digoxin and Hyperglycemia

Increase of peroxisome proliferator-activated receptor δ (PPARδ) expression by digoxin in the heart of diabetic rats has been documented. The present study investigated the mediation of PPARδ in lipid metabolism improved by digoxin in the heart of diabetic rats and in the hyperglycemia-treated cardiomyocytes using the primary cultured cardiomyocytes from neonatal rat. The lipid deposition within the heart section was assessed in diabetic rats by oil red O staining. The fatty acid oxidation genes in cardiomyocytes were also examined. Inhibitor of calcium ions and siRNA-PPARδ were employed to investigate the potential mechanisms. After a 20-day digoxin treatment, the PPARδ expression was elevated in hearts of diabetic rats while the cardiac lipid deposition was reduced. In neonatal cardiomyocytes, digoxin also caused an increase in expressions of PPARδ and fatty acid oxidation genes. But both actions of digoxin were blocked by BAPTA-AM to chelate calcium ions and by siRNA-PPARδ in cardiomyocytes. The obtained results show that increase of PPARδ by digoxin is related to regulation of fatty acid oxidation genes in cardiac cells mediated by calcium-triggered signals.

Topics: Animals; Animals, Newborn; Diabetes Mellitus, Experimental; Digoxin; Egtazic Acid; Fatty Acids; Gene Expression Regulation; Hyperglycemia; Lipid Metabolism; Myocardium; Myocytes, Cardiac; Oxidation-Reduction; PPAR delta; Rats; RNA, Small Interfering

The purpose of this study is to investigate the regulation of P-glycoprotein expression in the kidney under diabetic condition. Renal P-glycoprotein expression was examined in inbred mice with type 1 or type 2 diabetes by Western blotting. The underlying mechanisms of P-glycoprotein regulation were examined in Madin-Darby canine kidney type II (MDCK-II) cells by Western blotting or qRT-PCR. (3)H-digoxin uptake was measured for P-glycoprotein activity in cells under various treatments. The results showed that P-glycoprotein expression was lower in kidneys of diabetic mice than in controls. In MDCK-II cells, treatments with insulin or IL-6 did not cause any change in P-glycoprotein expression, whereas TNF-α tended to increase P-glycoprotein expression at a concentration of 1 ng/ml. On the other hand, P-glycoprotein expression was reduced under high glucose conditions (450 mg/dl), while superoxide production was increased, and the reduction in P-glycoprotein expression was abolished by N-acetylcysteine (an antioxidant) and staurosporine (a nonselective PKC inhibitor). Treatment with oxidizing agents (H(2)O(2), BSO) or PMA (a PKC activator) reduced P-glycoprotein expression. Antioxidant (N-acetylcysteine or glutathione) co-treatment abolished the H(2)O(2)-induced and BSO-induced reduction in P-glycoprotein expression, whereas it did not prevent the effect of PMA. The PMA-induced P-glycoprotein down-regulation was prevented by co-treatment of LY333531 (a PKC-β inhibitor). (3)H-digoxin levels were higher in MDCK-II cells with high glucose, PMA or H(2)O(2) treatments. In conclusion, P-glycoprotein expression is lower in kidneys of diabetic mice and in MDCK-II cells under high glucose conditions. Hyperglycemia induced reactive oxygen species and activated PKC in MDCK-II cells, leading to the decrease in P-glycoprotein expression.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport; Blood Glucose; Body Weight; Cell Membrane; Diabetes Complications; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Digoxin; Dogs; Down-Regulation; Female; Hyperglycemia; Insulin; Interleukin-6; Kidney; Madin Darby Canine Kidney Cells; Male; Mice; Protein Kinase C; Reactive Oxygen Species; Tumor Necrosis Factor-alpha

Hypertensive obese subjects with glucose intolerance have hyperinsulinaemia, insulin resistance and intracellular cation imbalance resulting in increased sodium content. The aim of our study was to assess in these patients plasma levels of endogenous digoxin-like factor (EDLF), an inhibitor of the sodium-pump mechanism. We studied 14 hypertensive and 12 normotensive subjects with obesity and glucose intolerance for fasting blood glucose, and plasma insulin, C-peptide and EDLF levels: the two groups were matched for age and BMI and were studied after a 2-week wash-out period from hypotensive drugs. Compared with normotensives, hypertensive subjects had higher plasma insulin levels, a greater immunoreactive insulin/C-peptide ratio, a lower glucose/insulin ratio and higher plasma EDLF levels. Our results confirm that among obese people with glucose intolerance, hypertensives are more hyperinsulinaemic and insulin-resistant than normotensives and indicate that the intracellular cation imbalance in these patients may be attributable, at least in part, to EDLF.

