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Inverse relationship between linoleic acid in serum and in adipose tissue of patients with essential hypertension
ProstaglandinsLeukotrienesand Medicine 9: 603-613,1982
INVERSE RELATIONSHIPBETKEEN LINOLKIC ACID IN SERUM AND IN ADIPOSE TISSUE OF PATIENTS WITB ESSENTIAL KyPERTr;MSION. Peter Singer, SiegfriedVoigt and Wolfgang Godicke. Central Institutefor CardiovascularResearch,Academy of Sciences of the GDR, Wiltbergstr.50, DDR-1115 Berlin-Buch,GDR. (reprint requests to PS). ABSTRACT In patientswith labile essentialhypertensionwithout and with overweightas well as in normotensivecontrolsthe fatty acid pattern of serum triglyceridesand subcutaneousadipose tissue was estimated by gas liquid chromatography.In serum triglyceridesof hypertensiveslinoleic acid was increasedbut appeared decreased in depot fat. This inverse relationshipcould not be found for arachidonicacid. Correspondingly,the C 18:2/C 20:4-ratiowas higher in serum triglyceridesthan in adipose tissue. Only in depot fat of overweighthypertensives the percentageof arachidonicacid was decreasedwhen compared to subjectswith normal body weight. Linolenic acid remainedunchanged in serum triglyceridesbut decreasedsignificantlyin adipose tissue of hypertensivepatients.Eicosapentaeaoicacid was increasedin serum triglyceridesand depot fat of patients with essentialhypertensionof normal body weight. The results are discussedwith respect to the possible pathogenesisof essentialhypertensionand the hypotensivepotency of dietary linoleic acid which has been described in patientswith high blood pressure. INTRODUCTIO1T A deficiencyof renal prostaglandinsof the I and E series has been described in essentialhypertension(1-3). On the other hand, a high intake of dietary essentialfatty acids (EFA) leads to their accumulationand to enhancedprostaglandinformation in tissues (4,5). In small groups of patientswith labile essential hypertensiona blood pressure loweringeffect of a linoleic acid-richdiet was believedto be due to an increasedprostaglandin synthesis (6-8). This appears paradoxicalbecause in the early stages of the disease linoleic acid levels in serum
:_.iy”.&
are
Ii<_
$1
but become low i.rr sustained k&ypertension ./'?,lO:i _
It 1x3s Ieen reported -:-1-, at :)oijnlnsaturatcd :!‘atty3cids (IUFA) arterial wall ?.ncreascwith. the severity zf athe3. n lipids of the rosclerosis (11) whereas :Lnthe se~fim a decrease of :'UFA has been observed (12,13). From these and other data it :i.s r:leari,hat no conclusions can be drawn from the fatty acid ;,attern of serum l.ipids concernin::the composit~.onof the tissues (14,15). Considering our previous findings in serum of hypertensive subjects (10) the question arises as to whether an inverse relationship of PUFA also exists between serum and tissues in mild forms of essential hypertension. The present study is based on a comparison between the fatty acid pattern of subcutaneous adipose tissue obtained from biopsy specimens and that of serum triglycerides of hypertensive patients. FJATERIAL &?D I'JETHODS In 11 normotensive probands with normal glucose tolerance and serum lipids; in 15 patients with labile essential hypertension of stage I according to the WHO classification, with body weight, carbo'hydratetolerance and serum lipids within normal range; as well as in 9 overweight hy-pertensives the fatty acid pattern of serum triglyceride s was estimated by gas liquid chromatography. Some clinical and biochemical data of the patients are summarized in Table 1. TABLE 1: CLINICAL AND BIOCHEXUCAL DATA (MEAN*-xD>OF NORJ~OTENSIVE CONTROLS (I), HYPERTENSIVE PATIEXTS WITH NORMAL BODY WEIGHT (II) AND OVERWEIGHT (III)
(n$ll) Ace
(years)
Body weight Body height Systolic BP (kl?a) Diastolic BP &Pa) Triglycerides (mmol/l) Cholesterol (mmol/l)
37.6 25.5 67.8 f8.5 170 +-5 17.1 to.8 11.1 20.6 1.4710.24 5.5721.37
(rz5) 35.4 $11.8 73.6 z.8 175 ; 21.2 z 1.5 12.5 + 0.8 1.50$-0.28 5.60+-1.05
III @=9> 35.0 29.5 93.2 $7.8 173 25 22.2 22.1 12.4 Cl.2 1.53io.20 5.8621.33
The diagnosis of essential hypertension was based on clinical examination, on haemodynamic and laboratory data as well as on radiological methods to exclude secondary i‘orms of hypertension. All atients were kept on a standard diet and did not receive any grm es for at least 3 weeks before the study. Body
604
weight had remained unchanged during the previous 2 months. Dlood
samples were withdrawn in a supine position following an overnight fast 30 minutes after Fnsertinca venous needle. From the majority of the subjects subcutaneousadipose tissue could be obtained for analyses of the fatty acid pattern. The clinical and biochemicaldata of these patientswere similar to the total groups. The specimens of the normotensivesubjectswere taken from the anterior abdominalwall durin,-cholecystectomyor herniotomy.Adipose tissue of hypertensivepatients (150-200rns) was obtainedusing an intracutaneousanaesthesia(procaine1 ;;) and a small infraumbilicalincision (0,5-1,Ocm) in the linea alba. In preliminarystudies no influenceof lxocaine on the Patty acid pattern of adipose tissue could be observed. Serum triglycerideswere determinedusing the modified method of Royer and Ko (E), serum cholesteroland glucose tolerance after oral glucose load (50 e;)accordingto DAD 7 (17). Gas liquid chromatof;raphy of triglycerides was carried out by the method which has been described earlier in detail (18). Statistical analyses were performed usins Student's t-test.
