Anti-hypotensive treatment and endothelin blockade synergistically antagonize exercise fatigue in rats under simulated high altitude.


Rapid ascent to high altitude causes illness and fatigue, and there is a demand for effective acute treatments to alleviate such effects. We hypothesized that increased oxygen delivery to the tissue using a combination of a hypertensive agent and an endothelin receptor A antagonist drugs would limit exercise-induced fatigue at simulated high altitude. Our data showed that the combination of 0.1 mg/kg ambrisentan with either 20 mg/kg ephedrine or 10 mg/kg methylphenidate significantly improved exercise duration in rats at simulated altitude of 4,267 m, whereas the individual compounds did not. In normoxic, anesthetized rats, ephedrine alone and in combination with ambrisentan increased heart rate, peripheral blood flow, carotid and pulmonary arterial pressures, breathing rate, and vastus lateralis muscle oxygenation, but under inspired hypoxia, only the combination treatment significantly enhanced muscle oxygenation. Our results suggest that sympathomimetic agents combined with endothelin-A receptor blockers offset altitude-induced fatigue in rats by synergistically increasing the delivery rate of oxygen to hypoxic muscle by concomitantly augmenting perfusion pressure and improving capillary conductance in the skeletal muscle. Our findings might therefore serve as a basis to develop an effective treatment to prevent high-altitude illness and fatigue in humans.





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Publication Info

Radiloff, Daniel, Yulin Zhao, Alina Boico, Gert Blueschke, Gregory Palmer, Andrew Fontanella, Mark Dewhirst, Claude A Piantadosi, et al. (2014). Anti-hypotensive treatment and endothelin blockade synergistically antagonize exercise fatigue in rats under simulated high altitude. PLoS One, 9(6). p. e99309. 10.1371/journal.pone.0099309 Retrieved from

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Gregory M. Palmer

Professor of Radiation Oncology

Greg Palmer obtained his B.S. in Biomedical Engineering from Marquette University in 2000, after which he obtained his Ph.D. in BME from the University of Wisconsin, Madison. He is currently an Associate Professor in the Department of Radiation Oncology, Cancer Biology Division at Duke University Medical Center. His primary research focus has been identifying and exploiting the changes in absorption, scattering, and fluorescence properties of tissue associated with cancer progression and therapeutic response. To this end he has implemented a model-based approach for extracting absorber and scatterer properties from diffuse reflectance and fluorescence measurements. More recently he has developed quantitative imaging methodologies for intravital microscopy to characterize tumor functional and molecular response to radiation and chemotherapy. His awards have included the Jack Fowler Award from the Radiation Research Society.

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Mark Wesley Dewhirst

Gustavo S. Montana Distinguished Professor Emeritus of Radiation Oncology

Mark W. Dewhirst, DVM, PhD is the Gustavo S. Montana Professor of Radiation Oncology and Vice Director for Basic Science in the Duke Cancer Institute. Dr. Dewhirst has research interests in tumor hypoxia, angiogenesis, hyperthermia and drug transport. He has spent 30 years studying causes of tumor hypoxia and the use of hyperthermia to treat cancer. In collaboration with Professor David Needham in the Pratt School of Engineering, he has developed a novel thermally sensitive drug carrying liposome that has been successfully translated to human clinical trials. He has utilized the thermal characteristics of this liposome to develop an MR imageable form that can accurately reflect drug concentrations in tumors, which then is related to the extent of anti-tumor effect in pre-clinical models. This property has been widely used by other investigators, world-wide, particularly in the area of high intensity focused ultrasound, where it would be possible to literally paint drug to a target zone and visualize this process in real time, during heating. For his work in this area, Dr. Dewhirst was named a Fellow in the AAAS. Dr. Dewhirst has well over 500 peer-reviewed publications, book chapters and reviews, with >20,000 citations and an H-index of 73. He has given named lectures at the University of Western Ontario, Thomas Jefferson University and the New Zealand Cancer Society. He was awarded the Failla Medal and Lecture at the Radiation Research Society in 2008, the Eugene Robinson award for excellence hyperthermia research in 1992 and a similar award from the European Society for Hyperthermic Oncology in 2009. He was named a fellow of ASTRO in 2009 and was awarded the prestigious Gold Medal from the same society in 2012. He is a Senior Editor of Cancer Research and Editor-in-Chief of the International Journal of Hyperthermia. He has mentored 24 graduate students, and many postdoctoral fellows, residents, junior faculty and medical students. He has been particularly skillful in assisting those he has mentored to obtain DOD and NIH fellowships, K awards and first R01 grants. His skill in mentoring has been recognized by the Duke Comprehensive Cancer Center, the Medical Physics Graduate Training programs and the School of Medicine, where he has received “Mentor of the Year” awards. In 2011 he was selected to become the first Associate Dean of Faculty Mentoring in the Duke School of Medicine. In this position, he is implementing a comprehensive program to enhance success in obtaining NIH funding. He graduated from the University of Arizona in 1971 with a degree in Chemistry and Colorado State University in 1975 and 1979 with DVM and PhD degrees, respectively.


