Catecholamine metabolism in health and disease

PROGRESS

IN ENDOCRINOLOGY

AND METABOLISM

C a t e c h o l a m i n e M e t a b o l i s m in H e a l t h and Disease Robert Hoeldtke

N T H E T H R E E decades since the discovery of norepinephrine (NE), 1 the role of catecholamines in metabolism and systemic physiology has been extensively investigated. Each of the enzymatic steps in catecholamine synthesis 2 and metabolism 3 has been defined and characterized. The development of histofluorescence has made it possible to localize and study individual catecholamine-containing brain neurons? The function of the sympathetic neuron and its dense core vesicle are now well understood, and this has greatly enhanced our knowledge of a wide variety of drugs that affect cardiovascular physiology and the central nervous system. 5 Yet the clinical applications of this information have frequently lagged considerably behind the basic research. A 10-yr interval elapsed between the discovery of low dopamine (DA) levels in the basal ganglia of the parkinsonian patient 6 and the realization that the disease could be properly treated with dihyroxyphenylalanine (DOPA). 7 It has been difficult for a number of reasons to develop methods for the study of physiology and metabolism of catecholamines in the living patient. In studies of urinary metabolites, dietary catechols have frequently contaminated the endogenous metabolite pools. Until very recently, reliable, specific methods for the estimation of plasma catecholamines have not been available? The pathways for catecholamine degradation are complex, and, in addition to the free amines, a whole host of free and conjugated metabolites are excreted. N E and DA are metabolized by similar but distinct pathways, the major difference being that the aldehyde intermediate in the monoamine oxidation is generally converted to the acid derivative for DA, wheras both neutral and acid metabolites of N E are formed (Figs. 1 and 2). Epinephrine (EPI) metabolism overlaps considerably with that of NE, the major end products for both compounds being methoxy-hydroxyphenylglycol ( M H P G ) and vanillymandelic acid (VMA). For this reason it is difficult to know whether an alteration, for example, in M H P G excretion represents a change in catecholamine turnover in brain, adrenal medulla, or sympathetic neurons. Since sympathetic neurons innervate a wide variety of mammalian tissues, many studies of catecholamine excretion have yielded data that are difficult, if not impossible, to interpret. In spite of the many problems, a considerable a m o u n t of useful information has been gained with the available methodology. It has been possible to study those physiologic stimuli (cold exposure, 9 exercise, l~ and starvation li) that cause widespread activation of noradrenergic n e u r o n s . Several disease states

I

From the Laboratory of Neurochemistry, Health Services and Mental Health Administration, Mental Health Intramural Research Program, Bethesda, Md. Received for publication November 27, 1973. Reprint requests should be addressed to Robert Hoeldtke, M.D., Laboratory of Neurochemistry, 36/3D-30, Mental Health Intramural Research Program, Bethesda, Md. 20014. 9 1974 by Grune & Stratton, Inc.

Metabolism, VoL 23, No. 7 (July), 1974

663

664

ROBERT HOELDTKE

Sulfate Conjugate

Norepinephrine

Sulfate Conjugate

Normetanephrine

3,4 - Dihydroxyphenylglycol aldehyde

3-Methoxy - 4 -hydroxyphenylglycol aldehyde A D /

3- Methoxy - 4 - hydr ox y mandelic acid (Vanillylmandelic acid, VMA)

3,4-Dihydroxyphenyl glycol

~CD

3,4-Dihydrox yrnandelic acid

COMT

=COMT

:5-Meth oxy - 4 - hy drox y phenylglycol (MHPG)

3 - Methoxy - 4 hydroxymandelic acid (Vani Ilyma nde li acid , VMA)

Sulfate

Conjugate Fig. 1. Summary of norepinephrine metabolism. MAO, monoamine oxidase; COMT, catechol-Omethyl transferase; ADD, acid dehydrogenase; and ALD,alcohol dehydrogenase.

Sulfate Conjugate

Dopami n e

COM/ Sul fate Conjugate ~

3= Methox;/-4- hydroxy phen~/iethylami ne

~MAO 5,4-Dihydroxy phe nylacet al dei~yde

I I

MAO

ACD I

I 3- Met hoxy -4 - hydroxy phenylocetaldenyd e

A 3-Methoxy-4-hydroxy phenylocetic acid (homovanillic acid, HVA

\\ ACD

P 3,4- Dihydroxy phenylethanol I I I COMT

I V

3-Met hoxy - 4 -hydroxy = phenylet hanoi

~

DD

3,4-Dihydroxyphenylacetic acid COMT 5-.Methoxy - 4 -hydroxy phenylacetic acid Ihomovanillic acid, HVA)

Fig. 2. Summary of dopamine metabolism. Abbreviations are the same as for Fig. 1; the dotted arrows indicate a minor pathway.

CATECHOLAMINE METABOLISM IN HEALTH AND DISEASE

665

have been identified in which distinct abnormalities in catecholamine synthesis or metabolism occur. Methods are being developed for making rough estimates of the relative contribution of the various catecholamine-containitig tissues to the specific metabolite pools. ~2,13 The available data indicate their though urinary metabolite levels provide a reasonable index of catecholamine ttirflover in sympathetic neurons, they are of limited value for studies of brain metabolism. There are indications, however, that the measurement of cerebrospiri~il fluid metabolites will make it possible to study catecholamine metabolism in the ~entral nervous system.~4 URINARY CATECHOLAMINE METABOLITES

Dt~iary Sources of Error Affecting Catecholamine Excretion The presence of biogenic amines in plants and foods is widely appreciated. 15 The most thoroughly studied dietary source of biogenic amines is the banana. Anderson, Ziegler, and Doeden made the original observation that monkeys fed bananas excreted large amounts of the serotonin metabolite 5-hydroxindoleacetic acid.~6 The possibility was thus raised that banana ingestion by humans could lead to the false diagnosis of serotonin secreting tumors of the argentaffin cells of the gastrointestinal mucosa. NE and DA are also present in the banana, though these compounds are concentrated in the peel to a greater degree than is serotonin. 17 DA concentrations in the peel reach 700 #g/g, while the NE concentration has been estimated to be 120 #g/g. In the pulp both amines are present at concentrations of less than 10 ~tg/g. Banana ingestion by human subjects, however, does not significantly alter either the excretion of free catecholamines or their major metabolites, VMA and HVA. ~s,~9 The situation is thus fundamentally different for catecholamines than for serotonin. More importantly, there exists a highly efficient mechanism by which oral catecholamines can be directly conjugated in the gastrointestinal tract to ethereal sulfates. 2~ Direct conjugation is the most important metabolic route for orally ingested NE and DA. 22 The O-methylated amines, metanephrine and normetanephrine, are also readily conjugated. 23 Banana ingestion increases the excretion of conjugated 24 and O-methylated25 catecholamines, but has little effect on the excretion of HVA and VMA. ~9 Catecholamines are less widely distributed in plants than are tyramine and serotoriiil. DA is present in low concentrations in the avocado, and NE has been detected in potatoes and oranges, iv Very high concentrations of NE (2.5 mg/g) have been found in Portulaca oleracea L. This discovery was prompted by the Jamaican folklore that the administration of the plant had positive therapeutic effects in patients with cardiovascular diseases. 26 DOPA has been identified in several foods. Sealock reported large quantities of free DOPA (25 mg/g) in the seedlings, pods, and beans of Vicia faba. 27 DOPA glucuronide was subsequently identified in the green testa and hilum of a late ripening variety of V. faba. 28 DOPA extracted from the broad bean and administered to human subjects caused a 17-fold increase in urinary catecholamine excretion. 29 We have observed free DOPA in a laboratory rat food containing wheat, oats, and alfalfa?~ The DOPA in these cereals is derived from a tyrosine

666

ROBERT HOELDTKE

hydroxylating factor, presumably a tyrosinase enzyme, that can be inhibited by the copper chelating agent diethyldithiocarbamate. T h o u g h the a m o u n t of free D O P A in cereal products is low (less than 0.3 ~zg/g), the tyrosinase enzyme continues to catalyze D O P A synthesis within the lumen of the gastrointestinal tract. Rats ingesting a cereal diet excrete five times more free and conjugated dihydroxyphenylacetic acid (DOPAC) than animals consuming a casein diet. 3~ Similarly, cereal ingestion by h u m a n subjects is associated with a fourfold increase in conjugated DA excretion, and a twofold increase in conjugated urinary DOPAC. 32 Free DA and H V A excretion are not significantly affected by the cereal diet. Thus, the catecholamine excretion pattern following cereal intake is similar to that seen after banana ingestion. 19,24 D O P A has also been identified in brown rice koji. 33 The brown rice koji is made by incubating white rice with Aspergillus oryzae. Since incubation of the white rice with fungi other than A. oryzae does not lead to browning or DOPA formation, it has been proposed that a tyrosinase present in the A. oryzae is responsible for the D O P A formation. The browning reaction and D O P A formation are inhibited by preparing the brown rice koji in the presence of the tyrosinase inhibitor, diethyldithiocarbamate. Such unrecognized dietary source of error can lead to serious misinterpretations of both methodologic and physiologic studies of catecholamine excretion. Prior to our knowledge of dietary D O P A we reported " n o r m a l " urinary catecholamine levels that were considerably greater than any previously recorded in the literature. 34 The subjects in these studies were ingesting a constant diet which included ten oatmeal cookies per day. It is easy to envision how this type of error could obscure a study of catecholamine metabolism in disease. In the absence of proper dietary control, any illness associated with a nonspecific decrease in food intake might reasonably be expected to be associated with a decrease in urinary DA. It is possible, for example, that the increase in conjugated DA excretion seen during the manic phase of a bipolar depression represents increased food intake during this phase of the illness. 35

The Role of the Gastrointestinal Flora Interest in the role of the gastrointestinal flora in catecholamine metabolism was stimulated by the observation that Parkinsonian patients under DOPA treatment excrete increased amounts of meta-tyramine and meta-hydroxyphenylacetic acid (mHPAA). 36C o n c o m i t a n t administration of neomycin sulfate lessens the excretion of these meta-hydroxylated compounds. Similarly, conventional laboratory rats, but not animals raised in a germ-free environment, convert D O P A to m H P A A . 37 The para-dehydroxylation of D O P A 38 and D O P A C 39 by rat cecal contents has been observed in vitro. Boiling of the intestinal contents, or performing the reaction in the presence of oxygen, prevents the dehydroxylation, suggesting that an enzyme from an anaerobic bacteria catalyzes the reaction. 39 N o r m a l human urine contains meta-tyramine, m H P A A , and a wide variety of other meta-hydroxy aromatic acids. 4~ It seems reasonable to suspect that many of these excreted compounds are derived from dietary D O P A (or DA) that has been para-dehydroxylated by the gastrointestinal flora. Banana in-

