In rats the duration of diabetes influences its impact on cardiac autonomic innervations and electrophysiology

Xuan, Yongli; Wang, Ye; Xue, Mei; Hu, Hesheng; Cheng, Wen-Chieh; Li, Xinran; Yin, Jing; Yang, Na; Yan, Shi Fang

doi:10.1016/j.autneu.2015.01.003

Cited by 15 publications

(16 citation statements)

References 22 publications

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“…To understand the complex nature and consequences of CAN, its progression has been investigated in a variety of animal models (reviewed in ). While studies reported a decrease in HRV, some reported neuropathy of all autonomic nerve fibres, some of only sympathetic fibres and some no neuropathy at all, but rather an increase in cholinergic nerve density . Heart rate variability analysis on the db/db mouse using telemetry has both shown unchanged HRV at 8‐9 weeks of age and reduced HRV at 12 weeks of age in two separate studies; however, few studies have directly investigated the presence of CAN in the db/db mouse.…”

Section: Discussionmentioning

confidence: 99%

Aberrant sinus node firing during β‐adrenergic stimulation leads to cardiac arrhythmias in diabetic mice

et al. 2020

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Aim: Cardiovascular complications, including cardiac arrhythmias, result in high morbidity and mortality in patients with type-2 diabetes mellitus (T2DM). Clinical and experimental data suggest electrophysiological impairment of the natural pacemaker of the diabetic heart. The present study examined sinoatrial node (SAN) arrhythmias in a mouse model of T2DM and physiologically probed their underlying cause. Methods: Electrocardiograms were obtained from conscious diabetic db/db and lean control db/+ mice. In vivo SAN function was probed through pharmacological autonomic modulation with isoprenaline, atropine and carbachol. Blood pressure stability and heart rate variability (HRV) were evaluated. Intrinsic SAN function was evaluated through ex vivo imaging of spontaneous Ca 2+ transients in isolated SAN preparations. Results: While lean control mice showed constant RR intervals during isoprenaline challenge, the diabetic mice experienced SAN arrhythmias with large RR fluctuations in a dose-dependent manner. These arrhythmias were completely abolished by atropine pre-treatment, while carbachol pretreatment significantly increased SAN arrhythmia frequency in the diabetic mice. Blood pressure and HRV were comparable in db/db and db/+ mice, suggesting that neither augmented baroreceptor feedback nor autonomic neuropathy is a likely arrhythmia mechanism. Cycle length response to isoprenaline was comparable in isolated SAN preparations from db/db and db/+ mice; however, Ca 2+ spark frequency was significantly increased in db/db mice compared to db/+ at baseline and after isoprenaline. Conclusion: Our results demonstrate a dysfunction of cardiac pacemaking in an animal model of T2DM upon challenge with a β-adrenergic agonist. Ex vivo, higher Ca 2+ spark frequency is present in diabetic mice, which may be directly linked to in vivo arrhythmias. K E Y W O R D Sautonomic nervous system, baroreflex, calcium, electrophysiology, isoprenaline, type-2 diabetes

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Section: Discussionmentioning

confidence: 99%

Aberrant sinus node firing during β‐adrenergic stimulation leads to cardiac arrhythmias in diabetic mice

et al. 2020

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“…Indeed, an increase in sympathetic (i.e. noradrenergic) heart tone has been established to contribute to myocardial damage and therefore to cardiac disorders in patients with T1D [4,[8][9][10], as well as in animal models of T1D [11,12]. The impairment of cardiac sympathetic neurotransmission, among others, is strongly involved in the development of cardiac autonomic neuropathy (CAN), a microvascular complication leading to dysfunctional heart rhythm and vascular dynamics [4,9,10].…”

Section: Introductionmentioning

confidence: 99%

Exclusive Peripheral Overexpression of 5-HT5A Receptors is Involved in 5‑HT‑Induced Cardiac Sympatho-Inhibition in Type 1 Diabetic Rats

