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The Pharmacology of Autonomic Failure: from Hypotension to Hypertension

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The Pharmacology of Autonomic Failure: from Hypotension to Hypertension 1521-0081/69/1/53–62$25.00 http://dx.doi.org/10.1124/pr.115.012161 PHARMACOLOGICAL REVIEWS Pharmacol Rev 69:53–62, January 2017 Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics ASSOCIATE EDITOR: STEPHANIE W. WATTS The Pharmacology of Autonomic Failure: From Hypotension to Hypertension Italo Biaggioni Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt University, Nashville, Tennessee Abstract .....................................................................................53 I. Introduction . ...............................................................................54 A. Overview of Normal Cardiovascular Autonomic Regulation ...............................54 B. The Baroreflex . .........................................................................54 C. Pathophysiology of Orthostatic Hypotension and Autonomic Failure. ....................54 D. Ganglionic Blockade as a Pharmacological Probe To Understand Autonomic Failure.......55 E. Autonomic Failure as a Model To Understand Pathophysiology . ..........................55 II. Targeting Venous Compliance in the Treatment of Orthostatic Hypotension...................55 III. Pharmacology of Volume Expansion. .......................................................56 Downloaded from A. Fludrocortisone . .........................................................................56 B. Erythropoietin . .........................................................................56 IV. Replacing Noradrenergic Stimulation in the Treatment of Orthostatic Hypotension . ........56 A. Midodrine ...............................................................................57 B. Droxidopa ...............................................................................57 V. Harnessing Residual Sympathetic Tone To Treat Orthostatic Hypotension ....................57 by guest on September 26, 2021 A. Pyridostigmine. .........................................................................57 B. Yohimbine ...............................................................................58 C. Atomoxetine .............................................................................58 VI. The Hypertension of Autonomic Failure ......................................................58 A. Targeting Residual Sympathetic Tone . .................................................59 B. The Renin-Angiotensin Aldosterone System in Autonomic Failure.........................59 C. Nitric Oxide and Autonomic Failure ......................................................59 VII. Conclusions . ...............................................................................60 References...................................................................................60 Abstract——Primary neurodegenerative autonomic research model characterized by loss of baroreflex disorders are characterized clinically by loss of auto- buffering. This greatly magnifies the effect of stimuli nomic regulation of blood pressure. The clinical picture that would not be apparent in normal subjects. An is dominated by orthostatic hypotension, but supine example of this is the discovery of the osmopressor hypertension is also a significant problem. Autonomic reflex: ingestion of water increases blood pressure failure can result from impairment of central auto- by 30–40 mm Hg in autonomic failure patients. Animal nomic pathways (multiple system atrophy) or neuro- studies indicate that the trigger of this reflex is related degeneration of peripheral postganglionic autonomic to hypo-osmolality in the portal circulation involving fibers (pure autonomic failure, Parkinson’s disease). transient receptor potential vanilloid 4 receptors. Pharmacologic probes such as the ganglionic blocker Studies in autonomic failure patients have also trimethaphan can help us in the understanding of the revealed that angiotensin II can be generated through underlying pathophysiology and diagnosis of these noncanonical pathways independent of plasma renin disorders. Conversely, understanding the pathophysi- activity to contribute to hypertension. Similarly, the ology is crucial in the development of effective phar- mineralocorticoid receptor antagonist eplerenone macotherapy for these patients. Autonomic failure produces acute hypotensive effects, highlighting the patients provide us with an unfortunate but unique presence of non-nuclear mineralocorticoid receptor This work was supported by National Institutes of Health Grants PO1 HL056693, RO1 HL122847, and U54 NS065736. Address correspondence to: Dr. Italo Biaggioni, Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt University, 560A RRB, 1500 21st Avenue South, Nashville, TN 37212-8210. E-mail: [email protected] dx.doi.org/10.1124/pr.115.012161. 