T Fujita, K Ando, H Noda, Y Ito and Y Satoborderline hypertension.

Effects of increased adrenomedullary activity and taurine in young patients with

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 1987 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation doi: 10.1161/01.CIR.75.3.525

1987;75:525-532Circulation. 

http://circ.ahajournals.org/content/75/3/525the World Wide Web at:

The online version of this article, along with updated information and services, is located on

  http://circ.ahajournals.org//subscriptions/

is online at: Circulation Information about subscribing to Subscriptions: 

http://www.lww.com/reprints Information about reprints can be found online at: Reprints:

  document. Permissions and Rights Question and Answer information about this process is available in the

located, click Request Permissions in the middle column of the Web page under Services. FurtherEditorial Office. Once the online version of the published article for which permission is being requested is

can be obtained via RightsLink, a service of the Copyright Clearance Center, not theCirculationpublished in Requests for permissions to reproduce figures, tables, or portions of articles originallyPermissions:

at University of Washington on May 1, 2014http://circ.ahajournals.org/Downloaded from at University of Washington on May 1, 2014http://circ.ahajournals.org/Downloaded from

CLINICAL INVESTIGATION

Effects of increased adrenomedullary activity andtaurine in young patients with borderlinehypertensionToSHIRO FUJITA, M.D., KATSUYUKi ANDO, M.D., HIROSHi NODA, M.D., YASUSHI ITO, M.D., ANDYUJI SATO, PH.D.

ABSTRACT Recent studies showed that taurine, a sulphonic amino acid, could decrease bloodpressure and increase sympathoadrenal tone in DoCA-salt-treated hypertensive rats. To determinewhether taurine exerts its antihypertensive action in man in a similar fashion, we studied the effect oforal administration of taurine (6 g for 7 days) on blood pressure and plasma catecholamines in 19 youngpatients with borderline hypertension in a double-blind, placebo-controlled fashion. Systolic bloodpressure in the 10 patients who were treated with taurine decreased by 9.0 ± 2.9 mm Hg (mean ± SE;p < .05 by paired t test), compared with a 2.7 + 2.3 mm Hg decrease (NS) in the nine patients treatedwith placebo and diastolic blood pressure in the taurine-treated patients decreased by 4.1 + 1.7 mm Hg(p < .05) compared with 1.2 ± 3.0 mm Hg (NS) in the placebo-treated subjects. In the patientsreceiving taurine plasma epinephrine (E) decreased significantly, with a negligible decrease in plasmanorepinephrine (NE). The effect of taurine on plasma catecholamines and the response of plasma Eafter the stimulation with glucagon was also studied in 12 borderline hypertensive and nine age-matched normotensive subjects. Basal plasma E was significantly higher in borderline hypertensivethan in normal subjects, but basal plasma NE did not differ in the two groups. The intravenous bolusinjection of glucagon (1 mg) caused a rapid and transient increase in plasma E in each subject studied;plasma E reached a peak concentration 2 to 5 min after the injection of glucagon and thereafter declinedrapidly to the baseline level. The overall response of plasma E to glucagon stimulation was significantly(p < .01) greater in the borderline hypertensive than in the normotensive subjects. Taurine not onlyreduced mean blood pressure and basal plasma E, but also attenuated the increased response toglucagon in the borderline hypertensive subjects. In the normotensive subjects, however, the adminis-tration of taurine did not significantly change blood pressure, basal plasma catecholamines, or theresponse of plasma E to glucagon. Overall, there was a direct correlation (r = .670, p < .01) betweenthe decrements in mean blood pressure and those in plasma E after taurine in the 22 borderlinehypertensive subjects. Evidence presented suggests, therefore, that sympathoadrenal tone is increasedin young borderline hypertensive individuals, and that oral administration of taurine attenuates in-creased tone, leading to the reduction of blood pressure.Circulation 75, No. 3, 525-532, 1987.

YOUNG PATIENTS with borderline hypertension areat least three times more likely to develop establishedessential hypertension than age-matched normotensivesubjects.1'2 Thus, young patients with borderline hy-pertension have been of particular interest to investiga-tors because they may provide insight into the patho-genesis of essential hypertension. The majority ofstudies have reported increased average circulatingnorepinephrine levels in borderline hypertensive sub-

From the Department of Internal Medicine, Institute of ClinicalMedicine, University of Tsukuba, Ibaraki, Japan.

Address for correspondence: Dr. Toshiro Fujita, Department of Inter-nal Medicine, Institute of Clinical Medicine, University of Tsukuba,Ibaraki 305, Japan.

Received Feb. 11, 1986; revision accepted Oct. 23, 1986.

