Sympatholytic Therapy in Primary Hypertension: a User Friendly Role for the Future

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Journal of Human Hypertension (2002) 16 (Suppl 1), S118–S123  2002 Nature Publishing Group All rights reserved 0950-9240/02 $25.00 www.nature.com/jhh Sympatholytic therapy in primary hypertension: a user friendly role for the future

V DeQuattro and D Li Keck School of Medicine, University of Southern California, LA, California, USA

Effective therapy (Rx) in primary hypertension (PH) for induced NA release (retrograde ejaculation) and via 50 years, has featured sympathetic nervous system alphamethyl NA on central alpha-2 receptors (SNS) mechanisms. Ganglionic blockers and reserpine (depression). The alpha-2 and alpha-2 receptor antagon- were pre-eminent in the 1940s (mydriasis, ileus, impo- ists (␣RA) cause reflex tachycardia and first-dose hypo- tence, peptic ulcer). Guanethidine, and in the 1960s tension. Recently a two-fold incidence of congestive clonidine and methyldopa, were step II agents to thia- heart failure after ␣RA in treated primary hypertensives zide Rx in the 1950s. Reserpine depletes brain question their role in PH. The beta RA, with or absent (depression) and peripheral (PPH) noradrenaline (NA) ␣RA, remain premier since the 1970s due to mortality storage sites, guanethidine depleted NA storage via benefit in systolic dysfunction and post myocardial blockade of reuptake. Venomotor sympathoplegia infarction, certifying the role of the SNS in the pathogen- resulted in postural hypertension. An analogue, meta- esis and sequelae and Rx of PH. The future includes iodobenzyguandine is used in diagnosis and Rx of beta RA, specific IBS agents, angiotensin (AII) RA with pheochromocytoma. Clonidine lowers both central and avid presynaptic AII affinity and vasopeptidase PPH neuronal NA release via both stimulation of ␣ agon- inhibitiors that raise peptides and suppress SNS. ist adrenoreceptors (sedation) and specific imadazoline Journal of Human Hypertension (2002) 16 (Suppl 1), S118– binding sites (IBS). Methyldopa lowers pressure via PPH S123. DOI: 10.1038/sj/jhh/1001356

Keywords: primary hypertension; sympatholytic therapy

Introduction (vagal imbalance) seen when doses exceed 0.5 mg/day, and depression related to central ner- The sympatholytic and vagolytic effects of the vous system amine depletion. ganglionic blocking agents—such as hexamethonium, were utilised to control blood pressure in the 1940s. Their actions were enhanced by combining Sympathoplegic agents them with vasodilators such as hydralazine Guanethidine, an NA analogue, is taken up into (Table 1).1 However, their vagolytic side effects peripheral nerve storage sites, and though NA stor- (constipation, ileus, mydriasis, impotence), often age contents are lowered via release onto monoam- precluded their long-term use. Reserpine, a plant ine oxidase, it is antiadrenergic mainly by pre- alkaloid from the snake root—Rauwolﬁa serpentina, venting NA release into the synapse. An early largely supplanted the ganglionic blocking agents in hypertensive response may be seen. Although the the 1950s. Reserpine and the ganglionic blockers peripheral actions of guanethidine avoid the side could be administered orally and intravenously for effects of depression (ie, reserpine), those of erectile patients with mild, severe, and accelerated hyper- dysfunction, diarrhoea and postural hypertension tension. Reserpine depletes catecholamine stores were often severely debilitating, lasting for as long from central and peripheral sympathetic neurons. as a week after discontinuation of therapy. However, Their effects are delayed by the oral route, but act an analogue of guanethidine, metaiodobenzylguani- within hours after parenteral administration. The dine (MIBG), is very useful clinically as an imaging lowering of noradrenaline (NA) content in storage agent in the localisation of pheochromocytoma.3 sites enhances its synthesis, and thus turnover Methyldopa is an analogue of the natural amino (Figure 1).2 The side effects of reserpine that most acid dihydroxyphenylaline (DOPA) and inhibits the often lead to its discontinuation are peptic ulcer formation of dopamine (DA) by way of aromatic acid decarboxylase from L-DOPA. Methyldopa did not lower blood pressure in animal studies, but was Correspondence: V DeQuattro, MD, Keck School of Medicine, found serendipitously to lower blood pressure in University of Southern California, LA, California, USA man and became the premier antihypertensive agent Sympatholytic therapy in primary hypertension V DeQuattro and D Li S119 Table 1 Control of ‘benign’ arterial hypertension with hydrazinophthalazine and hexamethonium

