The Pharmacology of Autonomic Failure: from Hypotension to Hypertension

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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 inhibition 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 and are unable to compensate the diolateral columns of the spinal cord and make their orthostatic venous pooling with reflex sympathetic first synapse in paravertebral autonomic ganglia, where activation, and therefore develop profound orthostatic postganglionic fibers originate to innervate the vasculature hypotension.

ABBREVIATIONS: BP, blood pressure; CNS, central nervous system; LAAAD, L-aromatic-amino-acid decarboxylase; L-NMMA, L-NG-monomethyl arginine; MR, mineralocorticoid receptor; MSA, multiple system atrophy; NET, norepinephrine transporter; NO, nitric oxide; NTS, nucleus tractus solitarii; PAF, pure autonomic failure; PD, Parkinson’s disease; rHuEPO, recombinant human erythropoietin. Pharmacology of Autonomic Failure 55

D. Ganglionic Blockade as a Pharmacological Probe unopposed by the absence of baroreflex buffering. Evi- To Understand Autonomic Failure dence of this osmopressor reflex has subsequently been As mentioned above, the autonomic lesion in PAF and found in normal and hypertensive subjects as an increase PD is peripheral, with neurodegeneration of postgan- in sympathetic nerve traffic and a modest increase in BP glionic efferent noradrenergic fibers. In contrast, in (Scott et al., 2001; Callegaro et al., 2007). patients with multiple system atrophy, the lesion is Trimethaphan also allows us to eliminate baroreflex in central nervous system (CNS) autonomic nuclei, pathways that would normally restrain the cardiovas- whereas postganglionic noradrenergic fibers appear to cular effects of agonist or antagonists. As an example, be intact. Biochemically, this is translated in very low administration of the nitric oxide (NO) inhibitor L-NG- levels of plasma norepinephrine in PAF (Goldstein monomethyl arginine (L-NMMA) produces a significant et al., 1989) and lack of uptake of labeled catechols in but relatively minor increase in BP in humans (of about the heart (Goldstein et al., 1997). Conversely, plasma 6 mm Hg). The increase in BP, due to removal of tonic norepinephrine levels are near normal in MSA, and NO-induced vasodilation, is counteracted by barorecep- cardiac catechol uptake is intact. tor loading with sympathetic inhibition and partial It is possible also to make this distinction pharmaco- restoration of BP. If baroreflex pathways are eliminated logically, using a ganglionic blocker. Neurotransmission with trimethaphan, i.v. infusion of L-NMMA results in – at the level of the autonomic ganglia is mediated by an increase in BP of 20 30 mm Hg (Gamboa et al., 2007, presynaptic release of acetylcholine, which then acti- 2012). These findings are in agreement with the signif- vates postsynaptic Nn-cholinergic receptors. Trimetha- icant pressor response induced by L-NMMA in patients phan is an antagonist of these receptors, and i.v. infusion with baroreflex impairment due to severe autonomic of this drug results in acute and complete interruption of failure (Gamboa et al., 2008). Thus, ganglionic blockade all sympathetic and parasympathetic traffic. In patients with trimethaphan can be used to unmask the real with MSA ganglionic blockade interrupts their residual contribution of NO (and other autacoids) to BP modu- sympathetic tone and decreases BP. In contrast, in pa- lation in humans. tients with peripheral postganglionic lesions (PAF) ganglionic blockade has no significant effect on BP (Shannon II. Targeting Venous Compliance in the et al., 1997; Jordan et al., 2015). Treatment of Orthostatic Hypotension Ganglionic blockade, by acutely removing autonomic function, can also be used in humans to infer what effect As discussed above, gravitational venous pooling is tonic sympathetic tone has on physiologic and patho- the initial mechanism leading to orthostatic hypoten- logic processes. This is analogous to the use of the sion. Most of the venous pooling induced by standing ganglionic blocker hexamethonium in animals (Iida, occurs in the splanchnic circulation (Diedrich and 1999). Thus, trimethaphan has been used to infer the Biaggioni, 2004). The splanchnic venous circulation is contribution of sympathetic tone to hypertension (Diedrich a highly compliant venous bed that normally stores ; et al., 2003) and the metabolic defects associated with 25% of the blood volume (Rowell et al., 1972), and obesity hypertension (Shibao et al., 2007b), including receives up to 25% of the resting cardiac output insulin resistance (Gamboa et al., 2014). (Gelman, 2008). It represents the largest blood volume reservoir in the body and is highly innervated by E. Autonomic Failure as a