Vol. 75, No. 3, March 1987

jects,5 and more recently some studies have reportedhigher epinephrine levels in borderline or mildly hy-pertensive patients.` An increase in plasma norepi-nephrine reflects increased sympathetic activity,whereas an increase in plasma epinephrine is likely toreflect an adrenal hyperactivity. Several investigatorshave demonstrated that in patients with borderline hy-pertension there is an increased response of plasmacatecholamines to mental stress8 9 or orthostatic tilt-ing, 10 suggesting a net increase in the sympathoadrenaltone.11 These observations led us to the hypothesis thatnot only increased sympathetic activity but also adre-nomedullary hyperactivity may be involved in the de-velopment of essential hypertension. To assess the

525 at University of Washington on May 1, 2014http://circ.ahajournals.org/Downloaded from

FUJITA et al.

adrenomedullary activity in young patients with bor-derline hypertension, we therefore examined the re-sponse of plasma epinephrine after stimulation by theinjection of glucagon in young borderline hypertensiveand age-matched normotensive subjects.

Recently, there has been increased concern withascertaining the importance of nutrients in the regula-tion of blood pressure and the pathogenesis of hyper-tension. Since the majority of patients with elevatedblood pressure fall in the borderline and mildly hyper-tensive categories1` 2 there is a need to do research onnonpharmacologic strategies for management of thesepatients. It is well known that dietary nutrients such assodium, potassium, and calcium influence blood pres-sure.'3 15 Moreover, several investigators have sug-gested that dietary protein and amino acids could alsoinfluence blood pressure and thus affect developmentof hypertension.` ` Recently emphasis has been fo-cused on the relationship between taurine, a sulphonicamino acid, and cardiovascular disease.`8 Our recentstudies have indicated that supplementation of the dietwith taurine could attenuate the development ofDoCA-salt-induced hypertension in rats, possibly bythe suppression of increased sympathetic activity.1921Moreover, previous studies have demonstrated that theadministration of taurine in vitro not only suppressesthe high potassium-evoked release of norepinephrinefrom a variety of neuronal tissues,22 23 but also inhibitsthe stress-induced release of epinephrine from adrenalchromaffin granules.24 In contrast, neither methioninenor leucine (sulfur-containing amino acids metaboli-cally related to taurine) have been shown to have anypreventive effect on the release of epinephrine, sug-gesting that taurine has a specific preventive effect onstress-induced release of epinephrine in the adrenalgland.24To determine whether taurine is an efficacious

therapeutic modality in young patients with borderlinehypertension who are at risk for the development ofestablished hypertension, we studied the effect of theoral administration of taurine on blood pressure inyoung borderline hypertensive subjects in a double-blind, placebo-controlled fashion. To clarify the roleof sympathoadrenal function in the antihypertensiveaction of taurine, we also studied the effect of oraltaurine on the glucagon-induced release of epinephrinefrom adrenal glands in our young subjects with border-line hypertension.

MethodsForty male subjects (31 with borderline hypertension and

nine age-matched normotensive subjects) were included in this

study. Each subject underwent a physical examination and gavea medical history. Laboratory results, including those of urinal-ysis, tests for levels of serum electrolytes, creatinine, plasmarenin activity (PRA), and aldosterone, and results of electrocar-diographic examination were normal. Thus, there was no evi-dence of a known cause of hypertension in any of the subjects.Most had never been treated and in those few who had, antihy-pertensive drugs had been discontinued at least 2 months beforethe study. No patient was older than 25 years of age, and nonehad electrocardiographic or radiographic evidence of left ven-tricular hypertrophy, hypertensive retinopathy, or renal in-volvement. Each subject was informed of the nature of the studyand gave written consent. Patients were considered to haveborderline hypertension if, on examination in the outpatientdepartment, their diastolic pressures at times exceeded but atother times were lower than 90 mm Hg. l 5Subjects brought twocomplete 24 hr urine samples to each visit throughout the trialand sodium, creatinine, and taurine levels were determined ineach sample. Body weight was recorded at each visit. Whenpatients were supine, subjectively relaxed, and had a stablepulse rate, blood pressure was measured by sphygmomanom-eter.

Protocol 1. The subjects were studied on an outpatient basis.Each subject attended a special research clinic for examinationsat a fixed hour and day of the week. After screening visits. 19patients with borderline hypertension who were 20 to 25 yearsold were admitted to the trial. They were randomly assigned toreceive either taurine or placebo, 6 g/day, for 7 days. For eachtest procedure the subject was supine and had an indwellingcatheter inserted in an arm vein. At least 30 min after insertionof the indwelling catheter, but not before the patient was subjec-tively relaxed and had a stable pulse rate, blood for the determi-nation of catecholamines was drawn. This procedure was re-peated in each patient before and after treatment with taurine orplacebo.

