Dr Clemence Girardet, a postdoctoral fellow in Dr Andrew Butler’s laboratory, was awarded a scholarship from the Keystone Symposia Future of Science Fund and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) .
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Department of Pharmacological and Physiology
Room M 362 || 1402 South Grand Blvd
St. Louis, Missouri 63104
Mark M. Knuepfer, Ph.D.
Department of Pharmacological and Physiological Science
Ph.D., Iowa, 1981
previously on the staff of Johns Hopkins University,
University of Heidelberg and University of Western Ontario.
In my laboratory, we study the role of the central nervous system (CNS) in regulating arterial pressure and in the development of cardiovascular disease. We have spent much of the past two decades examining the adverse effects of stress and cocaine in rats that are susceptible or resistant to these pathological changes in the cardiovascular system. Due to differences in central neural pathways and neurotransmitters, our findings suggest that excessive responsiveness of the sympathetic nervous system leads to cardiovascular disease.
More recently, we have returned to studies we and others performed in the 1980’s demonstrating the role of renal (kidney) nerves in the development of hypertension. We studied these central projections of sensory afferent nerves from the kidney and the information transduced by the kidney. Recently, it has been demonstrated in human clinical trials that renal denervation ameliorates the symptoms of high blood pressure (hypertension), heart failure, diabetes, arterial stiffening and abnormal heart rhythms (arrhythmias). We have developed a procedure to remove only the sensory nerves and found that this technique prevents the development of experimental models of hypertension. We also demonstrated that renal denervation in a rat model leads to reinnervation of both the sensory and the motor (sympathetic) nerves in less than three months. We are continuing these studies to determine the mechanism by which renal nerves, particularly renal sensory nerves, may contribute to the development of a wide variety of cardiovascular diseases responsible for shortening the life of millions of Americans.
In the laboratory, we use neurophysiological, neuroanatomical and both physiological and pharmacological approaches to determine the role of renal nerves in facilitating the development of cardiovascular disease. We have the ability to study a wide variety of cardiovascular and neural variables in conscious rats. These procedures will be used to identify the role of renal sensory nerves on cardiovascular disease. Our hypothesis is that the kidney signals the CNS through these nerves to increase sympathetic nerve activity and promote the development of hypertension, heart failure and a host of other cardiovascular diseases. We hope to prove this by determining the signals from the kidney, the central projections to the CNS, the role these play in cardiovascular disease and to develop procedures that will more specifically treat these disease conditions in humans.
Mulder, J., T. Hokfelt, M.M. Knuepfer, U. Kopp. Renal sensory and sympathetic nerves reinnervate the kidney in a similar time dependent fashion following renal denervation in rats, Am. J. Physiol. (in press) 2013.
Miller, R.L., M.M. Knuepfer, M.H. Wang, G.O. Denny, P.A. Gray, A.D. Loewy, Fos activation of FoxP2 and Lmx1b neurons in the parabrachial nucleus evoked by hypotension and hypertension in conscious rats, Neuroscience 218:110-125, 2012.
Knuepfer, M.M. and J.W. Osborn. Direct assessment of organ specific sympathetic nervous system activity in normal and cardiovascular disease states. Exp Physiol 95.1:32-33, 2010.
Watanabe, M.A., S. Kucenas, T. Bowman, M. Ruhlman and M.M. Knuepfer, Angiotensin II and CRF receptors in the central nucleus of the amygdala mediate vascular response variability to cocaine in conscious rats. Brain Res. 1309:53-65, 2009.
Schwartz, J.A., N.S. Reilly and M.M. Knuepfer, Angiotensin and NMDA receptors in the median preoptic nucleus mediate hemodynamic response patterns to stress. Am J Physiol 295:R155-R165, 2008.
Knuepfer, M.M., K. Rowe, Julie A. Schwartz and L. Lomax. Role of angiotensin II and corticotropin-releasing hormone on hemodynamic responses to cocaine and stress. Regul. Peptides 127:1-10, 2005.
Knuepfer, M.M. Cardiovascular disorders associated with cocaine use: myths and truths. Pharmacol Ther 97:181-222, 2003.
Knuepfer, M.M. and P.J. Mueller. Review of evidence for a novel model of cocaine-induced cardiovascular toxicity. Pharmacol. Biochem. Behav. 63:489-500, 1999.