DHEA improves impaired activation of Akt and PKC zeta/lambda-GLUT4 pathway in skeletal muscle and improves hyperglycaemia in streptozotocin-induced diabetes rats.

AIM: Addition of dehydroepiandrosterone (DHEA) to a cultured skeletal muscle locally synthesizes 5alpha-dihydrotestosterone (DHT). It induced activation of glucose metabolism-related signalling pathway via protein kinase B (Akt) and protein kinase C zeta/lambda (PKC zeta/lambda)-glucose transporter-4 (GLUT4) proteins. However, such an effect of DHEA in vivo remains unclear. METHODS: Using streptozotocin (STZ)-induced rats with type 1 diabetes mellitus, we tested the hypothesis that a single bout of DHEA injection in the rats improves hyperglycaemia and muscle GLUT4-regulated signalling pathway. After 1 week of STZ injection (55 mg kg(-1)) with male Wistar rats, fasting glucose concentrations were determined in a blood sample taken from the tail vein. Blood glucose levels were then monitored for 180 min after DHEA or sesame oil (control) was injected (n = 10 for each group). RESULTS: Blood glucose levels decreased significantly for 30-150 min after 2 mg DHEA injection in the STZ rats. In the skeletal muscle, expression and translocation of GLUT4 protein, phosphorylation of Akt and PKC zeta/lambda, and phosphofructokinase and hexokinase enzyme activities increased significantly by DHEA injection. However, DHEA-induced improvements in Akt and PKC zeta/lambda-GLUT4 pathways were blocked by a DHT inhibitor. CONCLUSION: These results suggest that a single bout of DHEA injection can improve hyperglycaemia and activate the glucose metabolism-related signalling pathway via Akt and PKC zeta/lambda-GLUT4 proteins of skeletal muscles in rats. Moreover, these results show that a DHEA-induced increase in muscle glucose uptake and utilization might contribute to improvement in hyperglycaemia in type 1 diabetes mellitus.

Effect of nifedipine on left ventricular function during exercise in patients with stable effort angina. Relation of its efficacy to the severity of coronary artery disease.

To evaluate whether the effect of nifedipine on left ventricular function relates to the severity of coronary artery disease (CAD) or not, supine graded ergometer exercise testing was performed before and after sublingual administration of 10 mg nifedipine in 24 patients with stable effort angina. To minimize the effect of nifedipine on myocardial oxygen consumption, exercise before and after nifedipine was discontinued at the same target rate pressure product. Percent (%) left ventricular ejection fraction (EF) [EF during exercise/EF at rest.100] was measured before and after nifedipine by radionuclide angiocardiography. The angiographic degree of CAD was defined by Gensini's CAD scoring as follows: severe CAD: greater than or equal to 50, moderate: less than 50 greater than 20 and mild: less than or equal to 20. After nifedipine, left ventricular function (%EF) was improved in all 6 patients with mild CAD, but was worsened in all 9 patients with severe CAD. Maximal ST segment depression during exercise was improved in 5 of 6 patients with mild CAD, while improvement was induced in 5 of 9 patients with moderate CAD and in 3 of 9 patients with severe CAD. Jeopardy of coronary collateral vessels may have an influence on the effect of nifedipine. It is suggested that the effect of nifedipine on left ventricular function is influenced by the severity of CAD when most of its effect on myocardial oxygen consumption is eliminated.

Effects of nifedipine on left ventricular systolic and diastolic function in patients with ischemic heart disease. Radionuclide angiocardiographic studies at rest and during exercise.

The purpose of this study was to evaluate the acute effects of sublingual nifedipine (10 mg) on left ventricular systolic function (ejection fraction, peak ejection rate, time to peak ejection rate) and diastolic function (peak filling rate, time to peak filling rate, filling fraction during rapid filling) at rest and during exercise using radionuclide angiography in 17 patients with ischemic heart disease. The results of the study were as follows. Diastolic indexes in the patient group were significantly different from the values in the control group at rest and during exercise. Peak filling rate and filling fraction improved significantly after nifedipine administration. These values did not show significant differences from the values in normal subjects which were obtained before nifedipine administration. The peak filling rate during exercise after nifedipine administration increased significantly, although the value was lower than that in the control group. At rest, systolic indexes in the patient group showed abnormal values, although the differences from the control values were not significant. Ejection fraction and peak ejection rate were significantly lower than those in the control group during exercise. After nifedipine administration, peak ejection rate at rest and during exercise, and ejection fraction at rest in the patient group improved significantly. Seven of 17 achieved the same exercise workloads as control conditions without symptoms or ECG changes. These data suggest that nifedipine improved left ventricular systolic and diastolic dysfunction, as well as exercise tolerance in patients with ischemic heart disease.