Protocol 2. After screening visits, 12 patients with borderlinehypertension and nine normal subjects were admitted to thetrial. An indwelling catheter was placed in the antecubital veinthrough which isotonic solution was slowly infused at a rate of1.0 ml/min while subjects were kept at rest in a supine position.This catheter was also used for blood sampling and the injectionof glucagon. Blood pressure and pulse rate were measured seri-ally by an automated sphygmomanometer (Dinamap 845XT,Critikon, FL) every 1 min. After a 30 min observation period,blood was drawn for the measurement of plasma catechola-mines, PRA, aldosterone concentration, and taurine concentra-tion, and then 1.0 mg of glucagon (Novo Industri A/S, Copen-hagen, Denmark) was injected intravenously as a bolus. Theblood pressure and pulse rate were then measured at 1 minintervals, and blood specimens for determination of plasmacatecholamines were obtained at 1, 2, 3, 5, and 10 min after theinjection of glucagon. The same procedure was repeated aftertaurine was administered in an oral dose of 6 g/day for 7 days.

Laboratory procedures. Adequacy of urine collection waschecked by daily creatinine determinations. Sodium and potas-sium concentrations in the urine were determined by flamephotometry, with the use of lithium as an internal standard.Circulating norepinephrine and epinephrine were determined bythe radioenzymatic method,25 as previously reported.26 PRAand plasma aldosterone concentration were measured by ra-dioimmunoassay as previously reported.27 For the measurementof serum and urinary taurine concentrations, serum and 24 hrurine samples were deproteinized with sulfosalicylic acid andthe deproteinized samples were analyzed on a Durrum D-500amino acid analyzer.21

Statistical analysis. Values are expressed as the mean + SE.A paired t test was used for analysis of data before and after the

CIRCULATION526 at University of Washington on May 1, 2014http://circ.ahajournals.org/Downloaded from

PATHOPHYSIOLOGY AND NATURAL HISTORY-HYPERTENSION

TABLE 1Responses of systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MBP), plasmanorepinephrine (PNE), and plasma epinephrine (PE) to 1 week of treatment with taurine

Taurine (n = 10) Placebo (n = 9)

Before After Before After

SBP (mm Hg) 147.9 ± 6.3 139.0±4.7A 146.4±4.0 143.7 ± 2.7Decrease in SBP (mm Hg) 9.0± 2.9 2.7± 2.3DBP (mm Hg) 77.9±2.4 73.8±2.3A 79.0± 1.8 77.9±2.7Decrease in DBP (mm Hg) 4.1± 1.7 1.2± 3.0MBP (mm Hg) 101.3 ±2.1 95.6± 1.7A 101.5 ± 1.5 99.8 ± 2.0Decrease in MBP (mm Hg) 5.7± 1.8 1.7 ± 2.0PNE (pg/ml) 245.8± 18.6 223.5±21.5 221.3±22.1 202.0+27.7Decrease in PNE (pg/ml) 2.3 ± 24.3 10.3 ± 22.3PE (pg/ml) 65.3±6.3 50.7±4.2A 65.3±5.7 64.6±4.0BDecrease in PE (pg/ml) 14.6±4.7 1.9±4.2

Values are mean ± SE.Ap < .05 (vs before taurine, by paired t test).Bp < .05 (vs after taurine, by unpaired t test).

administration of taurine. Comparison of results in the border-line hypertensive and normotensive subjects was by the un-paired t test. Total epinephrine release after stimulation withglucagon was determined by calculating the areas under theplasma concentration curves between 0 and 10 min. The areasunder the curves were compared by paired or unpaired t test.Data on responses of blood pressure, heart rate, and plasmaepinephrine and norepinephrine to glucagon were analyzed byanalysis of variance and the Bonferroni method for multiplecomparisons.2? Statistical significance was defined as p < .05.

ResultsStudy 1. Table 1 shows the changes in blood pressure

and plasma catecholamines after taurine in 19 youngpatients with borderline hypertension studied in a dou-ble-blind, placebo-controlled fashion. Systolic anddiastolic blood pressure fell in the treatment group by9.0 + 2.9 and 4.1 ± 1.7 mm Hg, respectively, whileblood pressure in the control group decreased by 2.7± 2.3/1.2 ± 3.0 mm Hg. Mean blood pressure de-creased by 5.7 ± 1.8 mm Hg in taurine recipients (p <.05 by paired t test) compared with a decrease of 1.7 ±2.0 mm Hg in placebo recipients (NS). In the 10 sub-jects receiving taurine, plasma epinephrine also sig-nificantly (p < .01) decreased (from 65.3 ± 6.3 to50.7 + 4.2 pg/ml), but plasma norepinephrine did notchange (from 245.8 ± 18.6 to 223.5 ± 21.5 pg/ml,NS). In the nine subjects receiving placebo, neitherplasma epinephrine nor norepinephrine changed sig-nificantly (65.3 ± 5.7 to 64.6 + 4.0 pg/ml and 221.3± 22.1 to 202.0 ± 27.7 pg/ml, respectively). Thus,the average plasma concentration of epinephrine aftertaurine was significantly lower than that after placebo(50.7 + 4.2 vs 64.6 + 4.0 pg/ml, p < .05 by unpairedt test).

