum (Willars et al., 1989), increased sensitivity to angiotensin II (Kihara et al., 1999), increased adrenergic tone (White and Carrier, 1988), or decreased vasodilation from prostacyclin (Ward et al., 1989).
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A fundamental reason for reduced nerve tissue perfusion is that diabetes produces an endotheliopathy in vasa nervorum, paralleling that found in several other vascular beds. Metabolic alterations cause reductions in endothelial output/effects of the major vasodilators, nitric oxide (NO) and endothelium-derived hyperpolarising factor (EDHF) (Coppey et al., 2003; Kihara and Low, 1995; Maxfield et al., 1997). This reduces vasodilation and potentiates vasoconstriction by agents that may be elevated in diabetes, such as angiotensin II, endothelin 1 and sympathetic tone (Cameron et al., 2001).
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Diabetes mellitus is the most common endocrine disturbance of domestic carnivores and can cause autonomic neurological disorders, although these are still poorly understood in veterinary medicine. There is little information available on the quantitative adaptation mechanisms of the sympathetic ganglia during diabetes mellitus in domestic mammals. By combining morphometric methods and NADPH-diaphorase staining (as a possible marker for nitric oxide producing neurons), type I diabetes mellitus-related morphoquantitative changes were investigated in the celiac ganglion neurons in dogs. Twelve left celiac ganglia from adult female German shepherd dogs were examined: six ganglia were from non-diabetic and six from diabetic subjects.
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Citation Excerpt :
Such a phenomenon could be explained by the fact that the health of the C nociceptive fibers and, consequently, the SkBF mediated by these fibers are dependent on endothelial function. This hypothesis would be consistent with the notion that DPN is a microvascular disease dependent on endothelial function (Cameron et al., 2001; Flynn & Tooke, 1995; Kihara & Low, 1995; Malik et al., 1989, 1993; Maxfield, Cameron, & Cotter, 1997; Obrosova, 2003; Tuck et al., 1984). Another possible explanation for the correlation between the direct and indirect vasodilatation is that both are ultimately a measure of the number of cutaneous microvessels and/or of the ability of those cutaneous microvessels to dilate.
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We studied 11 placebo- and 9 RBX (32 mg/day)-treated patients who participated in a 1-year, double-masked, randomized, Phase 3 study of RBX for treatment of DPN sensory symptoms. Patients had type 1 or type 2 diabetes, a detectable sural sensory nerve action potential, and Neuropathy Total Symptom Score-6 (NTSS-6) >6 points. SkBF was measured by laser Doppler velocimetry, combined with iontophoresis of acetylcholine and sodium nitroprusside, at baseline, 3 months, and 1 year. Sensory symptoms and electrophysiology were also evaluated during the study. The relationship between endothelial and neural control of SkBF at baseline was assessed using linear regression.
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Regular articleImpaired vasoreactivity to nitric oxide in experimental diabetic neuropathy

Abstract

Brain Res.

Int. Rev. Neurobiol.

Prostaglandins

Eur. J. Pharmacol.

Prostaglandins

Life Sci.

Free Rad. Biol. Med.

Pharmacol. Ther.

FEBS Lett.

Exp. Neurol.

Enhanced arterial contractility to noradrenaline in diabetic rats is associated with increased phosphoinositide metabolism

Can. J. Physiol. Pharmacol.

Acetylcholine released from guinea-pig submucosal neurones dilates arterioles by releasing nitric oxide from endothelium

J. Physiol.

Inhibition of phospholipase

Br. Med. Bull.

Advanced glycosylation products quench nitric oxide and mediate defective endothelium-dependent vasodilatation in experimental diabetes

J. Clin. Invest.

Nerve blood flow in early experimental diabetes in rats: Relation to conduction deficits

Am. J. Physiol.

Plasma endothelin-like immunoreactivity levels in IDM patients with microalbuminuria

Diabetes Care

Analysis of Hz clearance curves used to measure blood flow in rat sciatic nerve

J. Physiol. (London)

Impairment of endothelium-dependent relaxation in aortae from spontaneously diabetic rats

Br. J. Pharmacol.

Aldose Reductase Inhibition. An Approach to the Prevention of Diabetic Complications

Increased plasma levels of endothelin in diabetic patients with hypertension

Am. J. Hypertens.

Omega-6 Essential Fatty Acids

The use of gamma-linolenic acid in diabetic neuropathy

Agents Actions Suppl.

Regulation of rat nerve blood flow: Role of epineurial alpha-receptors

J. Physiol.

Regular article
Impaired vasoreactivity to nitric oxide in experimental diabetic neuropathy