Claude Anthony Piantadosi

Professor Emeritus of Medicine

Dr. Piantadosi's laboratory has special expertise in the pathogenic mechanisms of acute organ failure, particularly acute lung injury (ALI), with an emphasis on the molecular regulatory roles of the physiological gases— oxygen, carbon monoxide, and nitric oxide— as they relate to the damage responses to acute inflammation. The basic science focuses on oxidative processes and redox-regulation, especially the molecular mechanisms by which reactive oxygen and nitrogen species transmit biological signals involved in the maintenance of energy metabolism and mitochondrial health, but also contribute to pathogenesis and to the resolution of tissue injury.

Clinically, ALI and the related syndrome of multiple organ failure has a high mortality, which is related to the host inflammatory response, but is not well understood scientifically; thus, the laboratory is devoted to understanding these mechanisms in the context of the host response to relevant but well-controlled experimental manipulations including hyperoxia, bacterial infections, toxic drugs, and cytokine/chemokine signals. The approach relies on animal models, mainly transgenic and knockout mice, and cell models, especially lung and heart cells to evaluate and understand the physiology, pathology, and cell and molecular biology of the injury responses, to test independent and integrated mechanisms, and to devise interventions to prevent damage.

Apart from the lung, significant work is devoted to understanding damage to the heart, brain, liver, and kidney caused by these immune mechanisms, specifically emphasizing the role of mitochondria, key targets and sources of oxidative damage. This damage compromises their ability to support energy homeostasis and advanced cellular functions, and impacts on the important roles these organelles play in cell death by apoptosis and necrosis as well as in the resolution of cellular damage and inflammation.


Bruce Klitzman

Associate Professor Emeritus in Surgery

Our overriding interests are in the fields of tissue engineering, wound healing, biosensors, and long term improvement of medical device implantation. My basic research interests are in the area of physiological mechanisms of optimizing substrate transport to tissue. This broad topic covers studies on a whole animal, whole organ, hemorheological, microvascular, cellular, ultrastructural, and molecular level. The current projects include:
1) control of blood flow and flow distribution in the microcirculation,
2) the effects of long-term synthetic and biologic implants on substrate transport to tissues,
3) tissue engineering; combining isolated cells, especially adult stem cells, with biomaterials to form specialized composite structures for implantation, with particular emphasis on endothelial cell physiology and its alteration by isolation and seeding on biomaterials.
4) decreasing the thrombogenicity of synthetic blood vessels and other blood-contacting devices, and improving their overall performance and biocompatibility.
5) reducing tissue damage resulting from abnormal perfusion (e.g., relative ischemia, anoxia, etc.) and therapies which minimize ischemic damage.
6) biosensor function, particularly glucose sensors in normal and diabetics.
7) measurement of tissue blood flow and oxygenation as an indicator of tissue viability and functional potential.
8) development of biocompatible materials for soft tissue reconstruction or augmentation.
9) improving performance of glaucoma drainage devices by directing a more favorable foreign body reaction
10) wound healing; particularly internal healing around foreign materials and the effect and prevention of microbes around implanted devices.

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