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

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Sympatholytic Therapy in Primary Hypertension: a User Friendly Role for the Future 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 hexamethon- ium, 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 combi- nation. 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 sym- pathoplegic agent that has both central and peri- pheral 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 com- pared 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 med- ulla 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 agon- ist 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
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