Study 2. Table 2 summarizes clinical and laboratory

findings in borderline hypertensive patients and age-matched normal subjects before and after the adminis-tration of taurine. There were no significant differ-ences with respect to age or body weight in the groups.In borderline hypertensive patients there was a signifi-cant increase in mean blood pressure as compared withthat in the normotensive subjects. There were no sig-nificant differences in plasma creatinine, sodium, orpotassium levels in the borderline hypertensive and thenormotensive subjects. Plasma epinephrine was sig-nificantly (p < .05) increased in the borderline hyper-tensive as compared with the normotensive subjects(62.6 ± 9.0 vs 41.0 + 5.4 pg/ml), although therewere no significant differences in PRA, plasma aldo-sterone, or plasma norepinephrine in the two groups.There were also no significant differences in plasmataurine concentration or in urinary taurine excretion inthe two groups. During the administration of taurine,both plasma and urinary taurine increased equally inboth groups. More than 90% of daily taurine intakewas excreted in the urine, indicating good compliancewith therapy.With the administration of taurine, mean blood pres-

sure was significantly (p < .05) decreased from 101.0± 2.1 to 93.6 + 2.4 mm Hg in the borderline hyper-tensive patients but it did not decrease significantly inthe normal subjects (87.3 ± 2.0 to 83.5 ± 1.9 mmHg, NS). With taurine, plasma epinephrine was sig-nificantly (p < .05) decreased (from 62.6 ± 9.0 to45.8 ± 7.3 pg/ml) to a level similar to that in normo-tensive subjects (41.0 + 5.4 pg/ml). However, in thenormotensive subjects taurine did not significantlychange plasma epinephrine (41.0 ± 5.4 to 35.3 + 3.8pg/ml, NS). Thus, the mean decrements in mean blood

Vol. 75, No. 3, March 1987 527 at University of Washington on May 1, 2014http://circ.ahajournals.org/Downloaded from

FUJITA et al.

TABLE 2Clinical and laboratory findings in the borderline hypertensive (BHT) and normotensive (NT) subjects before and afterthe administration of taurine

BHT NT

Before taurine After taurine Before taurine After taurine

Number 12 9Age (years) 22 2 21 2Body weight (kg) 67.6 1.7 67.9 +1.9 67.2 + 1.9 67.3 1.9Heart rate (beat/min) 70+2 68+2 67+2 65+2Mean blood pressure (mm Hg) 101.0 2.1 93.6 2.4A 87.3 ± 2.OB 83.5 1.9Plasma sodium (meq/l) 138.2 +0.5 138.0 0.6 137.4 ± 0.5 136.8 0. 8Plasma potassium (meq/l) 4.0 + 0.1 4.0 0.1 3.9 ± 0.2 4.0 0.2Plasma creatinine (meq/1) 1.0 0.1 1.0 ± 0.1 1.0 ± 0.1 1.0 ± 0.1Urinary sodium (meq/day) 198 10 208+ 15 204±15 198±9Urinary creatinine (g/day) 1.51 0.06 1.56 0.07 1.57 ± 0.07 1.52 ± 0.04PRA (ng/ml/hr) 1.65 0.14 1.85 +0.26 1.86 + 0.20 2.02 + 0.32Plasma aldosterone (pg/ml) 108.5 + 10.3 92.9 9.4 85.9 7.2 86.0 ± 6.7Plasma norepinephrine (pg/ml) 196.0 + 15.7 182.3 14.0 201.9 20.5 188.8 ± 14.1Plasma epinephrine (pg/mI) 62.6 ± 9.0 45.8 7.3A 41.0 5.4B 35.3 ± 3.8Plasma taurine (nmol/ml) 54.8 ± 2.3 275.6 77.9A 45.1+ 3.5 275.6 55.2AUrinary taurine (nmol/day) 1.12 ± 0.12 38.58+ 1.72A 1.03 +0.15 36.28 2.26A

Values are mean + SE.Ap < .05 (vs BHT before taurine or NT before taurine,Bp < .05 (vs BHT before taurine, by unpaired t test).

pressure were -7.4 + 2.8 mm Hg (p < .05) in theborderline hypertensive patients and - 3.8 ± 2.2 mmHg (NS) in the normotensive subjects. Accordingly,the mean decrements from basal plasma epinephrinewere -17.0 + 5.2 pg/ml (p < .05) and - 5.7 ± 4.5pg/ml (NS), respectively, in hypertensive and normo-tensive subjects. There were no significant changes inserum and urinary electrolytes, PRA, plasma aldoste-rone, or plasma norepinephrine with the administra-tion of taurine in either group (table 2).