Approximate average level No. Average blood pressure (mm Hg)a maintained at: Duration of control pressure (mm Hg)a of (weeks) cases 160/100 150/90 140/90 180/80

250/150 1 ––1b – 14 280/140 8 1b 2 ––17–20 210/130 9 3b – 83c 4–25 200/120 8 2c 8d 214–21 180/110 8 ––3 – 10–20 170/100 1 – 1 ––23

Total 25 6 6 9 4 aSystolic/diastolic. bUnsuccessful sympathectomy. cTwo patients discontinued treatment. dOne patient discontinued treatment.

pine in some countries, and the advantages of its sympathoplegic effecta were noted with this combination. Clonidine was introduced into the United States in the early 1960s from Germany, where a congener of naphazoline was developed as a topical agent to constrict nasal blood vessels. Clonidine, an alpha agonist which reduces the release of NA centrally via stimulation of presynaptic alpha-2 receptors, was discovered to be an antihypertensive quite by chance when the principal investigator’s reception- ist became hypotensive after topical intranasal administration of clonidine. Subsequently, by both the oral route and transdermal application, it remains an effective hypotensive agent. It is a sympathoplegic agent that has both central and peripheral actions, thereby lowering both the content of central or spinal ﬂuid NA as well as plasma NA (Figure 2).4,5 The side effects of clonidine (dry mouth, initial drowsiness, postural hypotension and

Figure 1 Alterations of noradrenaline turnover rate produced by reserpine and pargyline. The biological decay curves during pargyline above, and the curves during reserpine, below, are compared with the average curve of six untreated hypertensive patients. l-dopa-3H dose in each case was 15 ␮c/kg. The isotope was administered to GD and AT during the 4th week of pargyline therapy (75 mg/day orally) and to AL and WJ after 5 months and 1 year, respectively, of reserpine (0.25 mg/day orally). in the 1960s and 1970s. The major mechanism of action of methyldopa is via its conversion to its ana- logues—alphamethyl DA and alphamethyl NA. The latter is a potent alpha-2 receptor agonist in the medulla thereby reducing central neurogenic tone. Despite the side effects of depression, postural hypotension, retrograde ejaculation and galactor- rhoea, methyldopa was utilised as monotherapy or in combination with diuretic therapy for many Figure 2 Effects of clonidine treatment on cerebrospinal ﬂuid years. It remained popular in many countries well concentrations of noradrenaline (NE), adrenaline (E), and dopam- into the 1980s and in some parts of the world until ine (DA) in 10 subjects with primary hypertension. NS = not sig- the 1990s. In the 1980s it was combined with nifedi- niﬁcant.

