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

Abstract

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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Increased Contractile Response to Noradrenaline Induced By Factors Associated with the Metabolic Syndrome in Cultured Small Mesenteric Arteries

“…Downregulated α 2 -adrenoceptor activity thus leads to increased release of endogenous NA, when nerves are stimulated by NA, but not by PE or ISO. Such an effect has been demonstrated in caudal arteries of the Goto-Kakizaki rat which is a widely used rat model of T2DM [38]. Thus, pre-synaptic impairment of the α 2 -adrenoceptor function may play a role in vascular pathology in T2DM, and the results obtained in the present study display patterns which could explain this pathological effect.…”