García-Pedraza

Hernández-Abreu

Morán

et al. 2020

Preprint

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Abstract Background: In normoglycaemic pithed rats, cardiac sympathetic control is modulated by serotonin (5-hydroxytryptamine; 5‑HT), which inhibits the cardioaccelerator sympathetic outflow via the activation of 5-HT 1B , 5-HT 1D and 5-HT 5A receptors. Notwithstanding, type 1 diabetes impairs the functionality of the cardiac sympathetic innervation and leads to cardiovascular complications including cardiac autonomic neuropathy. On this basis, the present study investigated whether the influence of 5-HT on cardiac noradrenergic neurotransmission is altered in type 1 diabetic rats, by analysing the profile of the 5-HT receptors involved and their peripheral expression. Methods: Type 1 diabetes was induced in male Wistar rats with a single injection of streptozotocin (50 mg/kg, i.p.). Four weeks later, the rats were anaesthetized, pithed and prepared for producing tachycardic responses by either electrical preganglionic stimulation (C 7 ‑T 1 ) of the cardioaccelerator sympathetic outflow or i.v. bolus injections of exogenous noradrenaline. Immunohistochemistry analyses were performed to study the expression of 5‑HT 1B , 5-HT 1D and 5-HT 5A receptors in the stellate (sympathetic) ganglion obtained from normoglycaemic and diabetic rats. Results: The increases in heart rate evoked by both cardiac sympathetic stimulation and exogenous noradrenaline were not modified after saline in diabetic rats. Moreover, i.v. continuous infusions of 5‑HT induced a cardiac sympatho-inhibition that was mimicked by the 5‑HT 1/5A receptor agonist 5‑carboxamidotryptamine, but not by the agonists indorenate (5-HT 1A ), CP 93,129 (5‑HT 1B ), PNU 142633 (5-HT 1D ), or LY344864 (5‑HT 1F ) in the diabetic group. In contrast, the above agonists at 5-HT 1B , 5-HT 1D and 5-HT 1/5A receptors mimicked 5-HT-induced sympatho-inhibition in normoglycaemic rats. In diabetic animals, i.v. administration of SB 699551 (1 mg/kg; 5‑HT 5A receptor antagonist) abolished 5‑CT-induced cardiac sympatho-inhibition. Finally, the immunohistochemistry analysis in the stellate ganglion showed that, as compared to normoglycaemic rats, in diabetic rats (P<0.05): (i) the expression of 5-HT 1B receptors was slightly higher, whereas that of 5-HT 1D receptors was slightly lower; and (ii) there was a clear overexpression of 5-HT 5A receptors. Conclusions: Taken together, these results show the prominent role of the peripheral overexpression of prejunctional 5-HT 5A receptors in the inhibition of the cardiac sympathetic drive in type 1 diabetic rats. These findings may represent a new pharmacological strategy for the treatment of diabetes-related cardiac abnormalities.

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“…Alteration in basal cardiac rate and heart rate variability is often reported in experimental diabetic rats, changes associated with altered diastolic and systolic cardiac functions, and related to abnormal heart innervation that is present after four weeks of induced diabetes for streptozotocin injection in rats [5] [6] [7]. Heart sympathetic and parasympathetic innervations are abnormal in diabetic rats and the magnitude of the deterioration is related to the progression time and severity of hyperglycemia [8] [9].…”

Section: Introductionmentioning

confidence: 99%

“…Diabetic neuropathy is a frequent and early complication of diabetes, and evolution time of diabetes and a lack of glycemic control are major risk factors for neuropathy[8] [9]. More than half of all individuals with diabetes eventually develop neuropathy, and neuropathy increases mortality[1] [2] [3][4].…”

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confidence: 99%

“…Vagal impairment seen in early diabetes leads to a relative predominance of sympathetic activity in sympatho-vagal balance[8] [12]. In the early stages of chronic hyperglycemia, an increase in release and in the heart content of noradrenaline is reported, with the opposite changes in the late stages[9] [10][11]. Then it is currently accepted that cardiac autonomic neuropathy is associated with parasympathetic withdrawal, sympathetic dominance in early stages and a decreased sympathetic and parasympathetic tone in late stages.…”

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confidence: 99%

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Cerebrolysin Effects on Cardiac Neuropathy in Diabetic Rats

Zurita¹,

Huerta²,

Jesús³

et al. 2017

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Autonomic innervation of heart is abnormal in diabetes and produces altered cardiovascular parameters. Cerebrolysin is a neurotrophic factor that improves the dendritic tree and synapses in the central nerve system after brain damage. The aim of this study was to evaluate if cerebrolysin can improve the cardiac neuropathy generated in diabetic rats. Male Sprague-Dawley rats two months old were injected with streptozotocin (70 mg/Kg/, ip). Hyperglycemia and altered cardiac rate were confirmed after eight weeks of STZ injection, and cerebrolysin treatment was started in control and diabetic rats for two months (1 ml/kg/day, ip). Body weight, heart rate, heart rate variability, arterial blood pressure, and blood glucose levels were measured. Also heart weight and levels of nitrites, NGF and VEGF were measured in left ventricle homogenates. The results show that body weight was reduced and blood glucose levels were increased significantly in diabetic rats. Cerebrolysin treatment produced no significant changes in body weight either in blood glucose level in control and diabetic rats. Cerebrolysin treatment in diabetic rats shows an improvement in the altered basal cardiac rate (306 ± 6.5 lat/min) compared to diabetic saline group (272 ± 8.9 lat/min: P < 0.05), without changes in control rats. Levels of nitrites, VEGF, and NGF in the left ventricle increased in diabetic cerebrolysin treated rats. In conclusion, the results show that cerebrolysin improves some abnormalities observed in the diabetic cardiac neuropathy in rats and suggest that could be considered an additional treatment to prevent or reduce the cardiac autonomic alterations generated in diabetes.

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In rats the duration of diabetes influences its impact on cardiac autonomic innervations and electrophysiology

Cited by 15 publications

References 22 publications

Aberrant sinus node firing during β‐adrenergic stimulation leads to cardiac arrhythmias in diabetic mice

Aberrant sinus node firing during β‐adrenergic stimulation leads to cardiac arrhythmias in diabetic mice

Exclusive Peripheral Overexpression of 5-HT5A Receptors is Involved in 5‑HT‑Induced Cardiac Sympatho-Inhibition in Type 1 Diabetic Rats

Cerebrolysin Effects on Cardiac Neuropathy in Diabetic Rats

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