Effects Of Carvedilol On Streptozotocin Induced Diabetic Cardiac Autonomic Neuropathy In Wistar Rats

The prevalence of diabetic cardiac autonomic neuropathy (DCAN) is very high among patients with diabetes mellitus (DM). Despite intensive research on mechanism and treatment of DCAN, it still remains a major cause of mortality. Although carvedilol has been recommended for the treatment of heart failure, its role in the management of DCAN is yet to be established. This study investigated the effects of carvedilol on streptozotocin-induced DCAN rats. The objectives of the study were to determine the: (i) outcome of DM and DCAN induction in rats; (ii) effects of carvedilol on biochemical markers of autonomic nervous system in streptozotocin-induced DCAN rats; (iii) effects of carvedilol on heart rate variability (HRV) indices in streptozotocin-induced DCAN rats; and (iv) effects of carvedilol on cardiac histology and nerve densities (ND) in streptozotocin-induced DCAN rats.rnEighty-four Wistar rats were assigned into two groups in the induction phase; type 1 DM model (single high dose Streptozotocin (STZ) at 50mg/kg body weight (bw)) and type 2 DM model (high fat diet feeding for 8 weeks, thereafter 25mg/kg bw of STZ daily for five days) respectively. In the interventional phase; each model was sub-divided into five sub-groups comprising; i) a sham control sub-group; ii) three DCAN sub-groups receiving carvedilol at 0.1, 1 and 10mg/kg bw respectively for 28 days; and iii) a DCAN control sub-group without carvedilol. Blood glucose, C-peptide, insulin, homeostatic model for assessment of insulin resistance and pancreas histology were adopted in assessing DM induction. Holter electrocardiogram was used to access HRV indices. Antioxidant markers, autonomic biomarkers, cardiac histology and ND were evaluated using standard methods. Data, expressed as means ± standard errors of mean were analysed using one way analysis of variance and Bonferonni’s Post-hoc test at p<0.05.rnThe findings of the study were that:rn(i) STZ-induced DM rats had significantly (p<0.05) higher blood glucose (22.50 ± 7.53 vs. 4.68 ± 0.59 mmol/L) and lowered insulin and C-peptide. Advanced glycated end products (AGEs) (63.54 ± 2.09 vs. 23.04 ± 5.17 ng/ml and 91.61 ± 9.09 vs. 32.04 ± 6.37 ng/ml) and noradrenaline (528.21 ± 279.48 vs. 119.06 ± 57.88 pg/ml and 889.76 ± 299.48 vs. 111.56 ± 57.65 pg/ml) were significantly higher in both DM models respectively;rn(ii) choline acetyl tranferase (choactase) and nerve growth factor (NGF) were significantly reduced after STZ treatment;rn(iii) carvedilol significantly (p<0.05) increased gluthathione level, total anti-oxidant capacity, choactase activity (1.21 ± 0.04 vs. 0.71 ± 0.02 ng/ml and 1.14 ± 0.03 vs. 0.69 ± 0.02 ng/ml) and NGF whereas it reduced the AGEs and noradrenaline levels in both DM models;rn(iv) carvedilol significantly (p<0.05) increased high frequency power spectral (14,096.7 ± 238.5 vs. 5,403.5 ± 125.7 ms2 and 8,123.9 ± 167.3 vs. 3,057.8 ± 101.8 ms2 respectively) and other autonomic heart rate variables but reduced the low frequency power spectral in both models of DM; andrn(v) carvedilol had no significant (p>0.05) effect on cardiac axonal dystrophy and cardiac ND in both models.rnThe study concluded that carvedilol ameliorated cardiac autonomic neuropathy in both DM animal models. The study recommended multicenter randomized clinical trials to ascertain the role of carvedilol in DCAN patients.

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