Table of Contents

Viewpoints

• • Ryan M. Fryer,
  • Glenn A. Reinhart,
  • and Timothy A. Esbenshade

  Histamine in Cardiac Sympathetic Ganglia: A Novel Neurotransmitter?

  Mol Interv February 2006 6:14-19; doi:10.1124/mi.6.1.3
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  Although ganglia in the heart are well known to be cholinergic, many other neurotransmitters and neuropeptides also influence (and are produced in) cardiac neurons, including adrenergic and purinergic compounds. Recently, histamine was suggested as a possible neurotransmitter in cardiac tissue. Although histamine does elicit many effects in the heart, does it stand up to rigorous scrutiny and fulfill certain criteria that are used to define neurotransmitters?

• • Tobias Schmid and
  • Matthew R. Young

  Lights on for Low Oxygen: A Noninvasive Mouse Model Useful for Sensing Oxygen Deficiency

  Mol Interv February 2006 6:20-22; doi:10.1124/mi.6.1.4
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  In vitro experimentation is valuable as a precursor to in vivo research; however, as we all know too well, not every in vitro finding leads to confirmation in vivo. In fact, conflicting results often occur because in vitro experiments lack all the necessary factors that impinge upon normal physiology in live animals. We are fortunate when in vivo models can be created that allow for direct observation of pharmacological effects. Kaelin and colleagues have created a mouse line that expresses the oxygen-dependent degradation domain (ODD) of hypoxia-induced factor-1α (HIF-1α) fused to the common firefly luciferase gene, under the control of a promoter that ensures organism-wide expression. In conditions of normoxia, the protein is quickly degraded, but in hypoxic situations, the protein is not degraded and administration of substrate illuminates the areas of expression. This technique allows for the observation of the effects of agents on oxygen tension in particular organs. Implicit is the adaptability of this model, wherein other promoters (e.g., tissue-specific) can be utilized or other disease models can be studied.

• • Robert J. Tomko, Jr.,
  • Pallavi Bansal,
  • and John S. Lazo

  Airing Out an Antioxidant Role for the Tumor Suppressor p53

  Mol Interv February 2006 6:23-25; doi:10.1124/mi.6.1.5
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  The tumor suppressor p53 exerts its activity by preventing DNA-damaged cells from dividing until either the chromosomal repair is effected or the cell undergoes apoptosis. Reactive oxygen species (ROS) are enhanced through the action of p53-mediated transcription of apoptosis-promoting genes; however, p53 also can promote the expression of many antioxidant genes that prevent apoptosis. New research indicates that in low cellular stress, low concentrations of p53 induce the expression of antioxidant genes, whereas in severe cellular stress, high concentrations of p53 promote the expression of genes that contribute to ROS formation and p53-mediated apoptosis. p53-depleted cells injected into athymic mice increased significantly in tumor volume, whereas injected p53^+/+ cells did not grow to the same degree. Interestingly, administration of the antioxidant compound N-acetylcysteine (NAC) inhibited the growth of tumor volume in p53-depleted injected cells, and NAC supplementation of p53^−/− mice from birth greatly decreased the number of karyotype abnormalities and tumors formed in these mice by six months of age. Thus, under normal (or low stress) conditions, p53 appears to have an antioxidant role that protects cells from oxidative DNA damage and although this effect might depend on the concentration of p53, other cellular factors likely participate in a cell’s final fate.