CATECHOLAMINE METABOLISM IN HEALTH AND DISEASE

667

gestion has been observed to increase the excretion of mHPAA.'8 In addition, meta-tyramine has been identified in the rabbit intestinal contents, but not in tissue extracts. 4~ Thus, it would seem that both dietary enzymes and bacterial enzymes are involved in shift of the hydroxyl group from the para position on the parent amino acid to the meta position on mHPAA and perhaps other aromatic acids. The bacterial dehydroxylase is apparently specific for the hydroxyl group in the para position of the catechol nucleus. Neither DOPA nor DOPAC are dehydroxylated in vitro in the meta position; 37 accordingly, Parkinsonian patients under DOPA treatment excrete normal quantities of para-hydroxyphenylacetic acid (pHPAA). 42 However, these patients excrete increased amount of parahydroxyphenyllactic acid. Similarly, DOPA-treated rats excreted increased amounts of para-hydroxyphenylpyruvic acid. 43 Thus, it seems possible that some meta dehydroxylation of DOPA (or its metabolites) may occur, though there is no evidence that the flora of the host is responsible for this reaction. Gastrointestinal bacteria are capable of forming para tyramine by a completely different pathway involving decarboxylation of tyrosine. Gastrointestinal para tyramine is thought to make a significant contribution to the total amount of excreted tyramine and pHPAA. Awapara and co-workers originally made this proposal on the basis of the observation that tyrosine is a better substrate for the decarboxylase of streptococcus fecalis than for the mammalian enzyme, L aromatic amino acid decarboxylase. 44 In support of this concept was the observation that human subjects excreted decreased amounts of free tyramine following partial sterilization of the gastrointestinal tract. Perry et al. further observed a chronically constipated mongoloid patient with very high levels of urinary tyramine (1660 ug/100 mg creatine)? 5 This patient's tyramine excretion could be reduced to normal levels by sulfasuxidine administration, suggesting that stasis of the gastrointestinal contents provided the bacterial enzyme with a greater opportunity to decarboxylate tyrosine. Patients with cystic fibrosis and other forms of amino acid malabsorption have similarly been observed to excrete increased quantities of the tyramine metabolite pHPAA. 46 The bacterial decarboxylation of tyrosine probably also takes place in the rat intestine. Borud et al. have observed that conventional laboratory rats excreted much larger quantities ofpara-tyramine and pHPAA than did animals raised in a germ-free environment. 47 The gastrointestinal origin of urinary tyramine metaboiites in the healthy human subject, however, has not yet been demonstrated. A number of investigators have observed that partial sterilization of the gastrointestinal tract leads to an increase rather than a decrease in tyramine excretion. 4s'49 Moreover, inhibition of L-aromatic amino acid decarboxylase with a-methyl-DOPA causes a decrease in tyramine excretion, suggesting that the urinary amine is of endogenous origin. 5~ Tissue Sources of Urinary Catecholamines The major obstacle to the interpretation of urinary catecholamine data from humans is the lack of precise information on the relative contribution of the various catecholamine-containing tissues to the various excreted metabolite

668

ROBERT HQELDTKE

pools. The problem is compounded by the fact that the metabolic fate of EPI 5~,52is very similar to that of NE. 53'54 Since little is known about the relative rates o f catecholamine turnover in the human brain, sympathetically innervated organs, and adrenal medulla, it is difficult to attribute changes in catecholarnme excretion patterns to alterations in the metabolism of any of the above catec'h~Olamine-containing tissues. An attemp~ has been made to circumvent these difficulties by exploiting th~ fact thai, ate|east in some species, central NE metabolism ~iff~rs slightly from that in the'periphery. Guinea pig brain slices, for example, ~e0nvert ~HNE to the neutral met~olite, 3HMHPG, whereas liver slices convert 3HNE to the acidic tnetabolite 3HVMA) 5 When 3HNE is administered intraeisternally, the bulk of the radioactivity (53~) is excreted as 3HMHPG, wh_~reas when 3HNE is given intravenously the largest fraction of the radioactivity (35~o~ is excreted as 3HVMA. Maas and Landis have compared in dogs the fa~e of intracisternally administered dl-/3-3H NE and intravenously administered dl-/3~L4C NE and confirmed in this species the predominance of the reductive pathway (to MHPG) in the brain, and the oxidative pathway (to VMA) in the periphergy 12 The problem is that the reductive pathway in the periphery still appears to be quantitatively more important than the reductiVe pathway in the brain. Thus, the authors conclude that only 22~-27~o of urinary MHPG is derived from the brain, whereas less than 1~ of urinary VMA is of central origin. There are intrinsic limitations in attempts to study the tissue sources of urinary catecholamine metabolites by observing the fate of intravenously administered 3HNE. The most important problem is that the labeled NE is not taken up into many tissues that normally synthesize and release catecholamines and their metabolites. 3H catecholamines, for eXample, are taken up much more readily by the heart than by the vasculature 56or the brain) v Following administration of 3HNE to human subjects, the specific activity of urinary NE and urinary normetanephrine is ten times greater than the specific activity of excreted VMA and MHPG. 53 This means that these latter metabolites are deriTed in large part from body compartments not well penetrated by the intravenously administered isotope. Thus, there exists an obvious difficulty in the use of this approach for making quantitative estimates of the relative contribution of peripheral versus central catecholaminergic tissues to the various metabolite pools. The second general approach to the problem has been to study the excretion of catecholamine metabolites by animals whose central or peripheral catecholamine-containing neurons have been selectively damaged. Brody 58 and later Ceasar et al. 59 measured a variety of urinary amines and metabolites in rats wlaose peripheral noradrenergic neurons had been partially destroyed by immunosympathectomy. The administration of a specific nerve growth factor antisera shortly after birth to these rats prevented the normal development of their major paravertebral sympathetic ganglia. 6~This naturally led to a marked decrease in the endogenous NE levels in their heart, salivary glands, iris, and skeletal muscle vasculature. 61 The abdominal prevertebral ganglia, on the other hand, were little affected by the antisera, so that the sympathetic innervation of the visceral vasculature remained intact. The brain and adrenal medulla were

CATECHOLAMINE METABOLISM IN HEALTH AND DISEASE

669

spared the effects of the antisera. The immunosympathectomized animals excreted moderately decreased amounts of free NE (52~ of control) 58 and MH PG (45~o of control), but only slightly (and nonsignificantly) decreased amounts of DA and HVA. 59 6-Hydroxydopamine (6HD) can also be used to destroy selected populations of catecholaminergic neurons. 62 Repeated doses of intravenous or intraperitoneal 6HD (50-100 mg/kg) permanently destroy the sympathetic innervation of the heart, spleen, stomach, 63 intestine, and salivery glands. 64 Certain vascular noradrenergic neurons, however, such as those innervating the mesenteric arteries, are remarkably immune from the effects of the drug. 65 Though endogenous NE levels in the heart and spleen are barely detectable following peripheral 6HD treatment, NE levels in vascular tissues are only slightly lower than those of the control animals. Endogenous catecholamine levels in the brain and adrenal medulla are not altered by peripherally administered 6HD. 66 Thus, the population of neurons affected by peripheral 6HD treatment closely resembles the population damaged by immunosympathectomy. As might be expected, the catecholamine metabolite excretion pattern following these two treatments is quite similar (Table 1).13 In both groups of animals there is a disparity between the extent of the damage to the sympathetic neurons and the degree to which catecholamine metabolite excretion is altered. This is especially true for the 6HD-treated animals, whose cardiac NE levels were undetectable, but whose urinary NE and M H P G levels were only mildly decreased. Thus, a large fraction of these excreted compounds must be derived from those tissues (such as the vasculature, the adrenal medulla, or the brain) that are insensitive to peripherally administered 6HD and immunosympathectomy. Since the adrenal medulla contributes a negligible fraction of the NE excreted into the urine, 67 and since little or no free NE is secreted from the brain without prior deamination, ~2it follows that the vasculature is probably the major source of the urinary NE excreted by the peripherally sympathectomized animals. Thus, it would appear that as much as 50~ 58 to 6 0 ~ s of the NE excreted by the rat is derived from blood vessels. The same conclusion may hold for MHPG, but the situation is more complicated since both brain NE 6s and adrenal EP169 also contribute to this metabolite pool. This means, for example, that the relative resistance of urinary M H P G levels to peripheral sympathectomy may represent a compensatory increase in EPI synTable I. Comparison of Catecholamine Metabolite Excretion Following Immunosympathectomy and Chemical Sympathectomy NE

MHPG

Peripheral 6 hydroxydopamine treatment

65"

61~

Immunosympathectomy

52*

455

VMA

114

DA

DOPAC

HVA

82

85

73"

80

Data expressed as per cent of control; groups were compared by the nonpaired t test. *p < 0.05 tP < 0.01 Sp < 0.00]

79

670

ROBERT HOELDTKE

thesis in the adrenal medulla. 6HD causes a fall in blood pressure associated with a reflex increase in presynaptic input to the adrenal medulla, and an increase in adrenal tyrosine hydroxylase activity. 7~ A similar phenomenon may occur in immunosympathectomized animals whose adrenal N E levels have been reported to be paradoxically increased, w If either of these conditions are associated with enhanced catecholamines release, the anticipated fall in urinary M H P G would be diminished. The quantitative importance of this effect is difficult to evaluate, however, since there are no data in the literature on the relative contribution of adrenal EPI to the total M H P G pool. Peripheral 6 H D treatment also leads to a slight (27~o) but significant decrease in urinary HVA. ~3A lesser (nonsignificant) decrease in HVA excretion was observed in immunosympathectomized animals, s9 DA is present in relatively small concentrations in sympathetic neurons, presumably because it is rapidly /3-hydroxylated to form N E . 72 A decrease in HVA excretion subsequent to chemical sympathectomy suggests that an appreciable fraction of this metabolite pool derives from the DA present in 6HD-sensitive sympathetic neurons. This suggests that at least some of the DA present in these neurons is either released or metabolized intraneuronally rather than ~-hydroxylated. Collins and West 73 incubated the rabbit ileum with 3H-DOPA or 3H-DA, and then found that stimulation of the sympathetic innervation of the ileum caused 3H-DA release. 73 Similarly, 3H-DA has been found to be taken up by sympathetic neurons i n the cat spleen, and released by sympathetic nerve stimulation. 74 Further evidence for the release of DA by sympathetic neurons has been provided by the recent observation that quadriplegic patients with autonomic hyperreflexia excrete increased quantities of HVA in addition to increased quantities o f VMA and M H P G . 75 It is aiso possible to selectively damage central catecholamine-containing neurons by giving small doses of 6HD (50-250 ug per animal) either intraventricularly 76 or intracisternally. 7v Insignificant quantities of the drug so administered escape from the central nervous system to affect the periphery. 78 The situation is thus exactly the opposite of that following intravenous 6HD, in which only those noradrenergic neurons outside the brain are affected. There have been a number of studies of catecholamine metabolite excretion in animals centrally sympathectomized with 6HD. In the monkey, a 72~ decrease in brain N E led to a 33~o decrease in M H P G excretion. 79 Breese et al. reported that in the rat an 82~o depletion of brain N E was associated with a 29~o decrease in urinary M H P G . 8~ We have found in this species, however, that a less marked reduction in brain N E (67~o) was unassociated with a decrease in M H P G excretion. ~3 Even in Breese's study, the alteration in urinary M H P G following central sympathectomy is less p r o n o u n c e d than the changes reported following peripheral sympathectomy.13'59 This indicates that, in the rat, the fraction of excreted M H P G derived from sympathetic neurons is greater than that derived from brain. This same conclusion holds for the monkey 79 and the dog.12 Thus, the data from these experimental animals provide very tenuous support for the concept that human urinary M H P G is a reliable index of brain N E metabolism. 8~,82