Overall, there was a significant correlation (r.670, p < .01) between the decrements in mean bloodpressure and those in plasma epinephrine in the 22subjects with borderline hypertension receiving taurine(figure 1).

Figure 2 illustrates the changes in plasma epineph-rine after stimulation with glucagon. Bolus intrave-nous injection of glucagon induced an immediate risein blood pressure, heart rate, and plasma epinephrinein each subject studied. Plasma epinephrine reached apeak concentration 2 to 5 min after the injection ofglucagon and thereafter declined rapidly to reach thebaseline level by 10 min after the injection in bothborderline hypertensive and normotensive subjects.Throughout the experimental period, however, plasmanorepinephrine did not significantly change in eithergroup. There was no apparent difference with respectto timing of the response of plasma epinephrine in theborderline hypertensive and normotensive subjects,

528

by paired t test).

but the response tended to be of greater magnitudeearlier in the borderline hypertensive than in the nor-motensive subjects: the increments in plasma epineph-rine at 2 and 3 min after glucagon were significantlygreater in the borderline hypertensive than normoten-sive subjects (44.0 ± 12.3 vs 5.2 ± 4.5 pg/ml, p <.01, and 68.8 ± 13.2 vs 32.1 ± 8.9 pg/ml, p < .05,

aIl

a PE(pg/ml) a .

.

r=0.670P<O.O 1

FIGURE 1. The relationship between the changes in mean blood pres-sure (AMBP) and those in plasma epinephrine (APE) after 1 week ofthe treatment with taurine in 22 patients with borderline hypertension.There was a good correlation between the two variables (y - 0.595x +1.985, r = .670, p < .01).

CIRCULATION

.

at University of Washington on May 1, 2014http://circ.ahajournals.org/Downloaded from

PATHOPHYSIOLOGY AND NATURAL HISTORY-HYPERTENSION

FIGURE 2. The responses of mean blood pressure(meah BP), heart rate (HIR), plasma norepinephrine(NE), and plasma epinephrine (E) to the injection ofglucagon in borderline hypertensive patients before(0) and after (0) the administration of taurine, and inthe normotensive subjects before (O) and after (") theadministration of taurine. *p < .05 and *p < .01 forcomparison of time-matched data (0) from the bor-derline hypertensive subjects before taurine (by anal-ysis of variance and Bonferroni method for multiplecomparisons).

respectively). When the areas under the plasma con-

centration curves were analyzed, the mean area afterthe injection of glucagon was 328 ± 43 pg-min/ml forthe hypertensive subjects, which was significantly (p< .05 by unpaired t test) greater than 175 + 45pg.minIml for normal subjects. However, there were

no significant differences in the changes of mean bloodpressure or heart rate with the injection of glucagon inthe borderline hypertensive and the normotensivesubjects.With the admlnistration of taurine, the respolise of

plasma epinephrine to glucagon was significantly at-tenuated in the borderline hypertensive but not in thenormotensive subjects. The increments in plasma epi-nephrine 2 and 3 min after glucagon were significantlyless in the taurine-treated than the untreated subjectswith hypertension (3.0 + 6.3 vs 44.0 12.3 pg/ml, p< .01, and 26.4 + 4.5 vs 68.8 + 13.2 pg/ml, p <.01, respectively). When the areas under the plasmaconcentration curves were analyzed, the mean area

Vol. 75, No. 3, March 1987

was significantly decreased from 328 43 to 147 +

30 pg minIml (p < .01 by paired t test) after taurinetreatment in young subjects with borderline hyperten-sion. In the normotensive subjects, however, the ad-ministration of taurine did not significantly change theincrements in plasma epinephrine and 3 min afterstimulation with glucagon (2.4 + 3.0 vs 5.2 4.5pg/ml, NS, and 16.9 7.4 vs 32.1 -- 8.9 pg/ml, NS,respectively). Areas under the plasma concentrationcurves also did not change with taurine treatment inthis group of subjects (101 ± 40 vs i75 + 45pg.min/ml, NS). The administration of taurine did notchange the responses of mean blood pressure, heartrate, or plasma norepinephrine to glucagon injection ineither group.

DiscussionOur primary finding, in keeping with previous re-

ports,57 was that plasma epinephrine was increased inyoung patients with borderline hypertension compared

529

m 1 0cm* I

q5,_0g 5.sI.0 0

20cr 1 5

9 8 100 5

o A

WL 30.