Journal of Human Hypertension Sympatholytic therapy in primary hypertension V DeQuattro and D Li S120 rebound hypertension) have relegated the drug to flushing. Phentolamine by both intravenous and oral ‘add-on therapy’ to achieve blood pressure control routes provided rapid alpha blockade without the rather than monotherapy. However, its transdermal side effects, but its rapid and evanescent action application increases compliance, improving blood proved difficult for long-term clinical value. Phento- pressure control, and minimising side effects. Unfor- lamine, a nonspecific alpha-1,2 receptor antagonist, tunately, 10–20% of patients develop a skin allergy given intravenously is a diagnostic test in doses of to the adhesive, and eventually may be unable to use 2.5 to 10 mg, is useful along with nitroprusside and the patch. esmolol in hypertensive crises of patients with pheochromocytoma, and in those with rebound Beta receptor antagonists hypertension after abrupt cessation of alpha-2 agonist therapy. In the 1960s, phenoxybenzamine, a non- The beta receptor antagonists were introduced from specific alpha-1,2 antagonist, in doses of 10 to Great Britain by Black in the mid 1960s and became 40 mg/day, replaced phentolamine as a once a day, the premier antihypertensive agents, both as mono- long-acting agent for patients with pheochromocy- therapy and in combination with vasodilators well toma and is useful for some patients with renal fail- into the 1980s. In general, the beta receptor antagon- ure with raised sympathetic tone. ists are thought to exert their antihypertensive A subsequent series of alpha adrenal receptor effects in part by blocking beta receptors in the kid- antagonists were more specific for the alpha-1 recep- ney to reduce renin release, by reducing central tor, including prazosin, terazosin, and doxazosin. sympathetic tone, and via stimulating vascular pro- The latter two had longer durations of action and stacycline synthesis (Table 2). Beta receptor antag- were generally effective in upwards of 40–50% of onists have been found to be cardioprotective and hypertensives as monotherapy. Doxazosin was effec- reduce by 40 to 65% the morbidity and mortality of tive in blunting the rise in blood pressure produced patients with congestive heart failure (CHF), those by both isotonic and isometric exercise. It was less after myocardial infarction, type II diabetes, and effective in mitigating mental stress induced rises in hypertensive patients with renal failure. They are blood pressure.7,8 cardioprotective for high coronary risk patients Strangely, although thought initially to be a phos- undergoing the gauntlet of surgery. However, they can have adverse effects via glucose intolerance phodisterase inhibitor and later a specific alpha-1 related to both insulin resistance and pancreatic antagonist, doxazosin increased plasma NA levels in man.7 The changes in plasma NE levels were not insulin release. They may produce hyper- 7 triglyceridaemia and lower high-density lipoprotein associated with a rise in heart rate. Recent clinical in part via inhibition of lipoprotein lipase. On the findings of a raised incidence of CHF in the other hand, these sympatholytic effects prove valu- ALLHAT trial patients treated with doxazosin as 9 able in patients with high levels of plasma renin and compared with diuretic therapy, suggest that the 7 catecholamines who have reductions in plasma cat- rise in NA levels along with sodium and water echolamines and proportional reductions in blood retention may have been detrimental to cardiac pressure after beta receptor antagonists.6 function. Earlier studies in human CHF with prazosin reported lowering of left ventricular diastolic pressure and improved cardiac performance after Alpha receptor antagonists prazosin in CHF initially, but were not attended by The first alpha blockers developed in the 1950s had long-term morbidity/mortality benefits after prazo- potent histaminic effects causing tachycardia and sin therapy.

Table 2 Indices of sympathetic nervous system activity in patients with high-renin essential hypertension

Subjects Plasma Plasma Cardiac haemodynamics at rest renin noradrenaline activity, concentration Cardiac Heart Systolic time indices Mean left standing (ng/L) index rate/ ventricular (ng/m/h) 2 (L/min/m ) minPEPI LVETI ejection rate (msec) (msec) (ml/sec)

Normal subjects 2.10 ± 0.52 138 ± 36 2.66 ± 0.32 60 ± 7 130 ± 8 405 ± 16 150 ± 19

Essential hypertension subjects High-renin 4.82 ± 0.55* 261 ± 47* 3.28 ± 0.57† 69 ± 8† 119 ± 7† 405 ± 16 170 ± 14† Normal-renin 2.40 ± 0.61 161 ± 58 2.37 ± 0.33 60 ± 8 130 ± 6 394 ± 21 139 ± 29 Low-renin 0.96 ± 0.27 101 ± 54 2.30 ± 0.51 55 ± 7 141 ± 7† 396 ± 9 141 ± 45

PEPI: pre-ejection period index: LVETI: left ventricular ejection time index. Mean values and standard deviations are listed. The signiﬁ- cance of the differences between values for the hypertension renin subgroups and the normal subjects is indicated. *P Ͻ 0.01. Student’s t-test; †P Ͻ 0.05.