CATECHOLAMINE METABOLISM IN HEALTH AND DISEASE

671

CEREBROSPINAL FLUID CATECHOLAMINE METABOLITES

The development of methodology for the measurement of catecholamine metabolites in lumbar cerebrospinal fluid (CSF) has provided a promising new tool for the study of N E and DA metabolism in the human central nervous system. The use of this approach was p r o m p t e d by the finding that probenecid inhibits the active transport system for the renal.tubular secretion of the serotonin metabolite 5-hydroxindoleacetic acid (5HIAA). 83 This led to the discovery of a similar probenecid-sensitive active transport system by which HVA and 5 H I A A are removed from the rat 84 and dog brain. 85 The rate of brain indoleamine 86 and catecholamine synthesis s7 in rats can be approximated from measurements of the rate of accumulation o f the major amine metabolites following inhibition of their efflux from brain. The applicability of the m e t h o d to turnover studies in man was suggested by the finding that HVA and 5HIAA accumulate rapidly in human lumbar CSF following probenecid administration. L4 The catecholamine metabolites present in human lumbar CSF appear to derive from the central nervous system, and not the periphery. Gitlow and Mones observed a single patient with a p h e o c h r o m o c y t o m a and very high level of circulating M H P G but normal levels of CSF M H P G . 88 Intravenously administered ~4C M H P G 89 and 3H H V A 9~ do not penetrate in significant amounts into the CSF of cats or humans. Following 14C D O P A administration, however, 14C HVA appears in the occipital CSF after 2 hr and the lumbar CSF after 8 hr. The data suggest that the 14C D O P A is converted to 14C HVA in the brain and that the labeled metabolite then diffuses slowly to the occipital and lumbar CSF. A similar time interval (6-8 hr) has also been found necessary for the accumulation of significant amounts of HVA into CSF of patients receiving probenecid. 92,93 The measurement of CSF metabolites appears to be more useful for the study of brain DA turnover than for brain N E turnover. Though probenecid inhibits the efflux of M H P G sulfate from the brain of rats 94 and rabbits, 95 attempts to demonstrate the accumulation of either the free or the conjugated metabolite 89'96 in human lumbar CSF following probenecid have thus far been unsuccessful. In addition, the N E present in appreciable concentrations in the spinal c o r d 97 undoubtedly contributes significantly to the lumbar CSF M H P G pool. Spinal cord transection in a variety of experimental animals causes a dramatic lowering of N E below the lesion; 98 accordingly, human patients with spinal cord transections have significantly lowered CSF M H P G . 99 Moreover, the presence or absence of obstruction to CSF flow in quadriplegic patients is unrelated to M H P G levels. If the brain were the source of a large fraction of M H P G present in lumbar CSF, then any alteration in CSF flow would be expected to dramatically lower M H P G levels. Thus, the decrease in M H P G levels associated with spinal cord transection, coupled with the lack of effect of superimposed obstruction, suggest that the spinal cord is the source o f a major fraction o f lumbar CSF M H P G . Interestingly enough, the situation is just the opposite for HVA. Obstruction of CSF flow is associated with a dramatic

672

ROBERT HOELDTKE

lowering of lumbar CSF HVA; transection, per se, however, has no significant influence. The data fit nicely with the observation that DA levels in the spinal cord are much lower than those of NE. 97'98 This means that CSF HVA probably does, in fact, derive from brain DA. As might be expected, patients with Parkinson's disease have decreased quantities of CSF HVA both before and after probenecid. 10o,101 There are many problems yet to be resolved before CSF HVA can be accepted as a reliable index of brain DA turnover. The levels of HVA in the lumbar CSF are much lower than those in the ventricular CSF.I~ This means that the rate of probenecid induced accumulation of HVA in the lumbar CSF may considerably underestimate brain DA turnover. The uptake of probenecid into the CSF is quite variable. Significant positive correlations have been observed between CSF probenecid levels and CSF HVA levels, suggesting that in some patients the efflux of HVA is incompletely blocked even after large doses of probenecid (5-10 g/day). ~~ If efflux is only partially blocked, it is easy to envision how competition between organic acids for the transport system could be a source of confusion. Meek and Neff have reported that HVA, 5HIAA, and M H P G sulfate all partially inhibit the removal of 3HVMA from rat brain. 87 Even if CSF HVA is accepted as an index of brain DA turnover, it must still be realized that any alteration of CSF HVA levels in disease may represent a result of the illness rather than its cause. The increased level of CSF HVA during the manic phase of bipolar depression, for example, is probably secondary to the increased psychomotor activity associated with mania. 1~ Depressed patients who simulated the physical and psychic hyperactivity of manic individuals were found to have CSF HVA levels just as high as those of their truly manic counterparts. Physical activity alone had this same effect. Similarly, active mice have been reported to have higher levels of brain HVA than quiescent controls. ~~ The correlation between HVA and motor activity has implications for many clinical studies, especially those of neurologic diseases. Parkinsonian patients with akinesia, for example, have lower CSF HVA levels than patients without this symptom of the disease. 1~ It is possible that the lower HVA levels in this group of patients represent a distinct abnormality in their brain DA metabolism that leads to akinesia; alternatively, the lower HVA levels may be a nonspecific effect of a motor disability caused by some yet undiscovered factor. Similarly, the decrease in CSF HVA in bedridden patients with multiple sclerosis 107might merely be a reflection of these patients' lack of movement. CATECHOLAMINE METABOLISM IN DISEASE

The most important disease linked to catecholamines to date is Parkinsonism, because restoration of the deficit in brain DA 6 by administration of its amino acid precursor is of therapeutic benefit to many patients, v Similarly, the alteration in catecholamine metabolite excretion associated with tumors of chromaffin tissue is widely appreciated, l~ This review will focus on several disease states where the relationship to catecholamine metabolism is less well understood.

CATECHOLAMINE METABOLISM IN HEALTH AND DISEASE

673

Phenylketonuria Weil-Malherbe originally suggested that a deficit in catecholamine biosynthesis was responsible for the mental deficiency associated with phenylketonuria (PKU). The proposal was based upon the observation that patients with the disease had a moderately decreased plasma E P I and a slightly decreased plasma NE. 1~ Nadler and Hsia similarly observed that PKU patients have decreased levels of plasma EPI and NE and excrete decreased amounts of EPI, NE, and DA. ll~ The low catecholamine levels in blood and urine could be partially restored to normal by administering the patients a low-phenylalanine diet. Untreated PKU patients have also been reported to excrete decreased quantities of V M A , m MHPG, and H V A . ll2 The urinary metabolite data has been supplemented by recent evidence for a defect in brain catecholamine synthesis in P K U . ll3 The probenecid induced accumulation of HVA in the CSF of PKU patients is reduced, especially when plasma phenylalanine levels are high. In addition, direct analysis of postmortem PKU brains has revealed abnormally low caudate NE and DA levels. A variety of explanations have been offered for the defect in catecholamine biosynthesis in PKU. Nadler and Hsia tl~ cited in vitro evidence 114'115 for the partial inhibition of L aromatic amino acid decarboxylase (L AAAD) by phenylalanine metabolites, phenylpyruvate and phenyllactate, and suggested that a similar inhibition occurred in vivo in the PKU patient and was responsible for the decrease in catecholamine biosynthesis. This hypothesis, which is no longer tenable, was proposed prior to the realization that tyrosine hydroxylase is the rate-limiting step in catecholamine biosynthesis.116 Since L AAAD is normally present in tissues in considerable excess ~7 (the Km for DOPA is 4 x 10 -4 M), it is difficult to alter endogenous catecholamine biosynthesis by inhibiting this enzyme. H8 Tissue levels of phenyllactate and phenylpyruvate following phenylalanine hydroxylase inhibition in rats remain below 2 x 10 -5 M . 119 Following phenylalanine loading brain phenyllactate remains below 3 x 10 .4 M. 12~Since these compounds only partially inhibit L AAAD in vitro at concentrations of 3 x 10 -3 M, 114't15 it is unlikely that this effect could be responsible for a deficit in catecholamine biosynthesis seen in PKU. A second explanation for the decreased catecholamine and metabolite levels seen in the PKU patient is based upon the observation that phenylalanine, as well as tyrosine, can be hydroxylated by tyrosine hydroxylase.~2~ This appears to be a unique circumstance in which a single enzyme is capable of catalyzing two consecutive steps in a biosynthetic sequence. Following the intraventricular injection of ~4C phenylalanine it has been possible to isolate both 14C tyrosine and 14C catecholamines from rat brain. 122 Brain homogenates ~23 and isolated synaptosomal preparations ~24 have also been shown to convert labeled phenylalanine to labeled catecholamines. Since the reaction is blocked by the tyrosine hydroxylase inhibitor, a-methyl paratyrosine but unaffected by the phenylalanine hydroxylase inhibitor, parachlorophenylalanine, only the former enzyme is involved. 123'124 Less catecholamines are formed in vitro and in vivo from labeled phenylalanine (a two-step conversion) than from labeled

674

ROBERT HOELDTKE

tyrosine (a one-step conversion). Thus, in the P K U patient the high levels of tissue phenylalanine effectively compete with low levels of tissue tyrosine for tyrosine hydroxylase. Since phenylalanine is less efficiently converted to catecholamines than is tyrosine, the overall effect is a decrease in catecholamine synthesis. This conclusion, however, has recently been challenged by the observation that in the presence of the natural cofactor, tetrahydrobiopterin, and tyrosine hydroxylase purified from bovine adrenal medulla, phenylalanine is just as good a substitute for catecholamine biosynthesis as is tyrosine.125