RFSULTS my gas liquid chromatography24 fatty acids could be identified from which the most importantare listed in Tables 2 and 3. A striking finding is the significantincrease of linoleic acid in serum triglycerides(Table 2) associatedwith its significantly lower percentage in adipose tissue of patients with essentialhypertension (Table 3) when compared to nornotensive controls. This likewise occured in overweight hypertensives. Therefore, although the percentage of linoleic acid in serum triglycerides and depot fat was similar in the control subjects, it was significantly
higher in serum triglyceridesthan in adipose tissue of all patients with hypertension(compareTable 2 and 3). A similar alteration in serum and adipose tissue, however, could not be proved for arachidonic acid which is formed by desaturationand elongationfrom linoleic acid. Only in depot fat of overweighthypertensivesubjectswas its proportionsicnificantlylower than in normotensivesand hypertensiveswith normal body weight. When comparedto serum triglyceridesarachidonic acid was higher in adipose tissue of all subjects studied. Correspondingly,the C 18:2/C 20:4-ratiowas lower in subcutaneous fat than in serum triglycerideswithout major differencesbetween the groups~ No correlationbetween linoleic or arachidonicacids and the blood pressure level could be found.
605
TABLE 2: SEmCTBD PATTY ACIDS (EJEA&D) IN SERUM TRIGLYCEKCDES PATIBRTS OF I\TORMOTERSIVECOHTROLS (I , hliYI?ERTENSIVB 'VI'ITPH IJORMAL BODY VEIGI-IT(II AXD OTJ-ERWBIGXT(III)
(r&l) %4 %4:1 cl6 '16:l Cl3
2.0 0.2 26.2 1.1
'18:l '18:2 '18:3 '20:4
50.6 11.9 1.1 1.2 0.3 0.4 0.4
'20:5 '22:4 '22:5
'18:2 zz p/s
to.9 20.1 22.1 ++ to.8 ++
3.5 t0.c t3.1 +-1.9 f-k 20.7 to.7 to.2 -I-+ +-0.4 to.4
9.9 t4.7 0.50%0.11 l-1
II (n=lT) 1.7 0.7 21.1 3.1 3.3 48.0
+o.y %.7 22.7 Q.4 l-ic-o.7 24.8
14.2 1.1 1.4 1.2 0.3 0.3
+2.7 to.7 to.9 +-0.2++ 4-0.2 LO.4
10.1 f-7.2 0.7420.16
III (n=?r;) 1.2 0.7 20.6 1.9
3.5 51.5 15.3 0.9 1.1 0 .i 0.4 0.6
to.7 -1-: %.4 t3.2 f-k f-l.0
to.9 22.6 +-2.4-t-+ to.3 to.2 +-0.1-k to.1 to.3
13.9 +4.5 0.70~0.11 +-t-
' Significance between group I and group 111; ++ = P< 0.01, -k = PLL0.05. Alpha-Linolenic acid (C 18:3, n-6) remained uncharqed in serum triglycerides but decreased significantly in depot fat of hyper tensive patient s with a further fall when they were obese. In comparison to serum triglycerides it was 6enerall.yhigher in adipose tissue of all subjects. On the other hand, eicosapentaenoic acid which is formed by desaturation and elongation from alpha-linolenic acid appeared significantly increased in serum triglycerides and deot fat only in patients vith essential hypertension of normal g ody weight.