53 54 Biaggioni pathways. These are examples of careful clinical pharmacology to advance our knowledge of human research that integrates pathophysiology and disease. I. Introduction and the heart. Vagal fibers run through the vagus nerve A. Overview of Normal Cardiovascular and synapse in ganglia located within target organs. Autonomic Regulation Thus, the initial increase in BP ultimately leads to inhi- bition of sympathetic tone to the vasculature (resulting The autonomic nervous system provides modulatory in vasodilation) and to the heart (resulting in a decrease influence on a number of organ systems. It plays a in cardiac output), and activation of parasympathetic critical role in the regulation of cardiovascular function, tone to the heart (leading to a decrease in heart rate). providing instantaneous feedback for blood pressure These actions restore BP to baseline values. Thus, the (BP) homeostasis. Nowhere is there more evidence than baroreflex provides continuous and instantaneous reg- in patients with primary forms of autonomic failure. ulation of BP. The clinical picture in these patients is dominated by profound and disabling orthostatic hypotension (a drop C. Pathophysiology of Orthostatic Hypotension and in BP on standing). Pharmacological probes have helped Autonomic Failure us understand the pathophysiology of these disorders, Gravitational forces exerted by standing result in and, conversely, these patients provide us with an un- pooling of up to 700 ml blood in the legs and lower fortunate but unique human model to understand car- abdomen, venous return decreases resulting in a re- diovascular autonomic pathophysiology. This review duction in stroke volume and cardiac output, and a complements others on this topic (Shibao et al., 2006b, transient decrease in BP; these changes are normally 2012, 2013; Biaggioni, 2008; Jordan et al., 2015) by compensated by baroreflex-mediated sympathetic ac- focusing on the pharmacology relevant to the patho- tivation that induces splanchnic venoconstriction to physiology and treatment of BP abnormalities present partially restore venous return, increases heart rate in patients with autonomic failure: orthostatic hypoten- and cardiac output, and induces systemic vasoconstric- sion and supine hypertension. tion to restore BP. These autonomic pathways are essential for the B. The Baroreflex maintenance of upright posture, and their failure re- BP is modulated second by second by a feedback loop sults in orthostatic hypotension. Notably, heart rate that constitutes the baroreflex. A blood volume overload does not increase appropriately in response to the drop or an increase in BP is sensed by low-pressure recep- in BP, evidence that normal counter-regulatory mech- tors located in the heart and great veins, and by high- anisms are lost. pressure receptors in the carotid sinus, respectively; There are numerous diseases that can cause impaired this information is relayed to the nucleus tractus autonomic function, but the most severe cases are seen solitarii (NTS) of the brainstem, where it is integrated. in primary neurodegenerative diseases of the auto- The NTS provides excitatory input to modulate both nomic nervous system that result in pathologic lesions sympathetic and parasympathetic function; stimula- at different levels of baroreflex pathways. All have in tion of the NTS activates the cadual ventrolateral common the deposit of the neuronal protein a-synu- medulla, which provides inhibitory input for the ros- clein, but differ in their distribution. In multiple system troventrolateral medulla, where sympathetic tone is atrophy (MSA), these deposits form cytoplasmic in- thought to be generated; at the same time, stimulation clusion in glia located in central autonomic pathways, of the NTS activates the dorsal vagal nucleus of the whereas in pure autonomic failure (PAF) they form vagus and nucleus ambiguus, where parasympathetic Lewy bodies in peripheral noradrenergic fibers. Para- activity is generated. Thus, an increase in BP leads to doxically, in Parkinson’s disease (PD) the autonomic activation of arterial baroreceptors and activation of the lesions are also peripheral and indistinguishable from NTS, which induces parallel inhibition of sympathetic PAF, but, in addition, there are Lewy bodies in basal tone (through inhibition of the rostroventrolateral ganglia responsible for the movement disorder (i.e., the medulla), activation of parasympathetic tone (through movement disorder is central, but the autonomic lesion activation of the dorsal vagal nucleus of the vagus). is peripheral). In either case, the patients lose barore- Sympathetic efferent fibers run through the interme- flex mechanisms
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