Model To sympathetic nerves. Veins of the extremities, in con- Understand Pathophysiology trast, are less compliant and have relatively insignifi- Baroreflex pathways are interrupted in autonomic cant sympathetic innervation; thus, their role as blood failure patients (MSA and PAF), regardless of the level volume reservoir is relatively minimal (Gelman, 2008). of the lesion. These patients, therefore, lack baroreflex Consistent with this, compression of venous capacitance buffering, and this can unmask the effect of drugs or even beds in the lower body has been shown in laboratory physiologic processes that may not be apparent in settings to improve upright BP and orthostatic symp- normal individuals. The discovery of the osmopressor toms in patients with primary autonomic failure by reflex is an example of these phenomena. Acute ingestion increasing stroke volume and cardiac output (Smit of water (500 cc) triggers a dramatic pressor response in et al., 2004). Abdominal venous compression was sig- patients with autonomic failure, with an average in- nificantly more effective than leg compression in im- crease in BP of almost 40 mm Hg, and as high as 70 mm proving standing BP, presumably because of the smaller Hg (Jordan et al., 1999a). A combination of animal and volume reservoir in legs compared with the larger human studies suggests that water absorption induces a capacity of the abdominal vascular bed (Denq et al., 1997; hypo-osmolar stimuli in the portal circulation, likely Smit et al., 2004; Protheroe et al., 2011). involving activation of transient receptor potential vanil- From these observations, it follows that drugs that loid 4 (McHugh et al., 2010), which triggers a sympa- reduce splanchnic venous compliance would be effective thetic reflex (Jordan et al., 2000) that increases BP. This in treating orthostatic hypotension. Unfortunately, diffi- effect is apparent in autonomic failure because it is culties in measuring splanchnic compliance in humans 56 Biaggioni have limited our knowledge of treatments that can target Fludrocortisone produces an expansion of interstitial this problem. There is only indirect information about volume. The increase in plasma volume is a nonselec- the effect of medications used to treat orthostatic hypo- tive product of this increase and is only transient; it tension on the venous circulation. Midodrine improves peaks during the first 2 weeks of treatment, but then venous return in a dog model of neurogenic orthostatic plasma volume returns to baseline values (mineralo- hypotension (ganglionic blockade with hexamethonium) corticoid escape). Persistence of the pressor effects of presumably by producing splanchnic venoconstriction fludrocortisone appears to be related to potentiation of (Yamazaki et al., 1987). It is also an effective vasocon- the effects of norepinephrine and angiotensin II (Hickler strictor of isolated human veins (Thulesius et al., 1979). et al., 1959; van Lieshout et al., 2000). Furthermore, we However, the pressor effects of midodrine in autonomic recently found that mineralocorticoid receptor (MR) failure patients appear to be related mostly to an increase blockade with eplerenone acutely lowers BP in autonomic in arterial peripheral vascular resistance (Schrage et al., failure patients, suggesting the presence of pressor effects 2004; Duschek et al., 2009). Another example of a med- of MR activation unrelated to volume regulation (Arnold ication that can work at least partially through constric- et al., 2016). It is possible, therefore, that fludrocortisone’s tion of the venous circulation is octreotide, a somatostatic activation of this putative MR pathway contributes to its analog that inhibits the release of a number of gastroin- pressor effect. testinal vasodilating peptides. Octreotide produces sig- B. Erythropoietin nificant increases in BP in patients with autonomic failure and reduces orthostatic hypotension (Hoeldtke Patients with severe autonomic failure have a high and Israel, 1989). Octreotide reduces splanchnic capac- incidence of anemia, up to 38% in some series (Biaggioni itance and improves venous return in a dog model of et al., 1994a). The anemia of autonomic failure is associated orthostatic hypotension (Wong and Sheriff, 2011). In with impaired compensatory erythropoiesis with inappro- healthy young women, octreotide improved orthostatic priately low serum erythropoietin, and can be corrected tolerance in relation to a reduction in splanchnic arte- with treatment with recombinant human erythropoietin rial vasoconstriction (Jarvis et al., 2012). It is likely that (rHuEPO) (Hoeldtke and Streeten, 1993; Biaggioni et al., octreotide reduces splanchnic capacitance in humans, 1994a; Perera et al., 1995). The severity of anemia is but, to the best of our