Recent Grants
Use of RNA interference in the brainstem to examine endocannabinoid baroreflex regulation in normal and hypertensive rate
Signaling pathways responsible for anesthetic-induced preconditioning (APC)
Mechanisms of peripheral vascular anesthetic sensitivity
KATP channels in normal and injured sensory transduction
Mechanisms of cardioprotection by xenon
Mechanisms of cardioprotection by volatile anesthetics
Signaling pathways responsible for anesthetic-induced preconditioning (APC)
The Medical College has recently received a 5-year $1 million R01 grant to study anesthetics and cardiac signal transductions. This research will investigate the signaling pathways responsible for anesthetic-induced preconditioning (APC) in isolated human atrial myocytes and determine the respective roles of sarc and mitoKATP channels in cytoprotection produced by volatile anesthetics. The proposal represents a comprehensive approach to significant and clinically relevant phenomenon of volatile anesthetic-induced cardioprotection against ischemia/reperfusion injury. The results from these studies will be of considerable value in defining anesthetic preconditioning.
Zeljko J. Bosnjak, PhD, Professor and Vice Chairman for Research of Anesthesiology, is the Principle Investigator for the project. He notes that results from the MCW, Anesthesiology laboratory were the first to demonstrate that volatile anesthetics produce cardioprotective effects against infarction comparable to that of ischemic preconditioning and this phenomenon was termed APC.
Mechanisms of peripheral vascular anesthetic sensitivity
The Medical College of Wisconsin recently received a $996,000 four-year grant from the National Institutes of Health titled, "Mechanisms of peripheral vascular anesthetic sensitivity". The principal investigator is Thomas A. Stekiel, MD, Associate Professor of Anesthesiology at the Medical College of Wisconsin. The objective of this study is to clarify mechanisms by which anesthetics alter the peripheral regulatory components of the cardiovascular system and, thereby contribute to circulatory instability during anesthesia. This research will lead to an enhanced understanding of the coupling between mechanisms of anesthetic action on vascular smooth muscle tone and resultant overall cardiovascular stability during anesthesia. The intent is for this information to contribute to improved anesthetic techniques, particularly in individuals with enhanced sensitivity to these agents.
KATP channels in normal and injured sensory transduction
Constantine Sarantopoulos, MD, PhD, is the Principle Investigator for a 5 year grant from the National Institute of Neurological Disorders and Stroke, titled, "KATP channels in normal and injured sensory transduction". Dr. Sarantopoulos is Associate Professor of Anesthesiology at the Medical College of Wisconsin and the Medical Director of the Pain Clinic at the Zablocki Veterans Affairs Medical Center. This funded project aims to investigate the molecular pharmacology and roles of KATP channels in peripheral sensory neurons, in the normal state, as well as after painful neuropathic injury. Chronic neuropathic pain is not only highly prevalent in humans, but resistant to most treatments as well. The latter is mainly secondary to the fact that its pathophysiology and basic pharmacology remain unclear. ATP-sensitive potassium channels in other tissues (heart, pancreas, brain) mediate diverse functions, such as regulation of cellular excitability, transmitter release and protection from cell death, but their role in the peripheral nerves remains unknown. Preliminary studies from our laboratory have shown the presence of these channels on peripheral nerves and their loss after nerve injury. Increased neuronal excitability, neurotransmitter release, and cell death are key features of neuropathic injury that results in pain. Because KATP channels are implicated in the regulation of these functions, they are potentially significant foci of investigation and therapeutic interventions with potentially promising results. The project will explore the role and regulation of peripheral neuronal KATP channels employing electrophysiological, molecular and genetic techniques. The translational research emanating from this project will be pertinent to improving the care of those who suffer from chronic pain and neurodegenerative conditions.