C201"coE

E '10 .U), CD

1uQr'I -lo0

1 001r

801EC)

Een

0t9L

601

401

201

0'

i(min)

at University of Washington on May 1, 2014http://circ.ahajournals.org/Downloaded from

FUJITA et al.

with that in the age-matched normotensive subjects.Moreover, our study showed that there was an in-creased response of plasma epinephrine to stimulationwith glucagon in young borderline hypertensive sub-jects as compared with that in normotensive subjects.This finding is consistent with the results of a previousstudy showing that the response of urinary catechola-mines to the intramuscular injection of glucagon wassignificantly increased in young hypertensive patientsbut not in elderly hypertensives. 29 The observations ofincreased levels of plasma epinephrine and an in-creased response of plasma epinephrine to glucagon inyoung subjects with borderline hypertension mightsuggest increased sympathoadrenal tone. Over the past30 years, there has been a growing realization of theimportance of the role of adrenomedullary function inthe development and maintenance of animal and hu-man hypertension.3>32 In DoCA-salt-induced hyper-tension the conversion of radioactive tyrosine into cat-echolamines was found to be increased in the adrenalglands, 0 and the observed amelioration of hyperten-sion resulting from bilateral adrenalectomy indicatesthat increased adrenal catecholamine synthesis mightcontribute to the maintenance of high blood pressure.31Furthermore, a reduction in blood pressure was ob-served in a significant proportion of hypertensive pa-tients undergoing sympathectomy, splanchnictomy,and partial adrenalectomy before oral preparations ofantihypertensive drugs were available . Recently,much evidence has been presented suggesting that ex-cessive release of peripheral catecholamines, especial-ly epinephrine, in response to stressful stimuli mayplay a role in the development of essential hyperten-sion.6' 7 Several recent studies have demonstrated thatin young borderline hypertensive patients there is notonly an increased response of plasma norepinephrinebut also of epinephrine to physical stress such as stand-ing'` or to mental stress such as arithmetic, suggestinga net increase in the sympathoadrenal tone.8'9We performed another study in a double-blind, pla-

cebo-controlled fashion to determine whether oral ad-ministration of taurine would be an efficacious thera-peutic modality in young patients with borderlinehypertension. After 1 week of 6 g/day of taurine orplacebo, blood pressure decreased by an average of 9.0± 2.9/4.1 + 1.7 mm Hg in the taurine-treated group,as compared with a negligible decrease in blood pres-sure in the placebo-treated group. While small, thiseffect of taurine on mean blood pressure (a decrease of5.7 ± 1.8 mm Hg compared with a decrease of 1.7 +

2.0 mm Hg in the control group) may be clinicallysignificant, since Rose33 has pointed out that decreas-

530

ing the mean blood pressure in a large population by aslittle as 3 mm Hg will reduce the number of individualswith mild hypertension, and thus substantially reducethe number of people at excess risk of cardiovascularmorbidity and mortality. Borderline hypertension ap-pears to be an early predictor of future establishedhypertension, and it carries an excess of overall mor-tality and specific cardiovascular morbidity.1 2 Wespeculate, therefore, that high dietary intake of taurinemight be effective protection from the development ofestablished hypertension and the excess risk of cardio-vascular morbidity and mortality. However, in thepresent study the sample size was too small and theobservation period too short to draw any conclusionsabout this issue.

Concomitant with the reduction of blood pressure,plasma epinephrine decreased significantly in the tau-rine-treated group while there was only a negligibledecrease in plasma epinephrine in the placebo group.In another study, oral administration of taurine re-turned increased plasma levels of epinephrine towardnormal in the young borderline hypertensive patients,but did not change it in the normotensive subjects.Overall, there was a significant relationship betweenthe decrements in blood pressure and those in plasmaepinephrine with taurine in 22 young patients withborderline hypertension, suggesting that the antihyper-tensive action of taurine may be attributable to thenormalization of the increased sympathoadrenal tone.This hypothesis is supported by results of a study invitro demonstrating that taurine inhibits the stress-in-duced release of epinephrine from adrenal chromaffingranules 24

In the present study, the oral administration of tau-rine attenuated the increased response of plasma epi-nephrine to stimulation with glucagon in the youngpatients with borderline hypertension when plasmataurine concentration was increased to five times thatat baseline. In contrast, the administration of taurinedid not significantly decrease blood pressure or basalplasma epinephrine concentrations, nor did it changethe response of plasma epinephrine to glucagon in thenormotensive subjects, although the increments inplasma taurine were the same in these subjects as in theborderline hypertensive patients.