Familial Dysautonomia Familial dysautonomia is a rare genetic disease that is transmitted as an autosomal recessive apparently confined to Ashkenazi Jews, characterized by diffuse disturbances in the function of the sensory and autonomic nervous systems. 126'127 Defective lacrimation, absent fungiform papilla on the tongue, emotional lability, and relative indifference to pain are hallmarks of the disease. 128 These patients also exhibit postural hypotension and paroxysms of hypertension and excessive sweating, all of which clearly suggest an abnormality of sympathetic neuronal function. 129 Dysautonomic patients excrete decreased amounts of VMA and M H P G , and increased amounts of HVA. 13~ The excretion of these metabolites is quite variable, especially in children, and there is considerable overlap between the metabolite excretion levels in the control and dysautonomic groups. Studies of individual 133 or small groups of patients ~34 have led to conflicting results. In the largest study to date (greater than 50 patients) a highly significant (p < 0.01) threefold increase in the H V A / V M A ration was demonstrated. 135 The obvious interpretation of the urinary metabolite data is that dysautonomic patients have a limited capacity to perform the 13-hydroxylation of DA. Direct evidence in support of this concept was provided by the observation that following 14C D A administration, patients with dysautonomia excreted decreased amounts of labeled N E and VMA, and increased amounts of labeled D O P A C and HVA. t36 With the recent discovery that dopamine /3-hydroxylase (DBH) is released intact from sympathetic neurons and adrenal medulla into the circulation, it became possible to assay the implicated enzyme in the living patient. 137 As anticipated, decreased levels of plasma DBH were observed in the dysautonomic children. 138"~39As with the urinary metabolite data, however, levels of DBH were found to be highly variable, and there was considerable overlap between levels in the patients and the normal controls. 14~ Although some patients have no detectable D B H in plasma, others have enzyme levels well within the normal range. Such a spectrum of data does not support the concept of a primary enzymatic deficiency. Thus, it appears that the changes in plasma DBH and the urinary metabolite pattern in dysautonomia are secondary to some as yet unexplained alteration in the development or the function of the sympathetic neuron or the granular vesicle. The catecholamine metabolite excretion pattern in familial dysautonomia ressembles that seen following reserpine administration, a drug known to disrupt the function of the granular vesicle. '4' The exaggerated hypertensive response to infused N E exhibited by dysautonomic individuals also suggests that the uptake system for catechola-

CATECHOLAMINE METABOLISM IN HEALTH AND DISEASE

675

mine inactivation (the granular vesicle) is not functioning normally. ~42 Such an abnormality might underlie both the postural hypotension (decreased catecholamine release) and episodic hypertension (decreased catecholamine inactivation) seen in these patients.

Hypopituitarism Spontaneous hypoglycemia and insulin sensitivity are well-recognized features of hypopituitarism.143 In the normal subject a decrease in blood glucose is a potent stimulus to the release of growth hormone, ~44 which acts as an insulin antagonist and promotes hyperglycemia. ~45 In the patient with growth hormone deficiency insulin sensitivity presumably results, in part, from the absence of its physiologic antagonist. Hypoglycemia is also seen in patients with defective ACTH production, but otherwise normal pituitary function. 146 This has generally been attributed to decreased gluconeogenesis secondary to adrenal cortical insufficiency.147 A clue to a further relation between ACTH and blood glucose regulation was provided by the early observations of Luft and von Euler that patients with Addison's disease 148 and hypophysectomized patients 149excrete less EPI in response to insulin-induced hypoglycemia than normal subjects. A decade passed before the significance of these observations was fully appreciated, with the discovery by Wurtman and Axelrod of a dramatic decrease in EPI content and the level of the EPI synthesizing enzyme, phenylethanolamine-N-methyl transferase (PNMT) in the adrenal medulla of hypophysectomized rats. ~5~PNMT levels in these animals could be restored to normal by administration of ACTH or large doses of a synthetic glucocorticoid.~5~ These observations provided fresh insight into the special relation between the adrenal medulla and its surrounding cortex. ~52 Immunochemical studies demonstrated that glucocorticoid production was essential not only for PNMT activity, but for the synthesis of the PNMT specific protein. ~Ss In addition, adrenal medullary protein synthesis, in general (as evidenced by the state of polysome aggregation), is dependent upon the integrity of the pituitary adrenal axis. ~53 Thus it is not surprising that, in addition to PNMT, other enzymes involved in catecholamine biosynthesis, tyrosine hydroxylase ~54 and dopamine/3-hydroxylase,15s are dependent upon the presence of adrenal cortical hormones. The decrease in catecholamine synthesizing enzymes associated with hypophysectomy leads to physiologically important alterations in EPI synthesis and release. Hypophysectomized dogs secrete decreased amounts of EPI into the adrenal vein in response to insulin-induced hypoglycemia. 156 The alteration in EPI release can be reversed by treating the hypophysectomized animals with ACTH. Basal urinary EPI levels of hypophysectomized human subjects have been reported to be below the sensitivity of fluorimetric assay.IS7 A single patient with an isolated ACTH deficiency and spontaneous hypoglycemia exhibited an abnormally low increase in urinary catecholamines subsequent to insulin treatment. ~58 As anticipated from the studies with animals, the hypoglycemia and defective catecholamine response could be corrected by ACTH therapy. ~58Dexamethasone treatment of normal human subjects decreases the ratio of excreted EPI to NE.159 The dose administered (l nag/day) was sufficient

676

ROBERT HOELDTKE

to block A C T H release, but too low to replace the glucocorticoids normally secreted from the cortex into the medulla. 156 Catecholamine biosynthesis in tissues other than adrenal medulla does not appear to be dependent on glucocorticoids. There is some evidence that actually the reverse is true A small population of hypophysectomized patients has been reported to excrete increased quantities of N E 16~and their urinary VMA levels also tended to be slightly elevated.157 The urinary N E levels returned to normal following A C T H administration. The data fit nicely with animal studies showing that hypophysectomy leads to an increase in cardiac N E synthesis and turnover. 161 This may explain why the decrease in plasma N E levels observed in diabetic patients with autonomic neuropathy return to normal following pituitary removal. 162

Essential Hypertension Ever since the discovery that the peripheral sympathetic neurotransmitter (NE) is a potent pressor agent, there has been the natural speculation that hypertension is a disease of noradrenergic neurons. 1 Alteration in N E metabolism have been observed in a variety of animal models of hypertension. The turnover of N E is accelerated in sympathetically innervated organs of animals made hypertensive by deoxycorticosterone D O C A and salt administration, 163 renal infarction, 164 or carotid sinus denervation. 165'166 I m m u n o s y m p a t h e c t o m y prevents the induction of hypertension by thyroxine and salt. 167 The development of D O C A salt hypertension ~6s and renal hypertension 169 is mitigated by adrenal demedullation and chemical sympathectomy. A number of clinically useful antihypertensive drugs have been developed that act predominately by altering sympathetic neuronal function. 170Until very recently, however, clinical studies of hypertensive patients have yielded unconvincing evidence for an abnormality in N E release or metabolism in this disease. In an early study of 500 hypertensive individuals, von Euler and associates observed that the vast majority of these patients excreted the same amounts of N E as controls, though a small group (16~o) was described with urinary N E levels above the normal range. 171 There have been subsequent reports of an increased excretion of N E or its metabolites in hypertension, 172 but the changes have been slight 173 and conflicting data have appeared.174 A number of groups have supported von Euler's claim that, though most hypertensive patients excrete normal amounts of NE, a small group exists with clearly elevated urinary NE. 175,176There is no proof, however, that these patients comprise a truly distinct population rather than one extreme extension of a normal distribution. Although the basal levels of urinary N E are not greatly elevated in hypertension, certain physiologic stimuli will cause a greater increase in N E excretion by patients with this disease than normal controls. In response to a head-up tilt from a supine position, those patients with an excessive rise in diastolic blood pressure (greater t h a n 10 mm Hg) also excreted significantly elevated urinary N E . 177 m correlation between diastolic blood pressure and the urinary N E levels of hypertensive patients has also been observed in the absence of provoking stimuli. 178 A high-saint diet t78 and mental stress 179 also lead to a greater increase in the urinary N E levels of hypertensive subjects than controls.

CATECHOLAMINE METABOLISM IN HEALTH AND DISEASE

677

Solid evidence for an abnormality in the function of the sympathetic nervous system in hypertension has awaited the development of the proper methodology for the assay of catecholamines in plasma. Both gas-chromatographic Is~ and double-isotope derivative studies ~81-~8~have revealed an increase in circulating catecholamines in essential hypertension. The plasma NE levels of the hypertensive subjects are positively correlated with their diastolic blood pressure. ~sz~83 Following ganglionic blockade, the decrease in diastolic blood pressure is significantly correlated with the decrease in plasma NE, ~83 suggesting that the level of circulating neurotransmitter is a reasonable index of the functional state of those sympathetic neurons regulating blood pressure. The levels of circulating NE in the hypertensive patients are quite variable, however, and it would be premature to conclude that a direct causal relation exists between the circulating NE levels and the blood pressure elevation.

Catecholamines and the Renin Angiotensin System Norepinephrine released from renal sympathetic neurons as well as circulating EPI provoke the secretion of renin. Stimulation of the renal sympathetic nerves,IS4 intravenous and intrarenal NE,I~s'Is6 insulin-induced hypoglycemia,'87 and excessive production of catecholamines by chromaffin tumors ls~ all lead to an elevation in plasma renin activity (PRA). EPI and NE increase renin production by the isolated, perfused kidney 1s9 and by renal cell suspensions. 19~ Activation of the sympathetic nervous system by hemorrhage, 191 the assumption of an upright posture, 192exercise, 193and cold 194all lead to parallel increases in PRA and catecholamine levels. Many of these effects can be inhibited by ganglionic blockade, 195 adrenergic receptor blocking agents, or other drugs known to alter the function of sympathetic neurons. 196 In spite of this impressive array of evidence, the relative importance of the sympathetic nervous system in the physiologic regulation of renin secretion remains open to question. 19v Although denervated kidneys contain decreased levels of renin, ~gs they secrete normal amounts of the proteolytic enzyme in response to the stress of hemorrhage. 199 This finding, and a large body of additional evidence, 19vsuggests that a renal vascular baroreceptor is of primary importance in the regulation of renin release. This means that many of the alterations in PRA associated with sympathoadrenal activation may result, in part, from systemic hemodynamic alterations that secondarily affect the baroreceptor, z~176 Of special clinical interest is the role of the sympathetic nervous system in the release of renin upon the assumption of an upright posture. It is widely appreciated that shifting from a supine to an upright position simultaneously leads to an increase in urinary catecholamine levels and PRA. 192 The per cent increase in plasma NE following a postural stress is significantly correlated with the per cent increase in PRA, 2~ and this response is inhibited by adrenergic blocking agents. 2~ Since patients with autonomic neuropathy do not excrete increased amounts of NE in response to a head-up tilt, z~ this naturally led to the suggestion that the postural hypotension seen in this disease results from failure of the sympathetic nervous system to activate the renin angiotensin system. This concept provided an explanation for the early observation that patients