knowledge, this has not been tested; typically modest, and its treatment with rHuEPO would arguably, the best model for such a study would be auto- not be justified clinically, but the increase in red cell mass is nomic failure patients. associated with increased BP and improved orthostatic tolerance. This pressor response is expected because it is a well-documented side effect of rHuEPO treatment in III. Pharmacology of Volume Expansion chronic renal failure patients. rHuEPO has the theoretical If impaired venous return and decreased stroke advantage that it selectively increases intravascular vol- volume are important contributors to orthostatic hypo- ume, compared with the transient increase in interstitial tension, an overall increase in blood volume may be volume induced by fludrocortisone. It is not clear, however, beneficial. The mineralocorticoid fludrocortisone has that the increase in intravascular volume is the main been used to stimulate sodium reabsorption and in- mechanism by which rHuEPO increases BP. Erythropoi- crease extracellular water. More recently, recombinant etin increases BP in animals and patients even if correction erythropoietin has been used to increase red cell mass, of anemia is prevented (Vaziri, 2001). resulting in a more selective increase in intravascular volume. However, as discussed below, it is not clear IV. Replacing Noradrenergic Stimulation in the whether the beneficial effects of these drugs are related Treatment of Orthostatic Hypotension to their effect on volume expansion. Neurogenic orthostatic hypotension is due, in its A. Fludrocortisone simplest concept, to a failure of noradrenergic stimula- Fludrocortisone is a synthetic steroid with selective tion that normally occurs in the upright posture. It mineralocorticoid effects. Fludrocortisone increases follows that a potential treatment is the administration renal sodium reabsorption and expands plasma vol- of noradrenergic agonists. The beneficial effect of this ume. These mineralocorticoid effects are seen at doses approach can be attributed mostly to a-receptor activa- of 0.1–0.3 mg/day. Selectivity may be lost with higher tion, rather to b-receptor stimulation. In general this doses, and corticosteroid effects may become appar- approach increases both supine and upright BP (and ent. Fludrocortisone has been used for the treatment often the increase in supine BP is greater than the of orthostatic hypotension for the past 40 years, even increase in upright BP). Hence, orthostatic hypotension though the evidence for efficacy is limited to one case (the difference between supine and upright BP) is often series in patients with diabetes mellitus (Campbell not improved, but rather upright BP is increased et al., 1976) and another in patients with PD (Hoehn, enough to prevent the fall in cerebral blood flow re- 1975). sponsible for orthostatic symptoms. Pharmacology of Autonomic Failure 57

A. Midodrine V. Harnessing Residual Sympathetic Tone To Midodrine is a prodrug; it is rapidly and almost Treat Orthostatic Hypotension completely absorbed following oral administration and Analternativetotheuseofdirecta agonists is to induce metabolized by enzymatic hydrolysis to the selective a1 the release of endogenous norepinephrine by increasing agonist desglymidodrine. Peak concentrations of the residual sympathetic tone that may still be present in active metabolite are reached in about 1 hour. The these patients. This has the theoretical advantage that it elimination half-life of the active metabolite is about will result in a more physiological restoration of norad- 3 hours (McTavish and Goa, 1989). Clinical studies have renergic function, with the potential to preferentially shown that midodrine improves upright BP in patients improve BP during upright posture, when residual sym- with orthostatic hypotension (Kaufmann et al., 1988; pathetic activity would be greater. Likewise, in theory this Jankovic et al., 1993; Low et al., 1997). The pharmaco- approach should be more effective in patients with im- logical actions of midodrine are those of a selective a1 paired central autonomic pathways but intact peripheral agonist of both a1A and a1B receptor subtypes. Hemo- noradrenergic fibers (MSA), than in patients with neuro- dynamically, this translates to vasoconstriction, increase degeneration of peripheral noradrenergic fibers (PAF, in peripheral vascular resistance, and elevated BP with- PD). In practice, even patients with peripheral autonomic out an increase in heart rate. a-Receptor activation can failure have some degree of residual sympathetic function, also induce venoconstriction, but it is not clear whether and even modest stimulation of norepinephrine release this effect contributes to the improvement in orthostatic can result in significant