Thus, our results suggest that taurine reduces bloodpressure by the normalization of increased sympatho-adrenal tone in the presence of borderline hyperten-sion, but it does not affect adrenomedullary activity orblood pressure in normotensive subjects with normalsympathoadrenal tone. This finding is consistent withthe results of our previous animal studies demonstrat-

CIRCULATION at University of Washington on May 1, 2014http://circ.ahajournals.org/Downloaded from

PATHOPHYSIOLOGY AND NATURAL HISTORY-HYPERTENSION

ing that taurine supplementation attenuates the devel-opment of hypertension by the suppression of in-creased sympathetic activity in DoCA-salt-treatedrats, but does not decrease blood pressure or sympa-thetic activity in vehicle-treated control rats.t2' More-over, this hypothesis is supported by a previous studydemonstrating that the addition of taurine in vitro sig-nificantly attenuates the Ca-dependent, K-evoked re-lease of [3H]-norepinephrine from a variety of neuronaltissues without affecting uptake or unstimulated (spon-taneous) release.22' 23

It has been reported that the epinephrine in chromaf-fin granules of the adrenal medulla is released by themechanism of exocytosis.34' ` It is well known that thestress of administration of glucagon itself stimulatesepinephrine release from adrenal glands.36 37 In theadrenal medulla, calcium plays an important role in".stimulus-secretion coupling" because of its ability toform stable complexes with various constitutes38 andits effects on membrane permeabilities. In this regard,it is of interest that taurine increases calcium content inthe heart mitochondria and the affinity of various cellu-lar components for calcium.39 Moreover, a recentstudy has suggested that taurine inhibits release of cal-cium from mitochondria,4 thus leading to a decreasein availability of intracellular calcium in sympatheticnerve. If these findings are applicable to the adrenalmedulla, the administration of taurine might modulatethe glucagon-induced release of epinephrine from ad-renal medulla, possibly by interacting with retentionmechanisms for calcium within adrenal granules.

In summary, young patients with borderline hyper-tension had significantly higher mean plasma levels ofepinephrine under basal conditions and significantlylarger increments in plasma epinephrine in response toglucagon than did age-matched normotensive controlsubjects. Oral administration of taurine abolishedthese differences. Evidence presented suggests, there-fore, that sympAthoadrenal tone is increased in youngpatients with borderline hypertension and that taurineattenuates this increased tone, leading to a reduction inblood pressure. Thus, taurine may be helpful in themanagement of these patients.

References1. Julius S, Esler M: Autonomic nervous cardiovascular regulation in

borderline hypertension. Am J Cardiol 36: 685, 19752. Frohlich ED, Kozul VJ, Tarazi RC, Dustan HP: Physiological

comparison of labile and essential hypertension. Circ Res26127(suppl I): 55, 1970

3. Cousineau D, DeChamplain J, Lapointe L: Circulating catechola-mines and systolic time intervals in labile and sustained hyperten-sion. Clin Sci Mol Med 55: 65s, 1978

4. Miura Y, Kobayashi K, Sakuma H, Tomioka H, Adachi M, Yo-shinaga K: Plasma noradrenaline concentrations and hemodynam-

Vol. 75, No. 3, March 1987

ics in the early stage of essential hypertension. Clin Sci Mol Med55: 69s, 1978

5. Fujita T, Noda H, Ando K: Sodium susceptibility and potassiumeffects in young patients with borderline hypertension. Circulation69: 468, 1984

6. Franco-Morselli R, Elghozi JL, Joly E, Di Giuiluio S, Meyer P:Increased plasma adrenaline concentrations in benign essential hy-pertension. Br Med J 2: 1251, 1977

7. Horikoshi Y, Tajima I, Igarashi H, Inui M, Kasahara K, NoguchiT: The adreno-sympathetic system, the genetic predisposition tohypertension, and stress. Am J Med Sci 289: 186, 1985

8. Falkner B, Kushner H, Onesti G, Angelakos ET: Cardiovascularcharacteristics in adolescents who develop essential hypertension.Hypertension 3: 521, 1981

9. Light KC, Obrist PA: Cardiovascular reactivity to behavioral stressin young males with and without marginally elevated casual systol-ic pressures. Comparison of clinic, home, and laboratory mea-sures. Hypertension 2: 802, 1980

10. Robertson D, Shand DG, Hollifield JW, Nies AS, Frolich JC,Oates JA: Alterations in the responses of the sympathetic nervoussystem and renin in borderline hypertension. Hypertension 1: 1 18,1979

11. Folkow B: Physiological aspects of primary hypertension. PhysiolRev 62: 347, 1982

12. Horan MJ, Blaustein MP, Dunbar JB, Grundy S, Kachadorian W,Kaplan NM, Kotchen TA, Simopoulos AP, Vanltallie TB: NIHreport on research challenges in nutrition and hypertension. Hyper-tension 7: 818, 1985

13. Fujita T, Sato Y: Changes in renal and central noradrenergic activ-ity with potassium in DOCA-salt rats. Am J Physiol 246: F670,1984

14. Fujita T, Sato Y: Natriuretic and antihypertensive effects of potas-sium in DOCA-salt hypertensive rats. Kidney Int 24: 731, 1983

15. McCarron DA, Morris CD, Cole C: Dietary calcium in humanhypertension. Science 217: 267, 1982

16. Sved AF, Femstrom JD, Wurtman RJ: Tyrosine administrationreduces blood pressure and enhances brain norepinephrine releasein spontaneously hypertensive rats. Proc Natl Acad Sci USA 76:3511, 1979

