Table of Contents

February 2006; 6 (1)

Speaking of Pharmacology



  • 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?

  • 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.

  • 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.


  • For about fifty years, scientists have investigated the ubiquitous role of free radicals in aging. In eukaryotes, the metabolic dynamics that generate these highly reactive, highly damaging intermediates emanate from the cell’s “power plants”—the mitochondria. Reactive oxygen species (ROS) are inevitable by-products of electron-wielding mitochondria, but these organelles have evolved a number of genetic programs to limit ROS damage. Mitochondrial metabolic efficiency, as well as the reduction of ROS production per se, are optimized by a number of protein expression patterns, including the expression of proteins involved in oxidative phosphorylation (e.g., cytochrome c) and enzymes that mitigate ROS reactivity (e.g., superoxide dismutase). Remarkably, both arms of the mitochondrial mission—metabolic efficiency and ROS squelching—are activated in response to estrogen. This finding bears a number of intriguing implications for potential clinical development, especially because mitochondrial dysfunction has been implicated in age-related disorders and a number of disease states. Data that establish the presence of estrogen receptor α in mitochondria of the cerebrovasculature, for example, may be relevant to hormone and drug therapies in neurodegenerative disease. Mounting evidence indicates that the effects of estrogen depend highly on cellular and molecular context, and avenues for the design of drugs that might mimic the non-reproductive (e.g., anti-aging) effects of estrogen (in both female and male contexts) warrant exploration.

  • Almost 4500 years ago, Ayurveda, the ancient medicinal book of Hindus, lauded the health effects of darakchasava, the fermented juice of red grapes. Somewhat later, the Bible described red wine as a “gift of God,” presumably used in the service of both body and soul. In 1940, resveratrol was first identified as the medicinal component of grapes. Resveratrol, a polyphenol phytoalexin, possesses diverse biochemical and physiological actions, including estrogenic, antiplatelet, and anti-inflammatory properties. Several recent studies determined the cardioprotective abilities of resveratrol. Both in experiments (acute) and in chronic models, resveratrol attenuates myocardial ischemic reperfusion injury, atherosclerosis, and reduces ventricular arrhythmias. It appears that resveratrol-mediated cardioprotection is achieved through the preconditioning effect (the best yet devised method of cardioprotection), rather than direct protection. Thus, resveratrol likely fulfills the definition of a pharmacological preconditioning compound. The long historical record concerning the health effects of wine production, along with current interest in resveratrol, has been an important element in the ascent of complementary and alternative medicine.

Beyond the Bench

Net Results