Alterations in cardiac contractility and gene expression during low-T3 syndrome: prevention with T3.

The low-T3 syndrome is a metabolic response resulting in a decreased serum triiodothyronine (T3) concentration that has uncertain effects on thyroid hormone-responsive gene expression and function. We measured cardiac myocyte gene expression and cardiac contractility in young adult female rats using chronic calorie deprivation as a model of the low-T3 syndrome. Sarcoplasmic reticulum calcium adenosinetriphosphatase (SERCA2) and myosin heavy chain (MHC) isoform mRNA content were measured after 28 days on a 50% calorie-restricted diet (low T3) with or without T3 treatment (6 micrograms.kg body wt-1.day-1). The low-T3 animals had decreased maximal rates of contraction (-13%; P < 0.05) and relaxation (-18%; P < 0.05) compared with the control and the T3-treated groups. There was a 21% (P < 0.05) increase in left ventricular (LV) relaxation time in the low-T3 animals vs. both control and T3-treated groups. The LV content of the SERCA2 mRNA was decreased significantly (37%) in the low-T3 rats and was increased (P < 0.05) with T3 treatment vs. controls. The alpha-MHC mRNA isoform decreased in the low-T3 animals but was unchanged in the T3-treated animals. T3 supplementation normalized both cardiac function and phenotype of calorie-restricted animals, suggesting a role for the low-T3 syndrome in the pathophysiological response to calorie restriction.

Zinc supplementation enhances the effectiveness of St. Thomas' Hospital No. 2 cardioplegic solution in an in vitro model of hypothermic cardiac arrest.

The present study was done to assess the effectiveness of a zinc-supplemented cardioplegic solution in an in vitro model of hypothermic arrest. Isolated hearts were perfused in the nonworking mode. All hearts were subjected to 2 hours of hypothermic arrest, at 10 degrees C, followed by 60 minutes of recovery. In protocol 1, arrest was initiated with infusion of cardioplegic solution with or without 30 mumol/l zinc for 5 minutes, which was then reinfused for 5 minutes every 15 minutes during arrest. In protocol 2, arrest was initiated with infusion of cardioplegic solution with or without 40 mumol/L zinc for 10 minutes. Cardioplegic solution (without zinc) was then reinfused for 5 minutes before the hearts were rewarmed. In protocol 1 hearts, peak postischemic left ventricular developed systolic pressure was 106 +/- 5 mm Hg and 80 +/- 3 mm Hg in zinc-treated versus control hearts, respectively (p < 0.05 by repeated-measures analysis of variance). In protocol 2 hearts, recovery of postischemic left ventricular developed systolic pressure peaked at 74 +/- 4 mm Hg and 46 +/- 8 mm Hg in zinc-treated and control hearts, respectively (p 0.05, repeated-measures analysis of variance). Similar effects were observed for the left ventricular rate of relaxation (p < 0.05, repeated-measures analysis of variance). Except for some minor effects, lactate dehydrogenase release was not affected by zinc supplementation. The present study demonstrates that zinc supplementation further enhances the normally observed preservation of postarrest cardiac function and suggests possible clinical utility for this metal as an additive to standard crystalloid cardioplegic solutions.

Inhibition of cellular antioxidants: a possible mechanism of toxic cell injury.

Cells that utilize molecular oxygen generate highly reactive oxygen-derived free radicals. Endogenous cellular oxidants inactivate oxidant free radicals and protect aerobic cells from oxidant injury. Glutathione, glutathione reductase, and superoxide dismutase are key components of this antioxidant defense. Inhibition of antioxidant components would be expected to result in cell injury. Using exposure to oxygen at high pressure to increase the level of oxidant free radicals, evidence is presented to support the hypothesis that inhibition of cellular antioxidants renders organisms more susceptible to oxygen toxicity. Diethyldithiocarbamate at doses of 250, 500 and 1000 mg/kg inhibited rat brain superoxide dismutase activity and shortened onset time to seizures in a dose-related manner in 4 ATA oxygen. Carmustine at doses of 12.5, 25 and 50 mg/kg inhibits glutathione reductase activity in rat brain in proportion to the dose. Time to onset of seizures of rats pretreated with carmustine prior to exposure to 4 ATA oxygen was shortened, and oxidized glutathione levels were increased in the cortex and subcortex. These data suggest that inhibition of antioxidant components results in organisms becoming more sensitive to oxygen toxicity. Compounds that inhibit cellular antioxidants may produce toxic cell injury by permitting intracellular oxidant free radicals to attack essential cell constituents.