Sympathetic autonomic neuropathy in the heart of the spontaneous diabetic BB rat

Addicks, Klaus; Boy, Christian; Rösen, P.

doi:10.1016/s0940-9602(11)80012-9

Cited by 19 publications

(14 citation statements)

References 21 publications

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“…In diabetic hearts histochemical visualization and quantification of intraneuronal catecholamines revealed a progressive loss of histofluorescent nerve fibers in the myocardium of streptozotocin-diabetic rats similar to that recently described for hearts of spontaneously diabetic (BB) rats [4]. These data indicate a loss of sympathetic nerve fibers and severe structural abnormalities that are very similar to alterations observed in peripheral nerves [35] (Figs. 6, 7).…”

Section: Pretreatrnent With Tocopherol the Experiments Withsupporting

confidence: 81%

Endothelial relaxation is disturbed by oxidative stress in the diabetic rat heart: influence of tocopherol as antioxidant

Rösen

Ballhausen

Bloch³

et al. 1995

Diabetologia

147

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Summary Increased oxidative stress has been suggested to contribute to disturbances in the regulation of coronary flow and the increased cardiac risk in diabetes mellitus. Using the isolated perfused heart of streptozotocin-diabetic rats our study shows that basal and maximal coronary flow (tested by infusion of sodium nitroprusside) are not altered in diabetes, but that 5-hydroxytryptamine (5-HT) stimulated endothelium-dependent increase in coronary flow becomes progressively impaired. This defect of the endothelium-dependent vasodilatation was prevented by perfusion of the hearts with superoxide dismutase and pretreatment of the diabetic rats with tocopherol-acetate. Morphological studies also revealed that pretreatment with tocopherol-acetate was cardioprotective, and largely prevented severe alterations of myocardial structure typically observed after a diabetes duration of 3 months; deterioration and fragmentation of myofilament bundles were seen less, and the numbers of areas of focal necrosis and of contraction bands were clearly reduced. In contrast to untreated diabetic hearts the autonomic nerve fibers detected by catecholamine fluorescence were running in parallel in hearts of tocopherol-treated diabetic rats, and the amount of catecholamines was not different from that of healthy control rats. Trichrome staining and immunohistochemical staining of collagen I and III showed a dramatic increase in the number and the size of deposits of collagen fibers at precapillary locations in the diabetic hearts which were significantly reduced by anti-oxidative treatment. These findings demonstrate that oxidative stress may not only play a major role in the impairment of endothelium-dependent regulation of coronary flow, but also in the development of perivascular fibrosis and severe changes of the autonomic nerves and contractile system in myocardium. [Diabetologia (1995[Diabetologia ( ) 38: 1157[Diabetologia ( -1168

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Section: Pretreatrnent With Tocopherol the Experiments Withsupporting

confidence: 81%

Endothelial relaxation is disturbed by oxidative stress in the diabetic rat heart: influence of tocopherol as antioxidant

Rösen

Ballhausen

Bloch³

et al. 1995

Diabetologia

147

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“…21) Moreover, Addicks et al have shown a decreased number of sympathetic nerve endings and innervation density in diabetic tissue, including spontaneous BB rat atria. 22) However, we did not directly investigate the changes in the numbers of nerve fibers in caudal arteries from GK rats in the present study. Further studies are required to determine the sympathetic nerve density in caudal arteries of GK rats.…”

Section: Discussionmentioning

confidence: 82%

Dysfunction of Neurotransmitter Modulation System on Adrenergic Nerves of Caudal Artery in Type 2 Diabetic Goto–Kakizaki Rats

Ishii-Nozawa

Mita

Miyake

et al. 2012

Biological & Pharmaceutical Bulletin

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The Goto-Kakizaki (GK) rat is a non-obese and spontaneous model of mild Type 2 diabetes mellitus. In the present study, we compared the regulatory mechanisms of endogenous norepinephrine (NE) release from sympathetic nerves of caudal arteries of 12-week-old GK rats and age-matched normal Wistar rats. Electrical stimulation (ES) evoked significant NE release from caudal arteries of Wistar and GK rats. The amounts of NE released by ES were almost equal in Wistar and GK rats, although the NE content in caudal artery of GK rats was significantly lower than that of Wistar rats. We examined the effects of an α 2 -adrenoceptor agonist, clonidine (CLO), and an α 2 -adrenoceptor antagonist, yohimbine (YOH), on the release of endogenous NE evoked by ES. CLO significantly reduced NE release from caudal arteries of Wistar but not GK rats. On the other hand, YOH significantly increased NE release from both rats. Furthermore, we examined the effects of an A 1 -adenosine receptor agonist, 2-chloroadenosine (2CA), and an A 1 -adenosine receptor antagonist, 8-sulfophenyltheophylline (8SPT), on the release of endogenous NE evoked by ES. 2CA significantly reduced NE release from caudal arteries of Wistar but not GK rats. On the other hand, 8SPT did not affect NE release from both rats. These results suggest that the dysfunction of negative feedback regulation of NE release via presynaptic receptors on sympathetic nerves in GK rats may be involved in the autonomic nervous system dysfunction associated with diabetic autonomic neuropathy.Key words adrenergic nerve; diabetes mellitus; autonomic neuropathy; norepinephrine release; presynaptic receptor; rat caudal artery Neuropathies of the central and peripheral nervous systems are known to be caused by hyperglycemia, a consequence of the deregulation of glucose in diabetes. Diabetic neuropathy is a painful complication involving progressive neuronal damage and dysfunction. Some reports indicate the appearance of peripheral neuropathy in a diabetic animal model, which affects the sensory nerves, 1) the autonomic nervous system 2,3) and even the central nervous system. 4) Autonomic dysfunction is a particularly significant complication of diabetes that may be responsible for orthostatic hypotension, skin ulceration, arterial calcification and abnormal temperature regulation. 5)However, most animal models of diabetic neuropathy are Type 1 diabetic models, namely, streptozotocin (STZ)-induced diabetic rats and mice. 6)Goto-Kakizaki (GK) rats were established as a model of inbred type 2 diabetes mellitus by selective breeding from originally non-diabetic Wistar rats using glucose intolerance. 7) GK rats have been shown to develop Type 2 diabetes without obesity spontaneously and to exhibit higher post-prandial plasma glucose levels and lower post-prandial immunoreactive insulin levels than Wistar rats. 8,9) GK rats are particularly relevant to human Type 2 diabetes because the pathogenesis of GK rats includes peripheral insulin resistance, hyperinsulinemia, hyperglycemia and glucose intole...

