Although testosterone deficiency is associated with increased risks of heart disease, the benefits of testosterone therapy are controversial. Moreover, current understanding on the cardiac effect of testosterone during cardiac ischemia-reperfusion (I/R) periods is unclear. We tested the hypothesis that testosterone replacement attenuates the impairment of left ventricular (LV) function and heart rate variability (HRV), and reduces the infarct size and arrhythmias caused by I/R injury in orchiectomized (ORX) rats. ORX or sham-operated male Wistar rats (n = 24) were randomly divided and received either testosterone (2 mg/kg, subcutaneously administered) or the vehicle for 8 weeks. The ejection fraction (EF) and HRV were determined at baseline and the 4^th and 8^th week. I/R was performed by left anterior descending coronary artery ligation for 30 minutes, followed by a 120-minute reperfusion. LV pressure, arrhythmia scores, infarct size and cardiac mitochondrial function were determined. Prior to I/R, EF and HRV were impaired in the ORX group, but were restored in the testosterone-treated group. During I/R, arrhythmia scores and the infarct size were greater, and cardiac mitochondrial function was impaired, whereas the time to 1^st VT/VF onset and the LV end-systolic pressure were decreased in the ORX group when compared to the sham group. Testosterone replacement attenuated the impairment of these parameters in ORX rats during I/R injury, but did not show any benefit or adverse effect in non-ORX rats. Testosterone replacement restores cardiac function and autonomic regulation, and exerts cardioprotective effects during the I/R period via mitochondrial protection in ORX rats.

Long-term high-fat diet (HFD) consumption leads to not only obese-insulin resistance, but also impaired left ventricular (LV) function. Vagus nerve stimulation (VNS) has been shown to exert cardioprotection. However, its effects on the heart and metabolic parameters under obese-insulin resistant condition is not known. We determined the effects of VNS on metabolic parameters, heart rate variability (HRV) and LV function in obese-insulin resistant rats. Male Wistar rats were fed with HFD for 12 weeks and were randomly divided into sham and VNS groups. VNS was applied for the next 12 weeks. Echocardiography, blood pressure and HRV were examined. Blood samples were collected for metabolic parameters. At the end, the heart was removed for determination of apoptosis, inflammation, oxidative stress and cardiac mitochondrial function. VNS for 12 weeks significantly decreased plasma insulin, HOMA index, total cholesterol, triglyceride, LDL and visceral fat. Serum adiponectin was significantly increased in the VNS group. VNS also significantly decreased blood pressure, improved HRV and LV function, decreased cardiac MDA, TNF-α and Bax levels and improved cardiac mitochondrial function. VNS improves metabolic and hemodynamic parameters and the LV function via its ability against apoptosis, inflammation and oxidative stress and preserved cardiac mitochondrial function in obese-insulin resistant rats.

Vagus nerve stimulation (VNS) therapy was shown to improve peripheral insulin sensitivity. However, the effects of chronic VNS therapy on brain insulin sensitivity, dendritic spine density, brain mitochondrial function, apoptosis and cognition in obese-insulin resistant subjects have never been investigated. Male Wistar rats (n = 24) were fed with either a normal diet (n = 8) or a HFD (n = 16) for 12 weeks. At week 13, HFD-fed rats were divided into 2 groups (n = 8/group). Each group was received either sham therapy or VNS therapy for an additional 12 weeks. At the end of treatment, cognitive function, metabolic parameters, brain insulin sensitivity, brain mitochondrial function, brain apoptosis and dendritic spines were determined in each rat. The HFD-fed with Sham therapy developed brain insulin resistance, brain oxidative stress, brain inflammation and brain apoptosis, resulting in the cognitive decline. The VNS group showed an improvement in peripheral and brain insulin sensitivity. VNS treatment attenuated brain mitochondrial dysfunction and cell apoptosis. In addition, VNS therapy increased dendritic spine density and improved cognitive function. These findings suggest that VNS attenuates cognitive decline in obese-insulin resistant rats by attenuating brain mitochondrial dysfunction, improving brain insulin sensitivity, decreasing cell apoptosis and increasing dendritic spine density.