678

ROBERT HOELDTKE

with a u t o n o m i c neuropathy excrete low levels of aldosterone, z~ Direct support for this hypothesis was first provided by the observation of a single patient with autonomic neuropathy, postural hypotension, low urinary aldosterone, and a failure of P R A and catecholamine levels to respond to the assumption of an upright posture. 194 A defective P R A response to posture has subsequently been observed in several other patients with this disease. 2~176 The sympathetic nervous system also appears to be involved in the augmentation of renin secretion associated with sodium depletion. Early studies showed that the renin secretion induced by exogenous catecholamine administration or renal nerve stimulation could be blocked by concomitant administration of sodium depleting diuretics. ~85 The data indicated that the renin response to both circulating and locally released catecholamines was dependent upon the presence of sodium. There is some evidence that the converse relation also holds; i.e., the renal sympathetic neurons play at least a permissive role in mediating the well-known effects of sodium depletion on renin secretion. Unilaterally denervated dog kidneys secrete less renin in response to acute sodium loss than the contralateral intact kidneys. ~~ Renal s y m p a t h e c t o m y , in dogs, has been found to delay z~ or abolish 2~ the increase in P R A associated with ingestion of a low-sodium diet. Renin secretion induced by naturiesis in man can be inhibited by adrenergic blocking drugs. 2~ One possible interpretation of these findings is that sodium depletion has a direct effect on the function of renal sympathetic neurons. This is an attractive hypothesis since m a n y sympathetically innervated tissues, when placed in a low-sodium environment, have a decreased capacity to store N E ~~ and an increased capacity for evoked N E release, m An increase in free urinary N E excretion in response to a low-sodium diet has been reported by a n u m b e r of investigators, '94'2~2'2~3though others have not confirmed this finding. 192,214 Kelsch and associates observed that though sodium restriction did not affect free N E excretion, it led to increased urinary conjugated N E and increased plasma NE. 2~5 Sodium deficiency, of course, has m a n y effects on renal physiology unrelated to sympathetic neurons. The macula densa and distal tubule are also involved in renin secretion and are directly affected by sodium depletion, so that it is difficult to evaluate the relative importance of the sympathetic nervous system in this connection, l%,lgv Nearly one third of all patients with essential hypertension have abnormally low basal levels of P R A and an inadequate P R A response to sodium deprivation and an erect posture. 214 It has been proposed that the deficient P R A response is secondary to an underlying defect in the activation of the renin angiotensin system by the renal sympathetic neurons, z~3 Decreased catecholamine excretion has been observed in patients with suppressed P R A on both normal/t6 and low-sodium diets. 213 Even infusion of catecholamines to this group of patients, however, fails to elicit a P R A response. 2~4 This means that even though the urinary catecholamine data m a y indicate that these patients have a less than normally active sympathetic nervous system, it does not necessarily follow that this is the cause for their inadequate renin response. In any case it is clear that in future studies of catecholamine metabolism in hypertension, it will be necessary to characterize the renin angiotensin system of the patients and segregate that group of individuals with decreased sympathetic neuronal activity and P R A responses.

CATECHOLAMINE METABOLISM IN HEALTH AND DISEASE

679

SUMMARY

T h e s y m p a t h e t i c n e r v o u s system is the m a j o r site o f e a t e c h o l a m i n e b i o s y n t h e sis in m a m m a l s , a n d the s o u r c e o f m o s t o f the e x c r e t e d N E , V M A , a n d M H P G . T h e N E m e t a b o l i z e d in the c e n t r a l n e r v o u s s y s t e m m a k e s a m i n o r c o n t r i b u t i o n to the M H P G p o o l , ~2 a n d E P I r e l e a s e d f r o m the a d r e n a l m e d u l l a is m e t a b o l i z e d to b o t h V M A a n d M H P G . 5~ T h i s m e a n s t h a t t h e m e a s u r e m e n t s o f these c o m p o u n d s p r o v i d e s o n l y an insensitive a n d n o n s p e c i f i c a s s e s s m e n t o f c a t e c h o l a m i n e m e t a b o l i s m in the h u m a n subject. Even with l i m i t e d m e t h o d o l o g y , h o w e v e r , it has been p o s s i b l e to identify a n u m b e r o f diseases in w h i c h c a t e c h o l a m i n e s y n t h e s i s a p p e a r s to be defective. In p h e n y l k e t o n u r i a , high tissue levels o f p h e n y l a l a n i n e c o m p e t e with t y r o s i n e for t h e rate l i m i t i n g b i o s y n t h e t i c e n z y m e , t y r o s i n e h y d r o x y l a s e ? 1~ This results in d e c r e a s e d c a t e c h o l a m i n e b i o s y n t h e s i s in a d r e n a l m e d u l l a , ~~ s y m p a t h e t i c n e u r o n s , H~ a n d b r a i n . H3 In f a m i l i a l d y s a u t o n o m i a the t 3 - h y d r o x y l a t i o n o f D A is defective, ~35,~36p r o b a b l y b e c a u s e the g r a n u l a r vesicles do n o t d e v e l o p n o r m a l l y . T h e resulting d e c r e a s e in N E synthesis a n d release leads to the p o s t u r a l h y p o t e n s i o n seen in this disease. ~38 I n h y p o p i t u i t a r i s m , c a t e c h o l a m i n e synthesis is selectively d e c r e a s e d in the a d r e n a l m e d u l l a . ~5~ T h e resulting i m p a i r m e n t in E P I release c o n t r i b u t e s to t h e insulin, sensitivity seen clinically f o l l o w i n g h y p o p h y s e c t o m y . 149 E s s e n t i a l h y p e r t e n s i o n a p p e a r s to be a s s o c i a t e d with an e n h a n c e m e n t o f N E synthesis o r release in s y m p a t h e t i c n e u r o n s . G a n g l i o n i c b l o c k i n g drugs a n d o t h e r a g e n t s affecting a d r e n e r g i c n e u r o n a l f u n c t i o n are useful in the t r e a t m e n t o f h y p e r t e n s i o n . ~7~ I n t e g r i t y o f t h e s y m p a t h e t i c n e r v o u s system is essential for the d e v e l o p m e n t o f a v a r i e t y o f a n i m a l m o d e l s o f h y p e r t e n s i o n . ~67 169 T h o u g h clinical studies o f c a t e c h o l a m i n e m e t a b o l i t e e x c r e t i o n have g e n e r a l l y been inc o n c l u s i v e , 173 t h e r e is n o w g o o d e v i d e n c e for an e l e v a t i o n in c i r c u l a t i n g catec h o l a m i n e s in h y p e r t e n s i v e p a t i e n t s . ~8~ It is p o s s i b l e , h o w e v e r , t h a t m a n y studies o f h y p e r t e n s i v e p o p u l a t i o n s h a v e been o b s c u r e d b y the i n c l u s i o n o f large subg r o u p s o f p a t i e n t s with s u p p r e s s e d P R A a n d d e c r e a s e d s y m p a t h e t i c n e u r o n a l f u n c t i o n . 216 REFERENCES

1. Euler USv: A specific sympathomimetic ergone in adrenergic nerve fibers (sympathin) and its relation to adrenalin and noradrenalin. Acta Physiol Scand 12:73, 1946 2. Blaschko H: Catecholamine biosynthesis. Br Med Bull 29:105, 1973 3. Axelrod J: Methylation reactions in the formation and metabolism of catecholamines and other biogenic amine. Pharmacol Rev 18: 95, 1966 4. Dahlstrom A, Fuxe K: A method for the demonstration of monamine containing nerve fibers in the central nervous system. Acta Physiol Scand 60:293, 1964 5. lversen LL: Role of transmitter uptake mechanisms in synaptic neurotransmission. Br J Pharmaco141:571, 1971

6. Horynykiewicz O: Dopamine in the basal ganglia. Br Med Bull 29:172, 1973 7. Cotzias GD, Van Woert HM, Schiffer LM: Aromatic amino acids and modification of Parkinsonism. N Engl J Med 276:374, 1967 8. Engelman K, Portnoy B: A sensitive double-isotope derivative assay for norepinephrine and epinephrine: Normal resting human plasma levels. Circ Res 26:53, 1970 9. Motelica I: Urinary excretion of catecholamines and vanilmandelic acid in rats exposed to cold. Acta Physiol Scand 76:393, 1969 10. Euler USv, Hellner S: Excretion of noradrenalin and adrenalin in muscular work. Acta Physiol Scand 26:183, 1952 11. Januszewicz W, Szhajderman-Ciswicka M, Wocial B: Urinary excretion of catechol-

680

amines in fasting obses subjects. J Clin Endocrinol Metab 27:130, 1967 t2. Maas JW, Landis DH: In vivo studies of the metabolism of norepinephrine in the central nervous system. J Pharmacol Exp Ther 163: 147, 1968 13. Hoeldtke R, Rogawski M, Wurtman RJ: Effect of selective destruction of central and peripheral catecholamine containing neurons with 6-hydroxy dopamine on catecholamine excretion in the rat. Br J Pharmacol 50:265, 1974 14. Tamarkin NR, Goodwin FK, Axelrod J: Rapid elevation of biogenic amine metabolites in human CSF following probenecid. Life Sci 9:1397, 1970 15. Waalkes TP, Sjoerdsma A, Creveling CR, Weissbach H, Udenfriend S: Serotonin, norepinephrine, and related compounds in bananas. Science 127:648, 1958 16. Anderson JA, Ziegler MR, Doeden D: Banana feeding and urinary excretion of 5hydroxyindoleacetic acid. Science 127:236, 1958 17. Udenfriend S, Lovenberg W, Sjoerdsma S: Physiologically active amines in common fruits and vegetables. Arch Biochem Biophys 85:487, 1959 18. Shaw KNF, Trevarthen J: Exogenous sources of urinary phenol and indole acids. Nature (Lond) 182:797, 1958 19. Cardon PV, Guggenheim FG: Effects of large variations in diet on free catecholamines and their metabolites in urine. J Psychiatry Res 7:263, 1970 20. Richter D, Macintosh FC: Adrenalin ester. Am J Physiol 135:1, 1941 21. Haggendal J: The presence of conjugated adrenalin and noradrenalin in human blood plasma. Acta Physiol Scand 59:255, 1963 22. Morgan CD, Ruthven CRJ, Sandier M: The quantitative assessment of isoprenaline metabolism in man. Clin Chim Acta 26:381, 1969 23. Kahane Z, Vesterguard P: Fluorometric assay for metanephrine and normetanephrine in urine. J Lab Clin Med 70:333, 1967 24. Crout JC, Sjoerdsma A: The clinical and laboratory significance of serotonin and catecholamines in bananas. N Engl J Med 261:23, 1959 25. Kahane Z, Esser AH, Kline NS, Vesterguard P: Estimation of conjugated epinephrine and norepinephrine in urine. J Lab Clin Med 69:1042, 1967 26. Feng PC, Haynes LG, Magnus KE: High concentrations of ( - ) noradrenaline in portulaca oleracea L. Nature (Lond) 191:1108, 1961

