Biomedical Research Infrastructure Center

Jeffrey Overholt, Ph.D.

Jeff Overholt PhD photoDr. Jeff Overholt and researchers from WSSU, WFUSM, and Metro Health Hospital in Cleveland are studying the control of the cardiovascular and pulmonary systems in health and disease.

One current study is investigating toxic side effects of drugs in the heart that induce a lengthening of the QT interval-which can lead to heart attack and stroke. The problem is a priority at the FDA, which now mandates that all new drugs be tested for side effects in the heart (as exemplified by the recent withdrawal of Vioxx, a popular pain and arthritis medicine). Researchers are examining the toxic effects of these drugs and their targets in the heart in order to create a model system for testing new drugs for similar effects. The study is funded by an American Heart Association Beginning Grant in Aid. After additional data is collected, Dr. Overholt hopes to submit an R01 to NIH and/or an Established Investigator award to the AHA. These grants will further fund these studies.

Another current study involves sympathetic control of the cardiovascular system and its involvement in hypertension. Hypertension is disturbingly higher in African Americans than in white Americans, and African Americans are more likely to die from stroke and heart disease related to hypertension. The causes are unknown. Previous studies from other investigators at BRIC suggest that increased peripheral sympathetic nervous system activity may contribute to hypertension. Researchers seek to understand the underlying cellular changes in sympathetic neurons and the altered autonomic synaptic transmission involved in increased blood pressure, and how this neuroplastic behavior can be modulated for preventive and therapeutic purposes. A third area of interest is the cellular effects of hypoxia and hypercapnia caused by many environmental and pathophysiological conditions. Researchers are especially interested in diseases such as sleep apnea, stroke, and myocardial infarction, and how intracellular pathways respond to reactive oxygen species, O2 and CO2. Elucidating the cellular effects of O2 and CO2 will allow researchers to better understand their effects from a systems level-leading to therapeutic strategies to alleviate the effects of many pulmonary and cardiovascular diseases associated with hypoxia and hypercapnia.

The laboratory uses a wide range of electrophysiological, biochemical, molecular, and imaging techniques to investigate the cellular mechanisms that control the cardiovascular system. Knowledge gained from these studies could lead to therapeutic strategies that alleviate the toxic side effects of drugs on the heart and in genetic forms of hypertension.

The NIH, the American Heart Association, and the general public are extremely interested in drug side effects and hypertension. Both affect millions of Americans.

Selected Publications

Prabhakar, N.R., Y.J. Peng, J.L. Overholt, and G.K. Kumar. Detection of oxygen sensing during intermittent hypoxia. Methods Enzymol. 381: 107-120, 2004.

Yu-Long, L., J.L. Overholt, N.R. Prabhakar, K. Patel, I.H. Zucker and H.D. Schultz. Attenuated outward potassium currents in carotid body glomus cells of heart failure rabbit: involvement of nitric oxide. J. Physiol. 555(1): 219-229, 2004.

Summers, B.A., J.L. Overholt and N.R. Prabhakar. CO2 and pH independently modulate L-type Ca2+ current in rabbit carotid body glomus cells. J. Neurophysiol. 88(2): 604- 612, 2002.

Overholt, J.L., B.A. Summers and N.R. Prabhakar. CO2/HCO3- modulates K+ and Ca2+ current in glomus cells of the carotid body. Adv. Exp. Med. Biol. 499: 61-66, 2001.

Prabhakar, N.R. and J.L. Overholt. Cellular mechanisms of oxygen sensing at the carotid body: heme proteins and ion channels (Invited Review). Respiration Physiology 122(2-3): 209-221, 2000.

Summers, B.A., J.L. Overholt and N.R. Prabhakar. Augmentation of L-type calcium current by hypoxia in rabbit carotid body glomus cells: evidence for a PKC-sensitive pathway. J. Neurophysiol. 84: 1636-1644, 2000.

Overholt, J.L, E. Ficker, T. Yang, H. Shams, G.R. Bright and N.R. Prabhakar. A HERG-like potassium current regulates the resting membrane potential in glomus cells of the rabbit carotid body. J. Neurophysiol. 83:1150-1157, 2000.

Bright, G.R., F.H. Agani, U. Haque, J.L. Overholt, and N.R. Prabhakar. Heterogeneity in cytosolic calcium responses to hypoxia in carotid body cells. Brain Research 706: 297-302, 1996.

Overholt, J.L., M.E. Hobert, and R.D. Harvey. On the mechanism of rectification of the isoproterenol activated chloride current in guinea-pig ventricular myocytes. J. Gen. Phys. 102: 871-895, 1993.

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