increases in BP due to activation tolerance. The side effects are also explained by activation of upregulated adrenergic receptors unopposed because of of a-receptors: piloerection, sensation of coldness, and the absence of baroreflex buffering. urinary retention. Desglymidodrine diffuses poorly across the blood-brain barrier, and is therefore not associated A. Pyridostigmine with central nervous system effects. Pyridostigmine is an inhibitor of cholinesterase, the enzyme that catalyzes the hydrolysis of the neurotrans- B. Droxidopa mitter acetylcholine into choline and acetic acid, a L-threo-3,4-dihydroxyphenylserine (droxydopa) is a reaction that occurs in the cholinergic synapse that synthetic catechol that is converted in the body to nor- essentially terminates the actions of acetylcholine. epinephrine, via decarboxylation catalyzed by L-aromatic- Pyridostigmine therefore facilitates cholinergic neuro- amino-acid decarboxylase (LAAAD; also known as dopa transmission, and, because acetylcholine is the neuro- decarboxylase). This is the same enzyme that converts transmitter in autonomic ganglia, pyridostigmine can levodopa, used in the treatment of PD, to dopamine. increase residual sympathetic tone. In this regard, its Inhibitors of LAAAD that do not cross the blood-brain actions are opposite those of trimethaphan discussed barrier are routinely given in combination with levodopa above (see Ganglionic Blockade as a Pharmacological in PD patients to increase CNS conversion to dopamine Probe To Understand Autonomic Failure). and prevent peripheral effects like nausea. In the supine position, when sympathetic tone is Peak plasma droxidopa levels occur at about 3 hours, normally low, neurotransmission at the level of sympa- followed by a monoexponential decline with a half-time of thetic ganglia is reduced and pyridostigmine would have 2–3 hours. Plasma levels of its main neuronal metabolite, less of an effect. In contrast, its effects are more prominent dihydroxyphenylglycol, increase in parallel, but at much during standing, when traffic through sympathetic gan- lower concentrations than the parent compound. Drox- glia is normally increased. This offers the theoretical ydopa increases BP in patients with neurogenic ortho- advantage of preferentially increasing upright BP in static hypotension (Freeman et al., 1999; Mathias et al., patients with autonomic failure and in proportion to their 2001; Kaufmann et al., 2003) and improves orthostatic orthostatic needs. Most other pressor agents increase tolerance (Kaufmann et al., 2014; Biaggioni et al., 2015; supine BP more than standing BP, and worsening of Hauser et al., 2015). Coadministration of high doses of supine hypertension can limit their use. This adverse the peripheral LAAAD inhibitor carbidopa prevents the effect would be minimized with pyridostigmine. BP effects of the droxidopa (Kaufmann et al., 2003), Indeed, in clinical trials pyridostigmine preferentially indicating that droxidopa increases BP by augmenting improved upright compared with supine BP in autonomic norepinephrine outside the brain. failure patients (Singer et al., 2003, 2006). The increase in Droxidopa is particularly effective in the treatment of upright BP was rather modest, only 4 mm Hg higher in dopamine-b-hydroxylase deficiency, a rare congenital the pyridostigmine group compared with the placebo disorder characterized by the lack of the enzyme that group 2 hours after drug administration. Nonetheless, converts dopamine to norepinephrine (Biaggioni and this modest increase in upright BP was associated with Robertson, 1987; Man in ’t Veld et al., 1988). Droxidopa a significant improvement in orthostatic symptoms. In bypasses the enzymatic defect and restored norepineph- theory, patients with residual sympathetic tone (i.e., rine levels. MSA) should be more responsive to enhancement of 58 Biaggioni sympathetic ganglia neurotransmission compared with neuroeffector junction. Increasing norepinephrine in patients with peripheral neuropathy (i.e., PAF or PD). peripheral noradrenergic fibers would increase BP. This, however, was not found, possibly because of the Conversely,intheCNSanincreaseinnorepinephrine small number of patients in each group. Nonetheless, will activate central a2-adrenergic receptors that have patients with relatively preserved baroreflex gain had a a clonidine-like sympatholytic effect. In normal sub- greater response, supporting the notion that the response jects these effects counteract each other, and no sig- to pyridostigmine is proportional to the degree of resid- nificant increase in BP is observed (Esler et al., 1991; ual sympathetic tone. It is likely that this treatment is Birkenfeld et al., 2005). effective in less severe patients with residual sympathetic These contrasting