ROBERT HOELDTKE

27. Sealock RR: ~-3,4-dihydroxyphenylalanine. Biochem Prep 1:25, 1949 28. Andrews RS, Pridham JB: Structure of a DOPA glucoside from Vicia faba. Nature (Lond) 205:1213, 1965 29. Spiegel-Adolf M, Siegel EA, Fabiani FR, Calise J: Urinary excretion of catecholamines after ingestion of fava bean extracts. Fed Proc 28:898, 1969 30. Hoeldtke R, Baliga BS, Issenberg P, Wurtman R J: Dihydroxyphenylalanine in rat food containing wheat and oats. Science 175: 761, 1972 31. Hoeldtke R, Wurtman RJ: Synthesis of DOPA in the rat stomach following ingestion of cereals. Metabolism 23:25, 1974 32. Hoeldtke R, Wurtman RJ: Cereal ingestion and catecholamine excretion. Metabolism 23:33, 1974 33. Ohba T, Murakami H, Hara S: Identification of L-Dopa and protocatechuric acid as main precursors of pigment of brown rice-koji. Agr Biol Chem 35:674, 1971 34. Hoeldtke R, Martin W: Urine volume and catecholamine excretion. J Lab Clin Med 75:166, 1970 35. Messiha FS, Agallianos D, Clower C: Dopamine excretion in affective states and following Li2CO 3 therapy. Nature (Lond) 225: 868, 1970 36. Sandier M, Goodwin BL, Ruthven CRJ, Calne DB: Therapeutic implications in Parkinsonism of m-tyramine formation from L-Dopa in man. Nature (Lond) 229:414, 1971 37. Goldin BR, Peppercorn MA, Goldman P: Contributions of host and intestinal microflora in the metabolism of L-Dopa by the rat. J Pharmacol Exp Ther 186:160, 1973 38. Bakke OM: Degradation of DOPA by intestinal micro-organisms in vitro. Acta Pharmacol Toxicol 30:115, 1971 39. Booth AN, Williams RT: Dehydroxylation of catechol acids by intestinal contents. Biochem J 88:66, 1963 40. Armstrong MD, Shaw KNF, Wall PE: The phenolic acids in human urine. J Biol Chem 218:293, 1956 41. Kakimoto K, Armstrong MD: The phenolic amines of human urine. J Biol Chem 237:208, 1962 42. Calne DB, Daroum F, Ruthven CRJ, Sandler M: The metabolism of orally administered L-DOPA in Parkinsonism. Br J Pharmacol 37:57, 1969 43. Kogan FJ, Gibb JW: p Hydroxyphenytpyruvic acid excretion in rats after the administration of reserpine and cemethyl-p-tyrosine,

CATECHOLAMINE METABOLISM IN HEALTH AND DISEASE

hydrocortisone, and L-DOPA. Fed Proc 31: 2113, 1972 44. Awapara J, Perry TL, Hanly C, Peck E: Substrate specificity of DOPA decarboxylase. Clin Chim Acta 10:286, 1964 45. Perry TL, Hestrin M, MacDougall L, Hansen S: Urinary amines of intestinal bacterial origin. Clin Chim Acta 14:116, 1966 46. Van Der Heiden C, Wauters EAK, Ketting D, Duran M: Gas chromatographic analysis of urinary tyrosine and phenylalanine metabolites in patients with gastrointestinal disorders. Clin Chim Acta 34:289~ 1971 47. Borud O, Midtvedt T, Gijessing LR: Urinary phenolic compounds in gnotobiotic and conventional rats on a free diet, and before and after L-DOPA loading on a milk diet. Acta Pharmacol T0xicol 30:185, 1971 48. DeOuattro VL, Sjoerdsma A: Origin of urinary tyramine and tryptamine. Clin Chim Acta 16:227, 1967 49. Boulton AA: The pink spot in parkinsonism. Prog Neurogenet 1:437, 1967 50. Oates JA, Gillespie L, Udenfriend S, Sjoerdsma A: Decarboxylase inhibition and blood pressure reduction by a methyl-3,4dihydroxy-DL-phenylalanine. Science 131:1890, 1960

51. LaBrosse EH, Axelrod J, Kopin IJ, Kety S: Metabolism of 7-H 3 epinephrine-d-bitartrate in normal young men. J Clin Invest 40:253, 1961 52. Alton H, Goodall McC: Metabolic products of adrenalin (epinephrine) during long term constant rate intravenous infusion in the human. Biochem Pharmaco[ 17:2163, 1968 53. Maas JW, Landis DH: The metabolism of circulating norepmephrine by human subjects. J Pharmacol Exp Ther 177:600, 1971 54. Sharman DF: The catabolism of catecholamines. Br Med Bull 29:110, 1973 55. Breese GR, Chase TN, Kopin IJ: Metabolism of some phenylethylamines and their B-hydroxylated analogs in brain. J Pharmacol Exp Ther 165:9, 1969 56. Berkowitz BA, Tarver JH, Spector S: Norepinephrine in blood vessels: concentration binding, uptake, and depletion. J Pharmacol Exp Ther 177:119, 1971 57. Axelrod J, Weil-Malherbe H, Tomchick R: The physiological disposition of H 3 epinephrine and its metabolite metanephrine. J Plaarmacol Exp Ther I27:25I, I959 58. Brody M J: Cardiovascular responses following immunological sympathectomy. Circ Res 15:161, 1964 59. Ceasar PM, Ruthven CRJ, Sandler M:

681

Catecholamine and 5-hydroxyindole metabolism in immunosympathectomized rats. Br J Pharmacol 36:70, 1969 60. Levi-Montalcini R, Booker B: Destruction of the sympathetic ganglia in mammals by an antiserum to a nerve growth factor. Proc Nat Acad Sci USA 46:384, 1960 61. Hamberger B, Levi-Montalcini R, Norberg KA, Sjoquist F: Monoamines in immunosympathectomized rats. Int J Pharmacol 4:9I, 1965 62. Thoenen H, Tranzer JP: Chemical sympathectomy by selective destruction of adrenergic nerve endings with 6-hydroxydopamine. Naunyn-Schmied Arch Pharmacol 261:271, 1968 63. Lytle LD, Hurko O, Romero JA, Cottman K, Leehey D, Wurtman R J: The effects of 6-hydroxydopamine pretreatment on the accumulation of dopa and dopamine in brain and peripheral organs following L-DOPA administration. J Neural Trans 33:63, 1972 64. DeChamplain J: Degeneration and regrowth of adrenergic nerve fibers in the rat peripheral tissues after 6-hydroxydopamine. Can J Physiol Pharmacol 49:345, 1971 65. Berkowitz BA, Spector S, Tarver JH: Resistance of noradrenalin in blood vessels to depletion by 6-hydroxydopamine or immunosympathectomy. Br J Pharmacol 44:10, 1972 66. Clark DW, Laverty R, Phelan EL: Longlasting peripheral and central effects of 6hydroxydopamine in rats. Br J Pharmacol 44: 233, 1972 67. Leduc J: Catecholamine production and release in exposure and acclimation to cold. Acta Physiol Scand 53 (Suppl 183):1, 1961 68. Schanberg SM, Schildkraut J J, Breese GR, Kopin IJ: Metabolism of normetanephrineH 3 in rat brain identification of conjugated 3-methoxy-4-hydroxyphenylglycol as the major metabolite. Biochem Pharmacol 17:247, 1968 69. Kopin IJ, Axelrod J, Gordon E: The metabolic fate of H 3 epinephrine and C 14 metanephrine in the rat. J Biol Chem 236:2109, 1961 70. Mueller RA, Thoenen H, Axelrod J: Adrenal tyrosine hydroxylase: compensatory increase in activity after chemical sympathectomy. Science 163:468, 1969 71. Carpi A, Oliverio A: Urinary excretion of catecholamines in the immunosympathectomized rat--balance phenomena between the adrenergic and the noradrenergie system, lnt J Neuropharmaeol 3:427, 1964 72. Costa E, Green AR, Koslow SH, Lefevre HF, Revuelta AV, Wang C: Dopamine and

682

norepinephrine in noradrenergic axons: A study in vivo of their precursor product relationship by mass fragmentography and radiochemistry. Pharmacol Rev 24:167, 1972 73. Collins GGS, West GB: The release of 3H-dopamine from isolated rabbit ileum. Br J Pharmacol 34:514, 1968 74. Masacchio JM, Fischer JE, Kopin IJ: Subcellar distribution and release by sympathetic nerve stimulation of dopamine and amethyldopamine. J Pharmacol Exp Ther 152: 51, 1966 75. Sell GH, Naftchi NE, Lowman EW, Rusk HA: Autonomic hyperreflexia and catecholamine metabolites in spinal cord injury. Arch Phys Med Rehabil 52:416, 1972 76. Uretsky N J, Iversen LL: Effects of 6hydroxydopamine on noradrenaline-containing neurones in the rat brain. Nature (Lond) 221: 557, 1969 77. Breese GR, and Traylor TD: Developmental characteristics of brain catecholamines and tyrosine hydroxylase in the rat: Effects of 6-hydroxydopamine. Br J Pharmacol 44:210, 1972 78. Breese GR, Traylor TD: Effect of 6hydroxydopamine on brain norepinephrine and dopamine: Evidence for selective degeneration of catecholamine neurons. J Pharmacol Exp Ther 174:413, 1970 79. Maas JW, Dekirmenjian H, Garver D, Redmond DE, Landis DH: Catecholamine metabolite excretion following intraventricular injection of 6-hydroxydopamine. Brain Res 41: 507, 1972 80. Breese GR, Prange AJ, Howard JL, Lipton MA, McKinney WT, Bowman RE, Bushnell P: 3-Methoxy-4-hydroxyphenlyglycol excretion and behavioral changes in rat and monkey after central sympathectomy with 6hydroxydopamine. Nature (New Biol) 240:286, 1972 81. Schildkraut J J, Keeler BA, Papousek M, Hartman E: MHPG excretion in depressive disorders: Relation to clinical subtypes and desynchronized sleep. Science 181:762, 1973 82. Jones FD, aas JW, Dekirmeijian H, Fawcett J: Urinary catecholamine metabolites during behavioral changes in a patient with manic depressive cycles. Science 179:300, 1973 83. Despopoulos A, Weissbach H: Renal metabolism of 5-hydroxyindoleacetic acid. Am J Physiol 189:548, I957 84. Werdinius B: Effect of probenecid on the levels of monoamine metabolites in the rat brain. Acta Pharmacol Toxicol 25:18, 1967