Journal of Human Hypertension Sympatholytic therapy in primary hypertension V DeQuattro and D Li S121 Labetalol is a hybrid compound sharing both Imidazoline receptor agonists alpha and beta receptor antagonism properties. Lab- etalol has a greater affinity for beta receptor vs alpha A more recent centrally acting antihypertensive receptor sites. A lack of significant alpha blockade agent acts on the I1 imidazoline receptors and lowers in some patients with pheochromocytoma is thought central sympathetic nerve discharge without stimul- to account for their exaggerated pressor responses ating alpha-2 receptors and the resultant sleep/ after the administration of this combined alpha and sedation side effects. Moxonidine, an I1 imidazoline beta receptor antagonist. We found that labetalol agonist lowers blood pressure by its action on rostral reduced the blood pressure responses to hand grip ventrolateral medulla inhibiting central sympathetic and isometric exercise,10 and also was effective in output to the peripheral vasculature, heart and kid- blunting the early morning pressure surge in hyper- ney. Moxonidine in doses of 200 to 400 mg daily reduces blood pressure, plasma catecholamines, and tensives associated with the rise plasma NA in the plasma renin activity.14 Further, moxonidine morning after awakening (Figure 3).11 In general, the reduces both sympathetic neural firing and blood side effects of labetalol, both lassitude due to central pressure responses to cold pressor tests, and iso- effect of the beta blocker, and postural hypotension metric handgrip exercise. Although moxonidine was due to the alpha blocker effects, have relegated it to found to inhibit resting sympathetic vasoconstric- a lesser role in the treatment of hypertension. tion tone and sympathetic reflex responses in Recently, the alpha and beta blocker, carvedilol, patients with CHF as well as those with hyperten- has been found to be very effective in reducing mor- 12 sion, in one large trial in CHF, moxonidine failed to tality in patients with congestive heart failure. reduce mortality. The study was stopped early due This agent and extended release metoprolol succi- to increased morbidity in patients receiving moxini- nate have raised the awareness of the value of beta dine. receptor antagonists as modulators of neural tone in congestive failure, reducing mortality as much as 65% in those patients.12,13 Carvedilol and metopro- Calcium channel antagonists lol have been found to control blood pressure in Verapamil, a calcium channel antagonist, was intro- upwards of 50–60% of hypertensives as mono- duced as a beta receptor antagonist in the 1970s, therapy. They have placed the sympathetic nervous because it had negative chronotropic and inotropic system into pre-eminence along with the renin- effects. Eventually, verapamil’s true identity as a cal- angiotensin system in cardiovascular disease, and of cium antagonist was uncovered. In general, calcium course specifically and especially, hypertension antagonists reduce the exocytic release of noradren- and CHF. aline from storage granules, but the rapid hypotensive properties of some dihydropyridines may lead to reflex sympathetic stimulation. Thus, with both verapamil and diltiazem, there may be an initial increase in sympathetic nervous system tone, but shortly thereafter, there is a reduction of norad- renergic tone.15 On the other hand, the dihydropyridine, nifedipine, appears to yield a reflex increase in neural tone, after both immediate16 and sustained17 release preparations. Unlike the other dihydropyridine calcium antagonists, amlodipine appears to have less stimulating properties on the central and peripheral sympathetic nervous system (SNS). The slower binding of the calcium antagonist, amlodipine, to its calcium channel generates a lesser SNS response and in some studies lowered plasma NA.15 The reflex SNS stimulation produced by the dihydropyridine calcium channel antagonists can be offset by coadminis- tration of either ACE inhibitors or beta receptor antagonists or alpha blockers. These may also enhance the hypotensive effect of the dihydropyridine calcium channel antagonists. In clinical studies, there is evidence for the cardioprotective effects of Figure 3 Mean 24-h ambulatory systolic blood pressure of 16 the sustained release heart rate controlling calcium patients with isolated systolic hypertension, adjusted for time of channel blockers18 and the dihydropyridine awakening (time 0). Data represent readings at the end of a 4-week 19 placebo period (open squares) and after 8 weeks of maintenance agents. The heart rate lowering calcium channel therapy with labetalol (closed squares). Broken lines linking open antagonists may provide more effective cardiopro- and closed squares indicate significant differences (P Ͻ 0.05). tection than the dihydropyridine calcium channel