effects of NET blockade can be tone. unmasked in humans by studying patients with dis- tinct forms of autonomic impairment; the peripheral B. Yohimbine pressor effects of NET blockade should be apparent Yohimbine is an indole alkaloid isolated from the in patients with intact peripheral sympathetic fibers bark of the Pausinystalia yohimbe tree. It is a selective (MSA), but not in patients with peripheral autonomic a2 antagonist. As such it has opposite pharmacologic denervation (PAF). Indeed, atomoxetine acutely in- and cardiovascular effects of the partial a2 agonist creased systolic BP by about 50 mm Hg in patients with clonidine; centrally yohimbine stimulates sympa- central autonomic failure, but by less than 5 mm Hg thetic outflow, and, in the periphery, it enhances the in patients with severe peripheral autonomic failure release of norepinephrine from adrenergic nerve fibers (Shibao et al., 2007c). Subsequent studies have shown by antagonizing presynaptic a2-adrenergic receptors that atomoxetine can also increase BP in PAF patients that normally inhibit norepinephrine release. It ap- with less severe autonomic failure (Ramirez et al., pears that both central and peripheral actions of 2014). yohimbinecontributetoitscardiovasculareffects. When compared with midodrine at doses that pro- Grossman et al. (1991) found in normal volunteers duce the same increase in seated BP, atomoxetine that steady-state infusion of yohimbine produced a produced a greater increase in upright BP (Ramirez 16% increase in mean arterial BP, 8% increase in et al., 2014). This is consistent with the concept that heart rate, and 67% increase in forearm vascular atomoxetine, as well as other therapies that harness resistance. Of interest, the increase in muscle sympa- residual sympathetic tone, provides a more physiologic thetic nerve activity (by 73%) was much smaller than approach to treat orthostatic hypotension. theincreaseinforearmnorepinephrine spillover (by The response to these drugs can provide insight 337%), suggesting that blockade of inhibitory pre- about the pathophysiology of these disorders. Cloni- synaptic a receptors resulting in stimulation of nor- dine reduces BP in MSA patients because of a re- epinephrine release contributes to the increase in BP duction in their residual sympathetic tone (Shibao induced by yohimbine. et al., 2006a), as determined by a reduction in plasma The pressor effects of yohimbine are seen in auto- norepinephrine (Young et al., 2006). This implies that nomic failure patients at doses that would have negli- central autonomic pathways involving postsynaptic gible effects in normal subjects (Biaggioni et al., 1994b). activation of a2-adrenergic receptors are preserved in In contrast, yohimbine has no effect in patients with MSA. In contrast, tonic presynaptic release of norepi- dopamine b-hydroxylase deficiency unable to synthe- nephrine in the CNS that normally decreases sympa- size norepinephrine (Biaggioni et al., 1994b). Thus, thetic tone appears to be impaired given that atomoxetine yohimbine requires norepinephrine synthesis and re- does not have this clonidine-like effect. This leaves lease to act; conversely, it can be used to harness the unopposed the peripheral pressor actions of atomox- residual sympathetic tone that is present even in etine, which depends on residual sympathetic outflow patients with severe forms of autonomic failure. As with tonic release of norepinephrine, known to be pre- expected, yohimbine increases BP more in patients with served in MSA. MSA and greater residual sympathetic tone compared with PAF, but there is significant overlap between VI. The Hypertension of Autonomic Failure groups (Shannon et al., 2000). In clinical practice, BP is routinely measured in the C. Atomoxetine seated position, and most patients with autonomic The norepinephrine transporter (NET) is located in failure will have a normal seated BP. It is not surprising the presynaptic neuron to reuptake norepinephrine that the diagnosis of orthostatic hypotension is delayed from the synapse, thus contributing to the termination until their clinical picture is dominated by disabling of the actions of norepinephrine. Atomoxetine is a orthostatic hypotension. Likewise, supine hypertension selective blocker of NET and, therefore, potentiates is also overlooked, even though over half of patients the effect of synaptically released norepinephrine by with autonomic failure have this problem. The preva- increasing neurotransmitter concentrations in the lence of hypertension is similar to what we would expect Pharmacology of Autonomic Failure 59 in this age group. Given their absent baroreflex func- B. The Renin-Angiotensin Aldosterone System in tion, it is not surprising that they are not able to Autonomic Failure