Uncoupling In Hearts Research Articles

Age-related differences of intraischemic gap junction uncoupling in hearts during ischemia

ObjectiveMyocardial ischemia leads to energetic, morphologic, metabolic, and functional alterations. To evaluate differences in ischemia tolerance between neonatal and adult hearts, we investigated gap junction uncoupling (GJU) and its correlation to myocardial intracellular edema formation during normothermic ischemia. MethodsHearts of landrace piglets (neonates, 7.4 ± 1.9 days of age, body weight 2.9 ± 0.5 kg, n = 5 and adults, 84 ± 9 days of age, body weight 30.5 ± 3.9 kg, n = 5) were investigated. After we harvested the hearts, the bioelectrical impedance spectra were measured continuously during normothermic global ischemia (35°C). Spectra of the dielectric permittivity, ε′(frequency), and conductivity, σ(frequency), were calculated from the impedance measurements, and GJU was identified in the sigmoidal time course of ε′ (13 kHz). The extracellular volume was estimated by the ratio σ (100Hz)/σ (1MHz). Dielectric data were correlated with electron-microscopical images. ResultsIntraischemic GJU was observed in neonates after 54 ± 9 minutes of ischemia and thus significantly earlier than in adults (90 ± 7 minutes, P < .05). A more than 20% increase of intercalated water was found in tissue samples of neonates after 20 ± 2 minutes, in contrast to adults after 137 ± 8 minutes (P < .05). ConclusionsIntraischemic formation of edema and earlier GJU indicate faster intraischemic changes in neonates compared with adults. Intraischemic GJU and determination of intracellular water shifts are an experimental approach to establish the period of life-threatening damage. Because both parameters are linked and occur significantly earlier in neonates, they distinctly demonstrate the lower ischemia tolerance of neonatal hearts as both events interact.

An ursolic acid-enriched Cynomorium songarium extract attenuates high fat diet-induced obesity in mice possibly through mitochondrial uncoupling

It has previously been demonstrated that HCY2, an ursolic acid-enriched fraction derived from Cynomorii Herba, induced mitochondrial uncoupling in heart, liver and kidney tissues of rats. In the present study, we investigated whether HCY2 co-treatment can reduce the body weight in high fat diet (HFD)-fed mice by virtue of mitochondrial uncoupling in skeletal muscle. The results showed that HCY2 co-treatment significantly reduced the body weight gain and white fat pads in HFD-fed mice. The weight reduction effect of HCY2 was associated with the induction of mitochondrial uncoupling in skeletal muscle, amelioration of HFD-induced hyperglycaemia and impairment in glucose tolerance as well as dyslipidaemia and fatty liver in HFD-fed mice. It is likely that HCY2 reduces body weight by increasing energy expenditure, presumably via mitochondrial uncoupling in skeletal muscle. HCY2 may therefore offer a promising prospect in preventing obesity and the associated metabolic syndrome and health consequences.

A New Approach for Resolution of Complex Tissue Impedance Spectra in Hearts

This study was designed to test the feasibility of using sinusoidal approximation in combination with a new instrumentation approach to resolve complex impedance (uCI) spectra from heart preparations. To assess that feasibility, we applied stimuli in the 10-4000 Hz range and recorded potential differences (uPDs) in a four-electrode configuration that allowed identification of probe constants (Kp) during calibration that were in turn used to measure total tissue resistivity ρt from rabbit ventricular epicardium. Simultaneous acquisition of a signal proportional to the supplied current (Vstim) with uPD allowed identification of the V- I ratio needed for ρt measurement, as well as the phase shift from Vstim to uPD needed for uCI spectra resolution. Performance with components integrated to reduce noise in cardiac electrophysiologic experiments, in particular, and provide accurate electrometer-based measurements, in general, was first characterized in tests using passive loads. Load tests showed accurate uCI recovery with mean uPD SNRs between 10 (1) and 10 (3) measured with supplied currents as low as 10 nA. Comparable performance characteristics were identified during calibration of nine arrays built with 250 μm Ag/AgCl electrodes, with uCIs that matched analytic predictions and no apparent effect of frequency ( F = 0.12, P = 0.99). The potential ability of parasitic capacitance in the presence of the electrode-electrolyte interface associated with the small sensors to influence the uCI spectra was therefore limited by the instrumentation. Resolution of uCI spectra in rabbit ventricle allowed measurement of ρt = 134 ± 53 Ω· cm. The rapid identification available with this strategy provides an opportunity for new interpretations of the uCI spectra to improve quantification of disease-, region-, tissue-, and species-dependent intercellular uncoupling in hearts.

Thermoregulatory, carboxyatractylate-sensitive uncoupling in heart and skeletal muscle mitochondria of the ground squirrel correlates with the level of free fatty acids

Thermoregulatory uncoupling of oxidative phosphorylation has been studied in heart and skeletal muscle mitochondria of ground squirrels. The respiratory rate of mitochondria in the presence of oligomycin was found to be much higher in winter (in hibernating, arousing, or aroused animals) than in summer. This additional respiration is strongly (arousing animals) or completely (hibernating and aroused animals) inhibited by carboxy-atractylate (CAtr) and bovine serum albumin (BSA). The CAtr- and BSA-induced decreases in the rate of respiration are accompanied by membrane potential increases. The rate of the CAtr- and BSA-sensitive respiration is proportional to the content of free fatty acids which, in the heart, decreases in the order: arousing > aroused = hibernating > summer animals. Maximal respiratory rates observed in the presence of dinitrophenol (arousing > aroused > summer > hibernating animals) do not parallel the fatty acid level. It is assumed that some heat production in the winter animals is due to fatty acid-induced, ATPIADP-antiporter-mediated uncoupling in heart and skeletal muscle mitochondria. The peak of heat production during arousal after hibernation also includes some other stimulatory effect on mitochondrial respiration.

Block of sodium current by heptanol in voltage-clamped canine cardiac Purkinje cells.

Heptanol blocks sodium current (INa) in nerve, but its effects on cardiac INa have not been well characterized. Block of INa by heptanol was studied in 16 internally perfused voltage-clamped cardiac Purkinje cells at reduced Na+ (45 mM outside, 0 mM inside). Heptanol block of peak sodium conductance was well described by a single-site binding curve with half block at 1.3 mM (20 degrees C) and showed no "use dependence." With 1.5 mM heptanol, block increased slightly by 0.7%/degrees C from 10 degrees C to 27 degrees C. With 3.0 mM heptanol, steady-state availability shifted by 9.4 +/- 1.3 mV (n = 6) in the hyperpolarizing direction, and steady-state activation shifted by 8.3 +/- 2.2 mV (n = 5) in the depolarizing direction, thus closing off the INa "window current." Heptanol also decreased the time to peak and accelerated the decay of INa. Similar results were found with octanol at lower concentrations. These alcohols have important effects on cardiac INa at concentrations used in studies for cellular uncoupling in heart.