Adenosine and cardiovascular control
Our results support the hypothesis that ischemic exercise releases adenosine, which then can activate chemosensitive afferent fibers and trigger systemic sympathetic activation. We are continuing our studies of how adenosine acts as a metabolic trigger of the exercise pressor reflex.
Central mechanisms in autonomic disorders
Our studies have indicated that subjects with orthostatic intolerance are characterized by an overall enhancement of noradrenergic tone at rest and by a blunted post ganglionic sympathetic response to standing with a compensatory cardiac sympathetic overactivity. Baroreflex mechanisms maintain their functional responsiveness. These observations suggest that in some patients with orthostatic intolerance, the functional distribution of central sympathetic tone to the heart and vasculature is abnormal.
Fluid balance in orthostatic intolerance
Changes in posture are associated with substantial alterations of plasma volume, presumably due to a shift of fluid between the intravascular and interstitial space. This has been thought to lead to orthostatic tachycardia as a response to decreased venous return to the heart. We are studying plasma volume and fluid shift changes in OI patients.
Ganglionic blockade and autonomic failure
nicotinic receptor blockade with trimethaphan results in near complete interruption of sympathetic and parasympathetic efferents and can be used to simulate autonomic failure. This agent is being used in studies designed to determine the mechanism of supine hypertension in patients with autonomic failure. We are also using trimethaphan to uncouple the baroreflex so that normal and abnormal physiological states can be compared without the “noise of baroreflex buffering.
Genetic disorders of impaired cardiovascular regulation
Adult patients with congenital absence of norepinephrine and epinephrine were reported simultaneously by our group and by colleagues in Rotterdam over a decade ago. Additional cases have been subsequently reported. Strong evidence was developed at the bedside implicating impaired function of dopamine-beta-hydroxylase. In 1999, we began to explore the genetic basis of this disorder. We have recently identified a consensus donor splice site mutation in two unrelated patients with dopamine-beta-hydroxylase deficiency.
Recently, defects in peripheral norepinephrine clearance have been recognized in some individuals with orthostatic intolerance. These patients, in general, exhibit markedly elevated heart rate upon standing, diminished cerebral perfusion, syncope and chronic fatigue that improves upon lying down. Given the prominent role of the norepinephrine transporter (NET) in regulation of heart rate, blood flow and norepinephrine inactivation, we examined the NET gene of one proband and her family for evidence of mutations that might disrupt NET expression or activity. Our studies revealed the presence of a coding mutation that was correlated with plasma norepinephrine, the ratio of norepinephrine to its intraneuronal metabolite, and heart rate.
We are extending our genetic studies to evaluate additional subjects for novel mutations.
Hormonal influences on autonomic function
A recent addition to our research endeavors is investigation into the role of reproductive hormones, estrogen in particular, in the onset and persistence of symptoms experienced by patients diagnosed with orthostatic intolerance. Women of child-bearing age are the primary patient population of this disorder, outnumbering men 6:1. While the preponderance of women suggests a link with estrogen, and it is well recognized that estrogen has broad ranging effects in the cardiovascular, central and peripheral nervous systems, little information is currently available linking this hormone to the pathophysiology of orthostatic intolerance. A focus of future research, therefore, is to determine whether there is a cyclical pattern to the symptoms of orthostatic intolerance in women, to determine whether there is an imbalance in the hypothalamic-pituitary-ovarian axis that could affect autonomic function, and to investigate the role of estrogen in autonomic regulation of heart rate and blood pressure in patients and normal controls.
Pathophysiology and diagnosis of baroreflex failure
We are studying patients with baroreflex failure and familial paragangliomata syndrome, to achieve an earlier diagnosis of these conditions and to distinguish them from autonomic failure. This will allow us to provide better treatment options. Human baroreflex failure is also being used as a means of exploring central mechanisms of sympathetic activation and its control.
Pathophysiology and therapy of human norepinephrine transporter deficiency
Studies are directed at elucidating the interplay between central and peripheral mechanisms of autonomic cardiovascular regulation in a model of NET deficiency, evaluating the physiologic and pharmacologic impact of NET blockade and NET deficiency, and testing specifically tailored pharmacologic interventions to correct the pathophysiologic perturbations in the syndrome. Consequences of norepinephrine transporter mutations on the functionality of the gene product are also being studied, in addition to NET genetic variation in psychiatric subjects linked to altered NE function.
Pathophysiology and therapy of multiple system atrophy
Multiple System Atrophy (MSA) is a neurogenerative disease affecting individuals in the sixth decade of life and oftentimes with rapid progression. The determinant of MSA is clinically based and the goal of therapy is to sustain a functioning level of daily activities for as long as possible. Although the disease is progressive and debilitating with widespread variation of symptoms, orthostatic hypotension, leading to dizziness and fainting is usually the reason for seeking medical advice. Our goal is to find ways to control the low pressure with medication and adjunctive therapy and support the individual's claim for independency.
Pathophysiology and therapy of neurally mediated syncope
The pathophysiology of neurally-mediated syncope (NMS) is poorly understood. It has been widely assumed that excessive generalized sympathetic activation is the precursor of the hemodynamic abnormality underlying recurrent neurally mediated syncope. Our data are not consistent with this view. We have found that yohimbine-induced enhancement of sympathetic tone in some patients with NMS improves orthostatic tolerance to tilt. Current studies are focusing on characterizing pathophysiologically distinct subgroups of patients with neurally mediated syncope.
Pathophysiology and therapy of orthostatic intolerance
We are testing the hypothesis that orthostatic intolerance (OI) is a heterogeneous entity comprised of diverse pathophysiologies involving partial dysautonomia as well as defects in volume regulation and vascular integrity. We are currently also studying central cardiovascular control in OI patients and how the autonomic nervous system of OI patients reacts to stressful conditions. Factors that influence the severity of OI symptoms are being examined.
Pathophysiology and therapy of supine hypertension
Half of patients with autonomic failure have supine hypertension, but the mechanisms for the high blood pressure are not known. We are conducting studies to learn why autonomic failure patients have high blood pressure when they lie down and to evaluate more effective means to treat it.
Pressor response to drinking water
Water ingestion has been shown to increase blood pressure in older normal subjects (10 mmHg) and in patients with pure autonomic failure and multiple system atrophy (40 mmHg). Its mechanism has not been determined. Current studies are aimed at elucidating this mechanism. The blood pressure response to drinking water in patients with hypertension is also being studied.
Role of nitric oxide in blood pressure control
Nitric oxide (NO) is a potent vasodilator produced by endothelial cells. It is also produced in the brain and in peripheral nerves and is thought to inhibit sympathetic tone. The importance of NO in normal blood pressure control is evident by the fact that if production of NO is reduced, blood pressure significantly increases. We are examining the interaction between NO and the autonomic nervous system and the role of NO in orthostatic intolerance, neurogenic syncope, and patients with autonomic failure and supine hypertension.