compensate, not only for the drop in BP on standing, The renin-angiotensin aldosterone system is widely but also for the mechanisms that drive hypertension recognized as an important contributor to the develop- with aging. It is not clear, however, whether the su- ment of essential hypertension, primarily through the pine hypertension of autonomic failure is simply the actions of angiotensin II at AT1 receptors to stimulate unmasking of essential hypertension, or if these pa- vasoconstriction, baroreflex dysfunction, and aldosterone tients develop unique pathophysiological mechanisms release. Initial studies had suggested that the renin- of hypertension. angiotensin aldosterone system plays little role in BP The supine hypertension of autonomic failure can regulation in autonomic failure. These patients have very be severe [BP as high as 230/140 mm Hg has been low and often undetectable levels of plasma renin activity, described (Shannon et al., 1997)] and associated with blunted renin responses to postural and pharmacologic end-organ damage, including left ventricular hypertro- stimuli, and loss of renin immunoreactive cells in autop- phy (Vagaonescu et al., 2000; Maule et al., 2006) and sied kidneys (Biaggioni et al., 1993). However, more recent impaired renal function (Garland et al., 2009). Autonomic studies in autonomic failure patients found circulating failure patients have arterial stiffness and hypertensive angiotensin II levels that were paradoxically elevated heart disease of similar magnitude as seen in patients compared with healthy subjects, despite low and often with essential hypertension with comparable BP values undetectable plasma renin activity (Arnold et al., 2013). (Milazzo et al., 2015). Supine hypertension may be asso- These findings raise the possibility that renin-independent ciated with long-term end-organ damage, but it can also mechanisms are involved in the formation of angiotensin II contribute to orthostatic hypotension. Supine hyperten- in autonomic failure. Consistent with this, AT1 receptor sion leads to pressure diuresis as a renal compensatory blockade with losartan, but not angiotensin converting mechanism to normalize BP. This translates as increased enzyme inhibition with captopril, effectively lowered over- nighttime diuresis (nocturia); patients lose on average 1 L night supine BP (Arnold et al., 2013). Taken together, these urine overnight due to this mechanism (Okamoto et al., results suggest that angiotensin II, produced through 2009). noncanonical pathways, contributes to supine hyperten- Hemodynamic studies suggest that supine hypertension in autonomic failure. sion is mediated by an increase in systemic vascular Aldosterone levels are also normal in these patients, resistance (Kronenberg et al., 1990); cardiac output is suggesting that downstream renin-angiotensin path- not increased, and total blood volume is similar in ways are intact in autonomic failure. Recent studies patients with or without supine hypertension (Shannon indicate that MR antagonism with eplerenone acutely et al., 1997). Supine hypertension is driven by their lowered BP in patients with autonomic failure and residual sympathetic activity in MSA patients because supine hypertension (Arnold et al., 2016). Maximal BP is normalized with ganglionic blockade with trime- hypotensive effects were seen about 8 hours after a thaphan (Shannon et al., 2000). In patients with PAF, single dose of eplerenone. Classic activation of the MR supine hypertension is associated also with increased results in translocation of the ligand-receptor complex systemic vascular resistance (Kronenberg et al., 1990), to the nucleus, where it binds hormone response but does not decrease with ganglionic blockade, con- elements in the promoter region of target genes to sistent with the low sympathetic tone that these patients stimulate transcription (Fejes-Toth et al., 1998). These have (Shannon et al., 2000). It remains unclear what pathways would not explain the acute hypotensive vasoconstrictive mechanisms drive supine hyper- effects of eplerenone in autonomic failure. Recently, tension in PAF. This is another clinical example in activation of cell surface or cytosolic MR has been shown which their response to pharmacological probes can to elicit nongenomic rapid effects of aldosterone, in- help define the underlying pathophysiology of this cluding vasoconstriction and sympathetic activation disease. (Funder, 2010). In addition, Ang II can activate vascular A. Targeting Residual Sympathetic Tone MR, through direct binding or indirectly through AT1 receptor transactivation, to induce vasoconstriction, arte- Because hypertension is driven by residual sympa- rial stiffness, and oxidative stress (Jaffe and Mendelsohn, thetic tone in MSA, it is not