Journal of Human Hypertension Sympatholytic therapy in primary hypertension V DeQuattro and D Li S122 blockers, related perhaps to the disparity of those blocker, candesartan or valsartan, was added to their neural effects. therapy. A newly released ARB, eprosartan, has been found to reduce stimulated NA release in the Angiotensin-converting enzyme (ACE) pith rat model and in one other animal model. It has been proposed that eprosartan, which is the only inhibitors and AII antagonists ARB devoid of the phenylthiazine ring, has a better Angiotensin-converting enzyme inhibition in both fit in the presynaptic angiotensin II site which regu- human and animal studies has been associated with lates NA release.23 Studies to corroborate these find- reduction in sympathetic nerve tone, as well as inhi- ings are planned in humans. bition of the renin-angiotensin-aldosterone system. Hypertensives with higher plasma NA levels have Dual metalloprotease inhibitors better blood pressure responses to ACE inhibitor therapy. Patients with CHF and higher levels of Lastly, the newest class of agents to be introduced plasma NA have greater risk and better reductions are a combined metalloprotease inhibitor omapatri- in mortality, related to NA levels. Studies with the lat. This agent lowers blood pressure by interfering angiotensin II receptor antagonists indicate a sympa- with the formation of angiotensin and by preventing thoplegic effect similar to that of the ACE inhibi- the degradation of the vasoactive peptides such as tors.20 In one CHF study ELITE I, Q-T dispersion, a ANP, BNP, bradykinin, and adrenomedulin. ANP marker of both neural tone and ventricular irrita- and BNP inhibit central SNS tone.24 bility, was raised in patients treated with the ACE inhibitor, captopril, but not after losartan. The lower rate of death and sudden death rate in ELITE I after Summary losartan-treated patients suggested that the ARB There is abundant evidence for the sympathoplegic 21 lowered ventricular irritability, but this effect was action of many classes of antihypertensive agents. absent in ELITE II. Those developed in the first three decades of antihypertensive therapy were often too laden with debilit- Combination therapy ating side effects and hampered their long-term use. The last three decades of antihypertensive agents The immediate future for sympathoplegic therapy have yielded drugs with improved efficacy and seems to lie in low dose combination therapy and lower side effects. Monotherapy with alpha receptor in refinements of some of the newer therapies. For agents may be less cardioprotective than combined example, the combination of beta-blocker and hyd- alpha and beta blockers as found in patients with rochlorothiazide in very low dose, such as bisopro- CHF. Combination therapy offers improved blood lol 2.5 mg and hydrochlorothiazide 6.25 mg, and pressure control for a majority of hypertensives; combinations of ACE inhibitor and hydrochlorothia- employing drugs like ACE inhibitors and ARBs zide such as benazepril 5 mg and hydrochlorothia- which reduce sympathetic tone in combination with zide 6.25 mg, seem to be as effective as full dose vasodilators like hydralazine, minoxidil, and dihy- monotherapy with a minimum of sympathoplegic dropyridine calcium blockers, which raise SNS side effects. The efficacy of mini-dose combination tone. It is likely that in the future, refinements in may be due in part to lesser perturbation of the auto- sympathoplegic therapy will result in improved nomic nervous system in responses to the lower blood pressure control and further reduction of car- dose of the diuretic. Recent analysis of the SHEP diovascular morbidity and mortality. trial finished over a decade ago now suggest that the diuretic doses utilised in this trial resulted in hypokalaemia (less than 3.5) prevalence of 7%, compared References with 0.7% hypokalaemia seen in the mini-dose com- 1 Schroeder HA. Control of hypertension by hexame- binations. The findings in the SHEP trial suggest that thonium and 1-hydrazionophthalazine. Preliminary the hypokalaemia and perhaps hypomagnesaemia, observation. Arch Int Med 1952; 89: 523–540. obviated the benefit in morbidity and mortality 2 DeQuattro V, Sjoerdsma A. Catecholamine turnover in reductions.22 It is also conceivable that part of the normotensive and hypertensive man: effects of anti- lack of benefit was related to excessive norad- adrenergic drugs. J Clin Invest 1967; 47: 2359–2373. renergic tone in these patients after larger doses of 3 Ansari AN, Siegel ME, DeQuattro V, Gazarian LH. diuretic therapy. The two effects of higher dose Imaging of medullary thyroid carcinoma and hyper- diuretic therapy, low potassium and raised NA lev- functioning adrenal medulla using iodine-131 meta- els, may have contributed to the cardiovascular mor- iodobenzylguanidine. J Nuclear Med 1986; 27: 1858– tality seen in these patients. 1860. 4 DeQuattro V et al. Central and peripheral norad- Combination therapy of an ACE inhibitor or ARB renergic mechanisms in primary hypertension. Fed with vasodilators like dihydropyridines should Proceed 1984; 43:47–51. therefore offer particular benefit. Patients with CHF 5 Sullivan PA, DeQuattro V, Foti A, Curzon G. Effects on ACE inhibitor therapy had a further reduction in of clonidine on central and peripheral nerve tone in sympathetic tone when the angiotensin receptor primary hypertension. Hypertension 1986; 8: 611–617.

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