17. Yamori Y, Horie R, Tanase H, Fujiwara K, Nara Y, Lovenberg W:Possible role of nutritional factors in the incidence of cerebrallesion in stroke-prone spontaneously hypertensive rats. Hyperten-sion 6: 49, 1984

18. Huxtable R, Chubb J, Azari J: Physiological and experimentalregulation of taurine in the heart. Fed Proc 39: 2685, 1980

19. Fujita T, Sato Y: The antihypertensive effect of taurine in DOCA-salt rats. J Hypertension 2: 563, 1985

20. Fujita T, Sato Y: Changes in blood pressure and extracellular fluidassociated with taurine supplement in DOCA-salt rats. Am J Phys-iol 250: R1014, 1986

21. Fujita T, Sato Y, Ando K: Changes in cardiac and hypothalamicnoradrenergic activity with taurine in DOCA-salt rats. Am J Phys-iol (in press, November 1986)

22. Kuriyama K: Taurine as a neuromodulator. Fed Proc 39: 2680,1980

23. Muramatsu M, Kakita K, Nakagawa K, Kuriyama K: A modulat-ing role of taurine on release of acethylcholine and norepinephrinefrom neuronal tissues. Jpn J Pharmacol 28: 259, 1978

24. Kuriyama K, Nakagawa K: Role of taurine in adrenal glands: Apreventive effect on stress-induced release of catecholamines fromchromalfin granules. In Huxley R, Barbeau A, editors: Taurine.New York, 1976, Raven Press, p 335

25. Peuler JD, Johnson GA: Simultaneous single isotope radioenzy-matic assay of plasma norepinephrine, epinephrine and dopamine.Life Sci 21: 625, 1977

26. Fujita T, Ando K. Hemodynamic and endocrine changes associatedwith potassium supplementation in sodium-loaded hypertensives.Hypertension 6: 184, 1984

27. Fujita T, Ando K, Noda H, Sato Y, Yamashita N, Yamashita K:Hemodynamic and endocrine changes associated with captopril indiuretic-resistant hypertensive patients. Am J Med 73: 341, 1982

28. Wallenstein S, Zucker CL, Fleiss JL: Some statistical methodsuseful in circulating research. Circ Res 47: 1, 1980

29. Mandai T, Ogihara T, Hata T, Okada Y, Ogasawara S, Mikami H,

531 at University of Washington on May 1, 2014http://circ.ahajournals.org/Downloaded from

FUJITA et at.

Nakamaru M, Kumahara Y: Urinary catecholamine response toglucagon in young and elderly patients with essential hypertension.J Am Geriatr Soc 28: 462, 1980

30. De Champlain J, Mueller RA, Axelrod J: Turnover and synthesis ofnorepinephrine in experimental hypertension in rats. Circ Res 25:285, 1969

31. De Champlain J, Van Amerigen MR: Regulation of blood pressureby sympathetic nerve fibers and adrenal medulla in normotensiveand hypertensive rats. Circ Res 31: 617, 1972

32. Smithwick RH, Thompson JE: Splanchnictomy for essential hyper-tension. JAMA 152: 1501, 1953

33. Rose G: Strategy of prevention: lessons from cardiovascular dis-ease. Br Med J 282: 1874, 1981

34. Greenberg R, Sabelli HC: Drug effects on epinephrine release fromrat adrenal medulla hemogenates and granule preparations. ProcSoc Exp Biol Med 16: 705, 1964

35. Schneider FH: Amphetamine-induced exocytosis of catechola-

mines from the cow adrenal medulla. J Pharmacol Exp Ther 183:80, 1972

36. Young JB, Landsberg L, Knopp RH: Effect of intravenous gluca-gon on urinary catecholamine excretion in normal man. Metabo-lism 25: 233, 1976

37. Sarcione EJ, Back N, Sokal JE, Mehlman B, Knoblock E: Stimula-tion of plasma epinephrine levels induced by glucagon in vivo.Endocrinology 72: 523, 1963

38. Douglas WW: Stimulus-secretion coupling: The concept and cluesfrom chromaffin and other cells. Br J Pharmacol 34: 451. 1968

39. Dolara P. Agresti A, Giotti A, Pasquini G: Effect of taurine oncalcium kinetics of guinea-pig heart. Eur J Pharmacol 24: 352,1973

40. Kuriyama K, Muramatsu M, Nakagawa K. Kakita K: Modulatingrole of taurine on release of neurotransmitters and calcium transportin excitable tissues. In Barbeau A, Huxtable RJ. editors: Taurineand neurological disorders. New York, 1978. Raven Press, p 201

CIRCULATION532 at University of Washington on May 1, 2014http://circ.ahajournals.org/Downloaded from