ROBERT HOELDTKE

85. Guldberg HC, Ashcroft GW, Crawford TBB: Concentrations of 5-hydroxyindoleacetic acid and homovanillic acid in the cerebrospinal fluid of the dog before and during treatment with probenecid. Life Sci 5:1571, 1966 86. NeffNH, Tozer TN, Brodie BB: Application of steady state kinetics to studies of the transfer of 5-hydroxyindoleacetic acid from brain to plasma. J Pharmacol Exp Ther 158: 214, 1967 87. Meek JL, Neff NH: Acidic and neutral metabolites of norepinephrine: Their metabolism and transport from brain. J Pharmacol Exp Ther 181:457, 1972 88. Wilk S, Mones R: Cerebrospinal fluid levels of 3-methoxy-4-hydroxyphenylethy[ene glycol in Parkinsonism before and after treatment with L-DOPA. J Neurochem 18:ITII, 1971 89. Chase TN, Gordon EK, Ng LKY: Norepinephrine metabolism in the central nervous system of man: studies using 3-methoxy-4hydroxyphenyl glycol levels in cerebrospinal fluid. J Neurochem 21:581, 1973 90. Pletscher A, Bartholini G, Tissot R: Metabolic fate of L[14C] DOPA in cerebrospinal fluid and blood plasma of humans. Brain Res 4:106, 1967 91. Bartholini G, Pletscber A, Tissot R: On the origin of homovanillic acid in the cerehrospinal fluid. Experientia 22:609, 1966 92. Korf J, VanPraag HM, Sebens J: Effect of intravenously administered prohenecid in humans on the level of 5-hydroxyindoleacetic acid, homovanillic acid, and 3-methoxy-4hydroxyphenylglycol in cerebrospinal fluid. Biochem Pharmacol 20:659, 1971 93. Lakke JPWF, Korf J, VanPraag HM, Schut T: Predictive value of the probenecid test for the effect of L-DOPA therapy in Parkinson's disease. Nature (New Biol) 236:208, 1972 94. Meek JL, Neff NH: Fluorometric estimation of 4-hydroxy-3-methoxy phenylethyleneglycol sulphate in brain. Br J Pharmacol 45:435, 1972 95. Extein I, Korf J, Roth RH, Bowers MB: Accumulation of 3-methoxy-4-hydroxyphenylglycol-sulfate in rabbit cerebrospinal fluid following probenecid. Brain Res 54:403, 1973 96. Goodwin FK, Post RM, Dunner DL: Cerebrospinal fluid amine metabolites in affective illness: The probenecid technique. Am J Psychiatry 130:73, 1973 97. Anton AH, Sayre DF: The distribution of dopamine and DOPA in various animals and

CATECHOLAMINE METABOLISM IN HEALTH AND DISEASE

a method for their determination in diverse biological material. J Pharmacol Exp Ther 145: 326, 1964 98. Magnusson T: Effect of chronic transaction on dopamine noradrenalin, and 5-hydroxytryptamine in the rat spinal cord. NaunynSchmied Arch Pharmacol 278:13, 1973 99. Post RM, Goodwin FK, Gordon E, Watkin DM: Amine metabolites in human cerebrospinal fluid: effects of cord transaction and spinal fluid block. Science 179:897, 1973 100. West KA, Roos BE: The ventricular fluid pressure and the concentration of homovanillic acid in different parts of the cerebrospinal fluid system in patients with Parkinson's disease. Confin Neurol 34:136, 1972 101. Chase TN, Ng LKY: Central monoamine metabolism in Parkinson's disease. Arch of Neurol 27:486, 1972 102. Gerbode FA, Bowers MB: Measurement of acid monoamine metabolites in human a'hd animal cerebrospinal fluid. J Neurochem ~5:1053, 1968 103. KorfJ, VanPraag HM: Amine metabolism in the human brain: Further evaluation of the probenecid test. Brain Res 35:221, 1971 104. Post RM, Kotin J, Goodwin FK, Gordon EK: Psychomotor activity and cerebrospinal fluid amine metabolites in affective illness. Am J Psychiatry 130:67, 1973 105. Bliss EL, Ailion J: Relationship of stress and activity to brain dopamine and homovanillic acid. Life Sci 10:1161, 1971 106. Papeschi R, Molina-Negro P, Sourkes TL, Erba G: The concentration of homovanillic and 5-hydroxyindoleacetic acids in ventricular and lumbar CSF. Neurology 22:1151, 1972 107. Sonninen V, Riekkinen P, Rinne UK: Acid monoamine metabolites in cerebrospinal fluid in multiple sclerosis. Neurology 23:760, 1973 108. Hingerty D, O'Boyle A: Tumours of the adrenal medulla (pheochromocytoma) and related tumours, in Kugelmass IN (ed): Clinical Chemistry of the Adrenal Medulla. Springfield, Ill., Thomas, 1972, p 37 109. Weil-Malherbe H: The concentration of adrenaline in human plasma and its relation to mental activity. J Mental Sei 101:733, 1955 110. Nadler HL, Hsia DY: Epinephrine metabolism in phenylketonuria. Proc Soc Exp Biol 107:721, 1961 111. Cession-Fossion A, Vandermeulen R, Dodinval P, Chantraine JM: Elimination urinaire de l'adrenaline de la noradrinaline, et de

683

l'acide VMA chez enfants oligophrenes phenylpyruviques. Pathol Biol 14:1157, 1966 112. Curtius H, Baerlocker K, Vollmin JA: Pathogenesis of phenylketonuria: Inhibition of dopa and catecholamine synthesis in patients with phenylketonuria. Clin Chim Acta 42:235, 1972 113. McKean CM: The effects of high phenylalanme concentrations on serotonin and catecholamine metabolism in the human brain. Brain Res 47:469, 1972 114. Hartman W J, Akawie RI, Clark W: Competitive inhibition of 3,4-dihydroxyphenylalanine (DOPA)decarboxylase in vitro. J Biol Chem 216:507, 1955 115. Fellman JH: Inhibition of DOPA decarboxylase-by aromatic acids associated with phenylpyruvic oligophrenia. Proc Soc Exp Biol Med 93:413, 1956 1i6. Levitt M, Spector S, Sjoerdsma A, Udenfriend S: Elucidation of the rate limiting step in norepinephrine biosynthesis in the perfused guinea pig heart. J Pharmacol Exp Ther 148:1, 1965 117. Lovenberg WH, Weissbach H, Udenfriend S: Aromatic L amino acid decarboxylasc. J Biol Chem 237:89, 1972 118. Pletscher A, Gey KF: The effect of a new decarboxylase inhibitor on endogenous and exogenous monoamines. Biochem Pharm 12:223, 1968 119. Edwards DJ, Blau K: Aromatic acids derived from phenylalanine in the tissues of rats with experimentally induced pfienylketonuria-like characteristics. Biochem J 130:495, 1972 120. Goldstein FB: Biochemical studies on phenylketonuria. J Biol Chem 236:2656, 1961 121. Ikeda M, Levitt M, Udenfriend S: Hydroxylation ofphenylalanine by purified preparations of adrenal and brain tyrosine hydroxylase. Biochem Biophys Res Commun 18:482, 1965 122. Bagchi SP, Zarycki EP: Formation of catecholamines from phenylalamine in brain effects of chlorpromazine and catron. Biochem Pharmacol 22:1353, 1973 123. Bagchi SP, Zarycki EP: Hydroxylation of phenylalanine by various areas of brain in vitro. Biochem Pharmacol 21:584, 1972 124. Karobath M, Baldessarini R J: Formation of catechol compounds from phenylalanine and tyrosine with isolated nerve endings. Nature (New Biol) 236:206, 1972 125. Shiman R, Akino M, Kaufman S: Solubilization and partial purification of tyrosine

684

hydroxylase from bovine adrenal medulla. J Biol Chem 246:1330, 1971 126. Riley CM, Day RL, Greeley DM, Longford WS: Central autonomic dysfunction with defective lacrimation: Report of five cases. Pediatrics 3~468, 1949 127. Riley CM: Familial dysautonomia. Adv Pediatr 9:157, 1957 128. Brunt PW, Mcresick VA: Familial dysa u t o n o m i a - - a report of genetic and clinical studies, with a review of the literature. Medicine (Baltimore) 49:343, 1970 129. Smith AA, Dancis Ji Catecholamine release in familial dysautonomia. N Engl J Med 277:61, 1967 130. Smith A~; Taylo/ T, Wortis SB: Abnormal catechoiamine metabolism in familial dysaut0ri6mia. N Engl J Med 268:705, 1963 131. Geltzer AI, Gluck L, Talner NS, Polesky HF: Familial dysautonomia studies in a newborn infant. N Engl J Med 271:436, 1964 132. Westlake RJ, Kopin IJ, Gordon EK: Catecholamine metabolite excretion by patients with familial dysautonomia and their mothers. Clin Res 13:336, 1965 133. Goodall J, Shine~ourne E, Lake BD: Early diagnosis of familial dysautonomia. Case report with special reference to primary pathophysiological findings. Arch Dis Child 43:455, 1968 134. Greer M, Williams CM: The sympathetic neurohormones in pheochromocytoma, neuroblastoma and dysautonomia. Trans Amer Neurol Ass 88:223, 1963 135. Gitlow SE, Bertani LM, Wilk E, Li BL, Dziedzic S: Excretion of catecholamine metabolites by children with familial dysautonomia. Pediatrics 46:513, 1970 136. Goodall McC, Gitlow SE, Alton H: Decreased noradrenalin (norepinephrine) synthesis in familial dysautonomia. J Clin Invest 50: 2734, 1971 137. Weinshilboum RM, Axelrod J: Serum dopamine B-hydroxylase: decrease after chemical sympathectomy. Science 173:931, 1971 138. Weinshilboum RM, Axelrod J: Reduced plasma dopamine B-hydroxylase activity in familial dysautonomia. N Engl J Med 285:937, 1971 139. Freedman LS, Ohuchi T, Goldstein M, Axelrod F, Fish I, Dancis J: Changes in human serum dopamine B-hydroxylase activity with age. Nature (Lond) 236:310, 1972 140. Weinshilboum RA, Raymond FA, Elveback LR, Weidman WH: Serum dopamine Bhydroxylase: sibling--sibling correlation. Science 181:943, 1973

ROBERT HOELDTKE

141. Kopin IJ, Weise VK: Effect of reserpi.t~e and metaraminol on excretion of homovanillic acid and 3-methoxy-4-hydroxyphenyl glycol in the rat. Biochem Pharmacol 17:1461, 1968 142. Iversen LL: Catecholamine uptake processes. Br Med Bull 29:130, 1973 143. Daughaday WH: The adenohypophysis, in Williams RH (ed): Textbook of Endocrinology. Philadelphia, Saunders, 1968, p 64 144. Roth J, Glick SM, Yalow RS, Berson SA: Hypoglycemia: a potent stimulus to secretion of growth hormone. Science 140:987, 1963 145. Cambell J, Davidson 1, Snair WD, Lei HP: Diabetogenic effects of purified growth hormone. Endocrinology 46:273, 1950 146. Green WL, Ingbar SH: Decreased corticotropin reserve as isolated pituitary defect. Arch Intern Med 180:945, 1961 147. Thorn GW, Emerson K, Doepf GF, Lewis RA, Olsen EF: Carbohydrate metabolism in Addison's disease. J Clin Invest 19:813, 1940 148. Luft R, Von Euler US: Urinary excretion Of catecholamines during insulin hypoglycemia in five patients with Addison's disease and in one patient after bilateral adrenalectomy. Acta Endocrinol 26:96, 1957 149. Luft R, Euler USV: Effect of insulin hypoglycemia on urinary excretion of adrenalin and noradrenalin in man after hypophysectomy. J Clin Endocrinol Metal~ t6:1017, 1956 150. Wurtman R J, Axelrod J: Adrenalin synthesis: cOntrol by the pituitary gland and adrenal glucocorticoids. Science 150:1464, 1965 151. Wurtman R J, Axelrod J: (~ontrol of enzymatic synthesis of adrenalin m the adrenal medulla by adrenal cortical steroids. J Biol Chem 241:2301, 1966 152. Pohorecky LA, Wurtman RJ: Adrenocortical control of epinephrine synthesis. Pharmacol Rev 23:1, 1971 153. Wurtman RJ, Pohorecky LA, Baliga BS: Adrenocortical control of the biosynthesis of epinephrine and proteins in the adrenal medulla. Pharmacol Rev 24:411, 1972 154. Mueller RA, Thoenen H, Axelrod J: Effect of pituitary and ACTH on the maintenance of basal tyrosine hydroxylase activity in the rat adrenal gland. Endocrinology 86:751, 1970 155. Weinshilboum R, Axelrod J: Dopamine B-hydroxylase activity in the rat after hypophysectomy. Endocrinology 87:894, 1970 156. Wurtman R J, Casper A, Pohorecky LA, Barrier FC: Impaired secretion of epinephrine in response to insulin among hypophysectomized dogs. Proc Natl Acad Sci USA 61:552, 1968