Topics: Blood Glucose; Blood Proteins; C-Peptide; Cardenolides; Digoxin; Female; Glucose Tolerance Test; Humans; Hyperglycemia; Hypertension; Insulin; Insulin Resistance; Male; Middle Aged; Obesity; Saponins; Sodium-Potassium-Exchanging ATPase

The effect of digoxin (0.035 mg/kg b.w., i.v.) on adrenaline-induced hyperglycemia (adrenaline: 50 micrograms/kg b.w., s.c.) and on insulin-induced hypoglycemia (insulin: 0.4 mU/kg b.w., s.c.) was studied in experiments on rabbits. Digoxin intensified the adrenaline-induced hyperglycemia at the 30th and 60th minutes of application. The hyperglycemia in this case subsided more rapidly. Digoxin alone caused on elevation of the blood sugar levels that was most pronounced at the 30th minute of introduction. These elevated levels fell to the initial value by the 180th minute. The blood sugar levels in the rabbits treated with physiological solution rose slightly. This was most noticeable at the 120th minute. Digoxin attenuated the insulin-induced hypoglycemia significantly at the 120th, 150th, and 180th minutes (p < 0.05). We suggest that the increase of the adrenaline-induced hyperglycemia and the attenuation of the insulin-induced hypoglycemia could be linked to the release of catecholamines in the acute stage of the action of Digitalis glycosides.

Topics: Animals; Digoxin; Epinephrine; Hyperglycemia; Hypoglycemia; Injections, Subcutaneous; Insulin; Rabbits

In order to validate a new method for quantifying coronary blood flow, we injected intravenously a bolus of rubidium-82 (Rb-82) into 28 open-chested dogs under a wide range of flow and physiologic conditions, using beta probes to monitor myocardial radioactivity. Extraction fraction and perfusion were measured using a functional model that separates the data into the free and trapped myocardial rubidium. Extraction and uptake of rubidium were lower during acidosis than during alkalosis and were unchanged by glucose-insulin, digoxin, or propranolol. Myocardial flow, as indicated by rubidium, correlated linearly with simultaneous measurements of flow by microspheres in the same sample volume over a wide range of flow (r = 0.97, n = 106, range 0.02-7.76 ml/min/g). Regional myocardial blood flow can be accurately determined using generator-produced Rb-82. Studies using current state-of-the-art, fast positron-emission tomographic cameras are required to determine the utility of this approach in man.

Topics: Animals; Coronary Circulation; Digoxin; Dogs; Heart; Hydrogen-Ion Concentration; Hyperglycemia; Methods; Microspheres; Myocardium; Propranolol; Radioisotopes; Radionuclide Imaging; Rubidium

Thirty intact dogs were studied to determine digoxin concentration in various tissues after ventricular tachycardia had been induced by digoxin infusion. A control group was infused solely with digoxin. A second group was made acutely hypokalemic by glucose-insulin infusion before the digoxin infusion. A third group was infused with glucose and digoxin to determine the effect of increased blood glucose levels and osmalarity on the induction of ventricular tachycardia. Results were: (1) The amount of digoxin infused to produce ventricular tachycardia did not differ getween the normal and hypokalemic groups. (2) The concentration of digoxin in various parts of the heart, other muscle tissue, renal cortex, and liver did not differ between the normal and acutely hypokalemic dogs although the amount excreted in bile and urine was reduced in hypokalemia. (3) Acute hypokalemia did not sensitize the myocardium to the arrhythmogenic effects of digoxin. (4) Ventricular tachcardia occurred at a similar plasma digoxin level in normal and acutely hypokalemic dogs. (5) In dogs with a lowered plasma potassium level, junctional tachycardia occurred whereas it did not occur in normal dogs or those with only a high blood glucose level. (6) Ventricular tachycardia occurred in the hyperglycemic dogs at a plasma digoxin level of 170 ng/ml, which was significantly greater than in the other experiments (7) Acute hyperglycemia reduced the mean rate of myocaridal uptake of digoxin into atria and right and left ventricular tissue; and the concentration of digoxin in atria, left ventricle, and interventricular septum was lower at the time of ventricular tachycardia than occurred in normal dogs. (8) Lowering the plasma potassium level in the presence of acute hyperglycemia, which occurred with the glucose-insulin infusion, did increase the myocardial uptake of digoxin. Similar effects of hyperglycemia were noted on mean hepatic uptake and excretion of digoxin and also the renal uptake of the glycoside.

Topics: Animals; Body Temperature; Digoxin; Dogs; Electrocardiography; Hyperglycemia; Hypokalemia; Myocardium; Tachycardia