David J. Adams, PhD, UNSW - US grants

The ionic mechanisms underlying excitability in neurons of parasympathetic ganglia of the heart and the actions of neurotransmitters on their function will be studied. Neurotransmitters influence the function of a variety of ion channels and intracellular proteins in excitable cells to alter resting and active electrical properties and, hence, the physiological responses of the cell. Ionic currents will be studied in neurons of both in situ guinea-pig cardiac ganglia and dissociated ganglion cells from the atria of guinea-pigs grown in tissue culture using single channel and whole cell patch clamp recording techniques. The primary objective is to characterize the biophysical and pharmacological properties of potassium-selective ion channels in cardiac neurons and the possible modulation of potassium channels by various neurotransmitters. Experiments will focus on specific ion conductance mechanisms underlying the slow (potassium-selective) synaptic response mediated by muscarinic receptors (m-AChR) and to determine the pharmacological sensitivity of the m-AChR potassium channels to specific muscarinic agonists and antagonists. The effect of neurotransmitters (and specific antagonists) on the kinetic and permeability properties of identified potassium channels will be determined from measurements of ionic currents through individual potassium channels. The patch clamp method offers unique advantages for the study of membrane responses that involve intracellular mediators (biochemical second messengers) between receptor and ion channel, because of the ability to control the ion composition and locus of drug application on both intracellular and extracellular surfaces of the cell membrane. This novel study will contribute to understanding neurotransmitter modulation of ion channels in cardiac ganglion cells and elucidate mechanisms by which a diversity of chemical signalling can act to influence neural regulation of the heart.

PHARMACEUTICAL RESEARCH SHARED RESOURCE David Adams, Ph.D., Ashley Morris-Engemann, Pharm.D., Co-Directors The Pharmaceutical Research Shared Resource consists of an lnvestigational Chemotherapy Service and a Cancex Clinical Pharmacology Laboratory, provides a broad range of services to support the conduct of clinical hematology/ontology research. The Investigational Chemotherapy Service (ICS) is available to all Cancer Center investigators for the purpose of maintaining drug accotmtability records and investigafional drug inventories according to FDA and CTEP guidelines. In addition, this resource provides design consultation, professional staff education, and implementation services for clinical research studies. The primary focus of the Clinical Pharmacology Lab (CPL) is to investigate the pharmacokinetics and pharmacodynamics of anticancer drugs and recombinant proteins used in the experimental therapy of cancer. This resource is also available for analysis of endogenous cytokine concentrations during investigational therapy. One of the major goals of the laboratory is to identify predictors of response and toxicity and implement methods to reduce inter-patient variability of drug exposure. The lab provides both consultative and analytic services regarding clinical pharmacokinetie studies of anticancer compounds and recombinant proteins. These include: aid with trial design, optimal sampling techniques, sample handling and stability, quantitative measurement of drug and metabolite concentrations (via HPLC, atomic absorption spcetrophotometry, gas chromatography/mass spectrophotometry, or ELISA), calculation of individual and population pharmacokinetic parameters and pharmacometric evaluation via sophisticated computer modeling programs. This resource has maintained a high level of usage by Cancer Center investigators including those from the Experimental Therapeutics Program, Breast and Ovarian Bone Marrow Radiation and Ontology, Transplantation, Neuro-Oncology, Oncology Hyperthermia, and Cancer Immtmobiology Programs. During the last fiscal year, 100% of the resource utilization was generated for peer-reviewed investigators.