Mechanisms of cardioprotection by xenon
Martin Bienengraeber, PhD, is an Assistant Professor of Anesthesiology, Pharmacology and Toxicology at MCW. Dr. Bienengraeber is the Principle Investigator of a new grant entitled, "Mechanisms of cardioprotection by xenon" that was funded by the Europe/Sweden Company, Linde. The grant begins September 1, 2005, and will involve research investigating and defining the cellular and sub-cellular mechanisms responsible for the novel actions of the noble gas, xenon. The goals of Anesthesiology research include the quest to find and develop safer anesthetic agents. Xenon contributes to that quest. One of the properties of xenon includes the capability of protecting the heart from ischemia by reducing myocardial injury after hypoxic stress. Cardioprotection by xenon, particularly when applied at the time of reperfusion, represents a potential therapeutic approach for patients with ongoing myocardial ischemia.
Mechanisms of cardioprotection by volatile anesthetics
The Medical College has received a five-year, $6 million program project grant from the National Institute of General Medical Sciences to define the mechanisms by which volatile anesthetics help protect hearts with inadequate circulation during surgery.
For this project, researchers will study the interactions of volatile anesthetics with ischemic myocardium (hearts with inadequate circulation) at the physiologic, cellular and molecular levels, and explore the underlying mechanisms of those interactions that may offer cardioprotection against tissue injury caused by a loss of blood flow.
David C. Warltier, MD, PhD, Professor and Senior Vice Chairman of Anesthesiology, Medicine (Cardiology), and Pharmacology and Toxicology will direct project I, which will characterize the degree of cardioprotection elicited by anesthetics in vivo and determine mechanisms by which volatile anesthetics produce pharmacological cardiac preconditioning.
Dr. Bosnjak will direct project II. This project will examine the effects of volatile anesthetics on potassium channels located in the cardiac cell membrane and those located inside the cardiac cells, isolated potassium channels placed in the artificial cell membrane, and the same channels expressed in the human kidney cells.
Wai-Meng Kwok, PhD, Assistant Professor of Anesthesiology, and Pharmacology and Toxicology will direct project III. The overall goal of this project is to establish the cellular mechanisms underlying volatile anesthetic action on electrical impulses of the heart. Meetha Medhora, PhD, Assistant Professor of Medicine (Pulmonary and Critical Care), and David R. Harder, PhD, Professor of Physiology and Director of the Cardiovascular Center, will co-direct the Core support laboratory for biochemical analyses.
Use of RNA interference in the brainstem to examine endocannabinoid baroreflex regulation in normal and hypertensive rate
Jeanne L. Seagard, PhD, Professor of Anesthesiology and Physiology, received a grant award from the Advancing a Healthier Wisconsin Program in January, 2006. The title of the grant is, "Use of RNA interference in the brainstem to examine endocannabinoid baroreflex regulation in normal and hypertensive rats." Dr. Seagard's grant, which will run from 2006-2007, will investigate a possible treatment for high blood pressure. Co-investigators include: Caron Dean, PhD, also from Anesthesiology, Cecilia J. Hillard, PhD from the Department of Pharmacology and Toxicology, and Michael Michalkiewicz, PhD from the Department of Physiology.
This study will examine central mechanisms involved in the control of blood pressure. Neural control of blood pressure involves a reflex, the baroreflex, that includes neurons in the brain that receive information from special nerve endings, called baroreceptors, that relay both the level of blood pressure and whether or not pressure is changing. Excitatory nerve activity from baroreceptors make its first synapse on neurons in the nucleus tractus solitarius (NTS) of the brainstem. This is a pivotal regulatory moment, because the signal conditioning at these gateway synapses determine the magnitude, pattern and duration of the baroreceptor signals transmitted to distal synapses in the central network to coordinate baroreflex output, which consists of changes in the levels of sympathetic and parasympathetic nerve activity. This study will examine the function of the baroreflex and the role that substances made in the brain, called endocannabinoids (ECBs), play in the modulation of the baroreflex. Endocannabinoids act at special receptors (CB1 receptors) in the brain to modulate the degree to which baroreceptors activate the NTS neurons. We will study control of blood pressure in normal and high blood pressure (hypertensive) awake rats and see if increasing or decreasing the amount of ECBs or CB1 receptors in the brain using RNA interference changes the way the different rats control blood pressure.