unexpected that clonidine 2005; Rautureau et al., 2011). decreases BP by about 30 mm Hg in these patients and reduces their nocturnal natriuresis (Shibao et al., C. Nitric Oxide and Autonomic Failure 2006a). Surprisingly, clonidine can also lower BP in in As described above (see Ganglionic Blockade as a PAF, probably because they have some residual sym- Pharmacological Probe To Understand Autonomic Fail- pathetic tone. In contrast, at higher doses clonidine can ure), hypertension in PAF is not primarily due to increase BP in patients with severe PAF and low residual sympathetic tone, raising the possibility that residual sympathetic, probably because of activation hormonal or metabolic factors are involved. NO is of vascular a2 adrenergic receptors. thought to be an important modulator of BP. Inhibition 60 Biaggioni of NO synthesis with L-NMMA results in a 30 mm Hg Probe To Understand Autonomic Failure). These obser- increase in BP in normal subjects in whom the restraining vations also validate the use of trimethaphan as a effect of the baroreflex was eliminated with ganglionic pharmacologic probe to assess the importance of auto- blockade (Gamboa et al., 2007). Impaired NO function nomic function in essential hypertension, insulin re- could be proposed to contribute to the supine hypertension sistance, and other common conditions. It can also be in PAF. However, current evidence suggests that PAF used to eliminate the confounding effect of the barore- patients have an increase in NO function (Gamboa et al., flex. Using this approach, one can unmask the real 2008); NO synthesis inhibition with L-NMMA produced a importance of, for example, NO; removal of NO with the greater increase in BP in autonomic failure compared NO synthase inhibitor L-NMMA revealed that, in the with normal subjects. Conversely, autonomic failure pa- presence of trimethaphan, tonic NO function normally tients have an exaggerated depressor response to silde- restrains BP by about 30 mm Hg in humans (see nafil, a phosphodiesterase inhibitor that potentiates NO Autonomic Failure as a Model To Understand Patho- signal transduction. physiology). The hypotensive response to clonidine in Nebivolol is a selective b1-adrenergic receptor MSA suggests that CNS nuclei pathways distal to origin blocker, and is considered a third-generation b-blocker of sympathetic tone are intact in these patients (see with unique vasodilatory actions (Gao and Vanhoutte, Targeting Residual Sympathetic Tone). 2012). It is proposed that augmentation of NO bio- Conversely, autonomic failure patients provide us availability underlies this vasodilatory effect (Bowman with an unfortunate but unique model devoid of barore- et al., 1994; Kubli et al., 2001; Dessy et al., 2005). The flex buffering. This greatly magnifies the effect of magnitude and relative contribution of NO-dependent stimuli that would not be apparent in normal subjects. vasodilation to the BP-lowering effect of nebivolol, An example of this is the discovery of the osmopressor however, are not known. In this regard, patients with effect of water ingestion (Autonomic Failure as a Model autonomic failure provide a unique model to examine To Understand Pathophysiology). Studies in autonomic the role of NO potentiation in the cardiovascular effects failure patients have also revealed the importance of of nebivolol. First, these patients lack autonomically noncanonical generation of angiotensin II independent mediated baroreflex buffering and therefore have exag- of plasma renin activity. Similarly, they reveal the acute gerated responses to most pressor and depressor agents hypotensive effects of MR blockade (see The Renin- (Jordan et al., 1998, 1999b, 1999c; Shibao et al., 2007a). Angiotensin Aldosterone System in Autonomic Failure). Second, traditional b-blockers have no BP effect in these They also revealed the contribution of potentiation of patients due to low b-adrenoreceptor tone (Man in’t NO function to the hypotensive actions of nebivolol (see Veld and Schalekamp, 1981; Man in’t Veld et al., 1982). Nitric Oxide and Autonomic Failure). These are exam- Finally, these patients have an exaggerated response ples of careful clinical research that integrates patho- to NO-mediated vasodilation, as discussed previously physiology and pharmacology to advance our knowledge (Gamboa et al., 2008). Indeed, nebivolol and sildenafil of human disease. significantly reduced nighttime BP compared with placebo, whereas metoprolol had no effect. Further- Authorship Contributions more, nebivolol decreased nighttime BP by 244 6 Wrote or contributed to the writing of the manuscript: Biaggioni. 13 mm Hg in patients that responded to sildenafil while having no effect in nonresponders (1 6 11 mm Hg). 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