The Early Years
Investigators at Vanderbilt University became interested in studying autonomic cardiovascular regulation in the late 1920's. By the early 1930's, Dr. Clay M. Greer, in Pharmacology, was developing extensive experimental evidence that norepinephrine rather than epinephrine was the primary sympathetic neurotransmitter in mammals, work carried on after Dr. Greer's incapacitating illness by Dr. U.S. von Euler in Sweden and for which he would eventually receive the Nobel Prize. At the same time, Dr. Tinsley R. Harrison in Medicine and Dr. Alfred Blalock in Surgery were collaborating in the study of shock and the pathophysiology of blood pressure regulation. Dr. Harrison's laboratory first recognized the central effects of the excitatory neurotransmitters, glutamate and aspartate, to regulate blood pressure and heart rate in 1937, a theme that would be rediscovered and amplified in the 1980's. Also in the 1930's, the clinical laboratory of Dr. John B. Youmans explored blood volume regulation with bed rest and was the first to recognize the rapid dynamic alterations in blood volume on assuming the upright posture.
In the 1950's and early 1960's several new investigators were recruited to Vanderbilt who made major contributions to the physiology and pharmacology of the autonomic nervous system. Dr. Grant W. Liddle in the course of his elucidation of glucocorticoid and mineralocorticoid function, introduced fludrocortisone into the treatment of orthostatic hypotension due to autonomic failure in 1956. This agent remains the treatment of choice for this disorder. Dr. Liddle also discovered the impaired renin release in autonomic failure. Dr. Elliot V. Newman studied the effect of posture and autonomic influence on renal sodium handling. Dr. John A. Oates developed methyldopa as an antihypertensive agent and established that it acted by impairing noradrenergic function centrally and peripherally. He also elucidated the importance of the norepinephrine transporter and its blockade in drug action. Dr. Earl W. Sutherland and Dr. Joel G. Hardman elucidated the role of cAMP as a second messenger and phosphodiesterase as a mechanism of its breakdown, work for which Sutherland was awarded the 1971 Nobel Prize. This lay the groundwork for much current work in intracellular signaling at Vanderbilt. Dr. Stanley Cohen in Biochemistry received the 1986 Nobel Prize for his work with growth factors, including nerve growth factor, a major determinant of sympathetic neuronal fate.
A third generation of autonomic investigators at Vanderbilt, represented by some of the physicians in the Autonomic Dysfunction Center, began their investigative careers in the 1970's. Drs. Lee E. Limbird, Alastair J.J. Wood, Rose Marie Robertson and David Robertson exploited radioligand binding techniques to elucidate the regulation of adrenoreceptors in animals and in human subjects. These studies led, over the subsequent decade, to exploration of the intracellular mechanisms of alpha-2-adrenoreceptor action by Dr. Limbird, and the role of beta-adrenoreceptor function in aging, hypertension and other pathophysiologic conditions by Drs. Wood and Robertson
The Autonomic Dysfunction Center
In 1975, Drs. David and Rose Marie Robertson began studying neurological disorders of blood pressure regulation. In parallel with these studies they later established the Autonomic Dysfunction Center for the inpatient and outpatient evaluation of autonomic disorders. It was the first clinic to devote itself exclusively to the study of autonomic disorders. In the mid-1980's, Dr. Italo Biaggioni became a collaborator in the Autonomic Dysfunction Center and Dr. F. Andrew Gaffney became associated with the Center in 1992. Since 1978, several thousand patients have been evaluated, with referrals increasingly drawn from throughout North America and overseas. Many investigators have visited our Center in order to set up similar programs at their institutions. Currently about 400 new patients per year are seen as referrals or consultations. Our Autonomic Dysfunction Center Database contains over 2500 patient entries of individuals with an autonomic disorder carefully phenotyped, perhaps the largest such registry in the world.
This Center was established to gain new insight into the etiology and optimal therapy of autonomic disorders. It was hypothesized that biochemical, physiological and pharmacological testing of these patients would make possible an improved understanding of pathophysiology. Suspecting that autonomic dysfunction was a heterogeneous disorder, we hoped also that with a large referral base we might identify previously unrecognized syndromes. This proved correct in 1986 when dopamine-beta-hydroxylase (DBH) deficiency was recognized as a congenital disorder of severe orthostatic hypotension and ptosis of the eyelids. In this disorder, there was a congenital absence of the enzyme which converts dopamine into norepinephrine; affected individuals had no norepinephrine, epinephrine, or octopamine in either the peripheral or central sympathetic nervous system. DBH deficiency thus became the first autonomic disorder for which a specific gene defect could be identified. This led to the development of a unique and efficacious therapy of the disorder, dihydroxyphenylserine. In 2000, the genomic basis of DBH deficiency was elucidated.
In 1993, the Autonomic Dysfunction Center reported characterization of the clinical and laboratory features of acute baroreflex failure. Over the years, some had considered baroreflex failure and autonomic failure to be largely synonymous terms which led to much confusion. What emerged from our investigation was a very different picture. Patients with acute baroreflex failure had many features resembling pheochromocytoma, and orthostatic hypotension was mild, if present at all. This contrasts strikingly with severe autonomic failure, in which profound orthostatic hypotension is usually the dominant clinical characteristic. This report led to the identification of many additional patients with baroreflex failure in medical centers here and abroad.
More recently, Dr. Biaggioni and coworkers have identified another previously unrecognized autonomic disorder in a family of three affected and three unaffected siblings. These individuals lack not only norepinephrine and epinephrine, but also have very low levels of dopamine, at least in the periphery. Absence or greatly reduced levels of tyrosine hydroxylase could be responsible for the findings in these patients, but no extrapyramidal symptoms or history of Parkinsonism can be elicited. Much work remains before the genetic lesion in this disorder can be fully understood.
In 1995, Dr. Randy Blakely was recruited to develop the Molecular Neuroscience Program at Vanderbilt. Dr. Blakely successfully identified the structures of a number of membrane transport proteins of relevance to autonomic and central nervous system function, including the norepinephrine transporter. His scientific achievements are greatly expanding our understanding of autonomic and neurological disorders at the molecular level and promise to provide novel techniques for diagnosis and therapy of certain abnormalities in the central nervous system. As a neuroscientist with an intense interest in and familiarity with human pathophysiology, Dr. Blakely has had a galvanizing impact on autonomic clinical research at Vanderbilt. In 2000, he collaborated with Drs. Robertson and Biaggioni in the discovery of norepinephrine transporter (NET) deficiency as a genetic disorder presenting as orthostatic intolerance. The recognition of NET deficiency as a new autonomic disorder promises to accelerate our understanding of dysautonomias and their treatment.