DEPARTMENT OF ANESTHESIOLOGY ANNUAL REPORT

An exciting development is the
establishment of formal ties with Dr.
Steve Eubanks in the Department of
Surgery and the members of the US
Surgical Endosurgical Research Center.
Utilizing the different strengths of each
group, collaborative projects will focus
on understanding the physiologic
responses to surgery, with a special
emphasis upon the fetal effects of nonobstetric
related maternal surgery
during pregnancy.
DEBRA A. SCHWINN, M.D.
Director, Molecular Pharmacology
Laboratory
Professor of Anesthesiology,
Pharmacology/Cancer Biology, and
Surgery
AREAS OF RESEARCH:
Molecular Pharmacology and Genetics of
Adrenergic Receptors
Our laboratory combines molecular
pharmacology approaches with translational
human functional genomics.
The laboratory is involved in studying
mechanisms underlying regulation of
adrenergic receptors (ARs) in health
and disease. Over the last ten years, we
(with help from several collaborators)
initially described and determined
mechanisms underlying acute myocardial
βAR desensitization during cardiopulmonary
bypass (a procedure
required to provide oxygenated blood
during heart surgery at most medical
centers world-wide) (Circulation, 1991;
84:2559; Circulation, 1998; 98:II275;
Anesthesiology, 1998; 89:602). Based on
successful animal studies, we initiated a
clinical interventional trial designed to
prevent acute myocardial βAR desensitization
during heart surgery. By
enhancing myocardial βAR functioning
after cardiopulmonary bypass, fewer
inotropic drugs should be required during
heart surgery, facilitating patient
recovery with fewer side effects.
In addition to studying βARs during
heart surgery, the laboratory primarily
focuses on regulation of α 1ARs in
health and disease. Since these receptors
are important in smooth muscle
and the heart, diseases such as hypertension,
myocardial hypertrophy, and
benign prostate hypertrophy are our
main focus. Three α 1AR subtypes exist
(α 1a, α 1b, and α 1d); over the years we
have been involved in cloning cDNAs
encoding each of these subtypes from
both animal and human sources
(PNAS, 1988; 85:7159; J Biol Chem,
1990; 265:8183; J Biol Chem, 1991;
266:6365; JPET 1995; 272:134). Our laboratory
recently demonstrated that
α 1aARs are present and functional in
human vasculature (particularly resistance
vessels and coronary arteries)
and are modified (increased, along
with the α 1aARs) by age (Circulation,
Dec 1999). In order to understand
mechanisms underlying these changes,
our laboratory is currently examining
regulation of the human α 1aAR at transcriptional
and protein levels (J Biol
Chem, 1997; 272:28237). After identification
of the α 1aAR in human prostate
smooth muscle (J Urol, 1993; 150:546),
we more recently examined a novel
role of other α 1ARs (specifically the
α 1dAR) in bladder hypertrophy associated
with BPH (J Urol, 1998; 160:937).
A new emphasis in the laboratory
is the role of genetic variability on human
cardiovascular disease. Specifically
the role of naturally occurring single
nucleotide polymorphisms (SNPs) and
insertions/deletions of α 1-adrenergic
receptors in hypertension is being investigated.
This involves using classical
genetic approaches, large scale genomic
sequencing, SNP identification, and
analysis for association with disease in
highly phenotyped populations. It also
includes investigating the biology of
each SNP in terms of α 1AR signal transduction
pathways.
A broad spectrum of individuals
interact and study in our laboratory
(undergraduates, medical students,
graduate students, postdoctoral fellows,
LABORATORY PROGRAMS
junior faculty, various collaborators),
and wide ranging approaches are utilized
(e.g. molecular biology, classical
pharmacology, biochemistry, pharmacogenetics,
and clinical trials). The
goal of our laboratory is to examine
clinically important questions using
basic science approaches, with the final
goal of ultimately taking answers back
to the clinic.
THOMAS F. SLAUGHTER, M.D.
Assistant Professor of Anesthesiology
AREAS OF RESEARCH:
Perioperative Hemostasis and
Thrombosis; Coagulation Factor XIII and
Tissue Transglutaminase
Both clinical and basic science investigations
are currently in progress to
define mechanisms of excessive bleeding
and thrombosis in the perioperative
period. Our clinical studies continue
to focus on the role of the fibrinolytic
system in perioperative abnormalities
of hemostasis and thrombosis and to
define pharmacologic approaches to
alleviate fibrinolytic bleeding in the
surgical patient. In addition, we are
engaged in field trials to develop novel
point-of-care assays of coagulation for
use in the perioperative setting. Basic
laboratory investigations continue to
focus on tissue transglutaminase and
factor XIII, members of an enzymatic
gene superfamily essential for intermolecular
stabilization. Recent evidence
suggests that transglutaminases
play an important regulatory role in the
life cycle of the cell by modulating cell
growth and angiogenesis. Our laboratory
is specifically interested in the role
of these enzymes in modulating the
extracellular matrix and consequently
the processes of thrombosis, angiogenesis,
and atherosclerosis. Recent
investigations have focused on mechanisms
for the post-translational regulation
of transglutaminase activity as well
as the role of transglutaminases in fibrin
stabilization.
LABORATORY PROGRAMS 123