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“…We tested the above hypothesis by examining the sympathetic innervation of the heart, which has received intensive study because DAN of the heart is a complication of type 1 diabetes that has been invoked as a cause of sudden death in individuals with diabetes (29). For example, loss of sympathetic nerve fibers in the heart of BB diabetic rats (28 weeks' duration) was inferred from morphometric quantification of catecholamines (30). STZdiabetic rats also exhibited sympathetic denervation of the left ventricle of the heart after 6 months of diabetes (31).…”

Section: Discussionmentioning

confidence: 99%

Early, Selective, and Marked Loss of Sympathetic Nerves from the Islets of Biobreeder Diabetic Rats

Mei

Mundinger

Lernmark

et al. 2003

J Peripheral Nervous Sys

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To discover whether islet sympathetic nerves are damaged during the autoimmune destruction of islet B-cells, we immunostained sections of pancreas from BioBreeder (BB) diabetic rats, using antibodies against vesicular monoamine transporter 2 (VMAT2), a marker of sympathetic nerve terminals. We found a marked decrease in the VMAT2-positive fiber area in the islets of BB rats that had been diabetic for only 1-2 weeks compared with their nondiabetic controls. In contrast, there was no significant decrease in the VMAT2-positive fiber area in the exocrine pancreas in these early diabetic BB rats. Furthermore, streptozotocin-diabetic rats showed no decrease in VMAT2-positive fiber area in their islets compared with controls. The classical diabetic autonomic neuropathy (DAN) that eventually occurs in the heart was not present in BB diabetic rats at this early stage as evidenced by normal cardiac VMAT2 immunostaining and normal cardiac norepinephrine content. Also, in contrast to DAN, this islet neuropathy did not worsen with duration of diabetes. These data provide evidence of a heretofore unrecognized early sympathetic islet neuropathy (eSIN). Because eSIN occurs selectively in the islet, is rapid in onset, and is associated with autoimmune but not chemically induced diabetes, it is distinct from DAN in location, time course, and mechanism. Diabetes 51:2997-3002, 2002 T he sympathetic nerves of the pancreas can inhibit insulin release from the islet B-cells (1,2) and stimulate glucagon release from the islet A-cells (1,2). For example, activation of these nerves is sufficient to mediate the glucagon response to insulin-induced hypoglycemia (3). It is interesting that this specific glucagon response is lost in type 1 diabetes (4).Type 1 diabetes in humans is associated with an autoimmune attack on islet B-cells involving a variety of cytokines, including interleukin 1 and tumor necrosis factor-␣ (5). These two cytokines are also neurotoxic (6) and therefore could injure islet nerves during the autoimmune attack on islet B-cells. Injured adult sympathetic nerves, in turn, are known to increase their dependence on nerve growth factor (NGF) for function and survival (7). Islet B-cells seem to be the source of the growth factors that influence both the sympathetic and sensory innervation of the islet (8), a specificity ascribed to NGF itself. Indeed, at least in vitro, islet B-cells seem to make NGF mRNA as demonstrated by RT-PCR and NGF protein as demonstrated by immunohistochemistry (9). In addition, they secrete NGF as demonstrated by bioassay and enzyme-linked immunosorbent assay (9). These observations suggest the possibility that the autoimmune attack on the B-cells during the development of type 1 diabetes will lead to a loss of the islet sympathetic nerves, first by injuring these nerves and then by depriving them of now critical neurotrophic support.To determine whether the hypothesized loss of islet sympathetic nerves actually occurs, we first needed a marker of the sympathetic innervation of the pancreatic islet...

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Sympathetic autonomic neuropathy in the heart of the spontaneous diabetic BB rat

Cited by 19 publications

References 21 publications

Endothelial relaxation is disturbed by oxidative stress in the diabetic rat heart: influence of tocopherol as antioxidant

Endothelial relaxation is disturbed by oxidative stress in the diabetic rat heart: influence of tocopherol as antioxidant

Dysfunction of Neurotransmitter Modulation System on Adrenergic Nerves of Caudal Artery in Type 2 Diabetic Goto–Kakizaki Rats

Early, Selective, and Marked Loss of Sympathetic Nerves from the Islets of Biobreeder Diabetic Rats

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