CATECHOLAMINE METABOLISM IN HEALTH AND DISEASE

157. de G. Moyano MB, Hauger-Klevene JH, Soto R J, Bergada C: Effects of hypopituitarism and ACTH on the urinary excretion of norepinephrine in man. J Clin Endocrinol Metab 37:1, 1973 158. Hung W, Migeon CJ: Hypoglycemia in a two-year old boy with adrenocorticotropic hormone (ACTH) deficiency (probably isolated), and adrenal medullary unresponsiveness to insulin induced hypoglycemia. J Clin Endocrinol Metab 28:146, 1968 159. Silberg S, Noble EP: Corticosteroids in psychiatric patients: subacute and diurnal effects on free fatty acid and catecholamine metabolism. J Psychiatry Res 10:59, 1973 160. Hauger-Klevene JH, Moyano MB: ACTH-induced alterations in catecholamine metabolism in man. J Clin Endocrinol Metab 36:679, 1973 161. Landsberg L, de Champlain J, Axelrod J: Increased biosynthesis of cardiac norepinephrine after hypophysectomy. J Pharinacol Exp Ther 165:102, 1969 162. Christensen N J: Plasma catecholamines in long-term diabetes with and without neuropathy in hypophysectomized subjects. J Clin Invest 51:779, 1972 163. de Champlain J, Mueller R, Axelrod J: Turnover and synthesis of norepinephrine in experimental hypertension in rats. Circ Res 25:285, 1969 164. Henning M: Noradrenalin turnover in renal hypertensive rats. J Pharm Pharmacol 21: 61, 1969 165. DeOuattro V, Nagatsu T, Maronde R, Alexander N: Catecholamine synthesis in rabbits with neurogenic hypertension. Circ Res 24: 545, 1969 166. Chalmers JP, Wurtman R J: Participation of central noradrenergic neurons in arterial baroreceptor reflexes in the rabbit. Circ Res 28:480, 1961 167. Willard PW, Fuller RW: Functional significance of the sympathetic nervous system in production of hypertension. Nature (Lond) 223: 417, 1969 168. de Champlain J, Van Ameringen MR: Regulation of blood pressure by sympathetic nerve fibers and adrenal medulla in normotensive and hypertensive rats. Circ Res 31:617, 1972 169. Grewal RS, Kaul CL: Importance of the sympathetic nervous system in the development of renal hypertension in the rat. Br J Pharmacol 42:497, 1971 170. Laverty R: The mechanisms of action of

685

some antihypertensive drugs. Br Med Bull 29: 152, 1973 171. Euler USv, Hellner S, Purkhold A: Excretion of noradrenalin in urine in hypertension. Scand J Lab Clin Invest 6:54, 1954 172. Stott AW, Robinson R: Urinary normetadrenalin excretion in essential hyperten, sion. Clin Chim Acta 16:249, 1967 173. Nestel PJ, Esler MD: Patterns of catecholamine excretion in urine in hypertension. Circ Res 26 (Supp II):75, 1970 174. Brunes S: Catecholamine metabolism in essential hypertension. N Engl J Med 271:120, 1964

175. Wolf RL, Mendlowitz M, Roboz J, Gitlow SE: Simultaneous urinary assays for the combined metanephrines and 3-methoxy-4hydroxyphenylglycol in patients with pheochromocytoma and primary hypertension. N Engl J Med 273:1459, 1965 176. De Ouattro V: Evaluation of increased norepinephrine excretion in hypertension using L-DOPA-3H. Circ Res 28:84, 1971 177. Esler MD, Nestel PJ: Sympathetic responsiveness to head-up tilt in essential hypertension. Clin Sci 44:213, 1973 178. Ikoma T: Studies on catechols with reference to hypertension. Japan Circulation J 29:1269, 1965 179. Nestel P J: Blood pressure and catecholamine excretion after mental stress in labile hypertension. Lancet 692, 1969 180. Imai K, Wang M, Yoshiue S, Tamura Z: Determination of catecholamines in the plasma of patients with essential hypertension and of normal persons. Clin Chim Acta 43:145, 1973 181. Engelman K, Portnoy B, Sjoerdsma A: Plasma catecholamine concentrations in patients with hypertension. Circ Res 25 (Suppl I): 141, 1970 182. DeOuattro V, Chart S: Raised plasma catecholamines in some patients with primary hypertension. Lancet 1:806, 1972 183. Louis WJ, Doyle AE, Anavekar S: Plasma norepinephrine levels in essential hypertension. N Engl J Med 288:599, 1973 184. Vander A: Effect of catecholamines and the renal nerves on renin secretion in anesthetized dogs. Am J Physio1209:659, 1965 185. Vander AJ: Control of rennin release. Physiol Rev 47:359, 1967 186. Wirier N, Chokski DS, Walkenhorst WG: Effects of cyclic AMP, sympathomimetic amines, and adrenergic receptor antogonists on renin secretion. Circ Res 29:239, 1971 187. Otsuka K, Assaykeen TA, Goldfien A,

686

Ganong W: Effect of hypoglycemia on plasma renin activity in dogs. Endocrinology 87:1306, 1970 188. Harrison TS, Birbari A, Seaton J: Malignant hypertension in pheochromocytoma: correlation with plasma renin activity. Johns Hopkins Med J 130:329, 1972 189. Vandougen R, Peart WS, Boyd GW: Adrenergic stimulation of renin secretion in the isolated perfused rat kidney. Circ Res 32: 290, 1973 190. Michelakis AN, Caudle J, Liddle GW: In vivo stimulation of renin production by epinephrine, norepinephrine and cyclic AMP. Proc Soc Exp Biol Meal 130:748, 1969 191. Birbari A: Effect of sympathetic nervous system on renin release. Am J Physiol 220:16, 1971 192. Cuche JL, Kuchel O, Barbeau A, Boucher R, Genest J: Relationship between .the adrenergic nervous system and renin during adaptation to upright posture: a possible role for 3,4-dihydroxyphenylethylamine. Clin Sci 43: 481, 1972 193. Kotchen TA, Hartley LH, Rice TW, Mougey EH, Jones LG, Vasson JW: Renin, norepinephrine, and epinephrine responses to graded exercise. J Appl Physiol 31:178, 1971 194. Gordon RD, Kuchel O, Liddle G, Island D: Role of symphatietic nervous system in regulating renin and aldosterone production in man. J Clin Invest 46:599, 1967 195. Kaneko Y, Takeda T, Ikeda T, Tagawa H, Ishii M, Takabatake Y, Ueda H: Effect of ganglionic blocking agents on renin release in hypertensive patients. Circ Res 27:97, 1970 196. Stein JH, Ferris TF: The physiology of renin. Arch Intern Med 131:860, 1973 197. Davis JO: The control of renin release. Am J Med 55:333, 1973 198. Taquini AC, Blaquier P, Taguini AC: On the production and role of renin. Can Med Ass J 90:210, 1964 199. Blaine EH, Davis JO, Prewitt RL: Evidence for a renal vascular receptor in control of renin secretion. Am J Physiol 220:1593, 1971 200. Reid I, Schrier R, Earley L: An effect of extrarenal beta adrenergic stimulation on the release of renin. J Clin Invest 51:1861, 1972 201. Molzahn M, Dissmann T, Halim S, Lohmnann FW, Oelkers W; Orthostatic changes of haemodynamics, renal function, plasma catecholamines, and plasma renin concentration in normal and hypertensive man. Clin Sci 42:209, 1972

ROBERT HOELDTKE

202. Winer N, Chokski DS, Yoon MS, Freedman AD: Adrenergic receptor medication of renin secretion. J Clin Endocrinol Metab 29: 1168, 1969 203. Goodall McC, Harlan WR, Alton H: Noradrenalin release and metabolism in orthostatic (postural) hypotension. Circulation 36:489. 1967 204. Slaton PE, Biglieri EG: Reduced aldosterone excretion in patients with autonomic insufficiency. J Clin Endocrinol Metab 27:37. 1967 205. Bozovic L, Castenfors J, Oro L: Plasma renin activity in patients with disturbed sympathetic vasomotor .control (postural hypotension). Acta Med Scand 188:385, 1970 206. Love PR, Brown J J, Chinn RH, Johnson RH, Lever AF, Park PM, Robertson J1S: Plasma renin in idiopathic orthostatic hypotension: differential responses in subjects with probable afferent and efferent autonomic failure. Clin Sci 41:289, 1971 207. Vander AJ, Luciano JR; Neural and humoral control of renin release in salt depletion. Circ Res 21(Supp 1I):69, 1967 208. Brubacker ES, Vander A J: Sodium deprivation and renin secretion in unanesthetized dogs. Am J Physiol 214:15, 1968 209. Mogil RA, Itskovitz HD, Russel JH, Murphy J J: Renal innervation and renin activity in salt metabolism and hypertension. Am J Physio1216:693, 1969 210. Garcia AG, Kirpekar SM; Release of noradrenaline from the cat spleen by sodium deprivation. Br J Pharmacol 47:729, 1973 211. Kirpekar SM, Wakade AR: Release of noradrenaline from the cat spleen by potassium. J Physiol (Lond) 194:595, 1958 212. Seria Y: A clinical study of the role of catecholamine in blood pressure regulation. Jap Circ J 29:433, 1965 213. Collins RD, Weinberger M, Gonzales C, Hokes G, Luetscher JA: Catecholamine excretion in low renin hypertension. Clin Res 18:167, 1970 214. Jose A, Crout RJ, Kaplan NM: Suppressed plasma renin activity in essential hypertension. Ann Int Med 72:9, 1970 215. Kelsch RC, Light GS, Luciano JR, Oliver W J, Vadnay L: The effect of prednisone on plasma norepinephrine concentration and renin activity in salt depleted man. J Lab Clin Med 77:267, 1971 216. Crane MG, Harris JJ, Johns VJ: Hyporeninemic hypertension. Am J Med 52:457, 1972.