606
FATTY ACIDS IN SUBCUTANEOUSADIPOSE TISSUE OF TABIZ 3: SFJiECTED NORWTENSlXE CONTROLS (I), HYPERmTSIVE PATIENTS WITH NORMAL BODY WEIGHT (II) AND OVERWEIGfIT (III) III (&)
(d6, c14 %4:1 % '16:l '18 %8:1 '18:2 '18:3 '20:4 '20:5 '22:4 '22:5 %8:2 Tzi
P/S
2.2
to.4
0.2
+0.1
2.6
20.4
+-2.7 0.8 +-0.5 ++ 3.2
+2.4
51.6 24.0 11.2 +1.9 -I4.1 to.9 -I3.4 $-1.6 -I-
to.5 -I0.3 to.1 21.3 t1.4
to.5
0.3
c-o.1
21.9 +-1.8
20.9
2.5
Lo
4.3
3.2
4.6
21.1
54.1
f2.4
8.6
to.9
51.0 8.9
‘42.1
++
il.7
3.2
+0.3 ++ 3.4 21.2 ++ 0.4 b.2
+0.1
0.3
to.2
0.1
to.2
0.3 0.1
3.3
22.5
2.G 50.9 +
2.0
2.3
0.2
0.80t0.24
@=9)
20.1 to.1
fi-
0.5620.12
2.5
++I
i-f
io.5 1.8 to.7 0.3 +-0.1 0.3 to.1 0.1 to.1
++ +c
4.8
3.2
-I-+
0.49+-0.09
++
' Significancebetween group I and group III; = P< 0.05. ++ = PL0.01, -IIn serum triglyceridesof the controlsthe polyunsaturate/ saturate (p/s) ratio was lower than in adipose tissue. Like linoleic acid it increasedin serum triglyceridesbut decreased in depot fat of both hypertensivegroups resulting in an inverse relationshipbetween controls and patientswith high blood pressure. Palmitic acid was lower in serum triglyceridesof hypertensive patients but remained unchanged in adipose tissue. Palmitoleic acid was significantlyincreasedin serum and adipose tissue of hypertensivepatientswith lower percentagein serum triglyceridesof obese hypertensives.Oleic acid appeared siGni-, ficantly higher in depot fat of hypertensiveswith overwei&t in comparisonto normotensivecontrols and hypertensivepatients with normal weight. 607
Although several fatty ac!_ds c ;:atienCs “1, i’._1I.1.1et;sen-L i.a1. 1up?c0Ktr~~l~; "tC ;ension are si~_;nificantly different Crcm ~iOiXlOtC!Xi~~e interpretation will be focused on li.noleicand.arnchidonic acids which are of particular relevance to SlOOci pressure l?e:,Qlc3t!.0Ti :6,7,13).
In general, a higher percentaGe of linoleic acid in serum triglycerides compared to adipose tissue has been described (15,20-23). On the other hand, no differences between linoleic acid in adipose tissue and arterial wall obtained from amputated patients could be ascertained in vivo (14). On the contrary, srachidonic and eicosapentaenoic acids were at the same level in triglycerides of serum and of the vessel wall, but were si.;nificantly lower in adipose tissue. Thus, from previous results the percentage of linoleic acid in adipose tissue appears comparable to that in triglycerides of the arterial wall. It remains? however, questionable whether this can be transferred to hypertensive subjects. No comparison seems possible between cholesterol esters of the depot fat and the vessel wall since their quantity is necligible in the former. The intention of the present paper was to find a rational base for the hypotensive effect of linoleic acid-rich diets. Such an effect might seen paradoxical in patients with essential hypertension because an already high percentage of this fatty acid as well as an increased p/s-ratio in the serum triglycerides of l,ypcrtensives have been found, at least in the early stage of the disease. Linoleic acid levels are normal in sustained hypertension 9,lO). The simultaneous finding of its lower level in adipose tand possibly in arterial) tissue represents a possible explanation of its effect on lowering blood pressure. Accordingly, a dietary increase of linoleic acid has been postulated as a desirable intervention to reduce cardiovascular risk (5,2O). The fatty acid -pattern of serum lipids does not reflect the composition of the tissues (14,15). Moreover, it differs from one tissue to another (4,24,25), in various functional or pathological states within one and the same organ (26) or in several tissues treated with the same drug (27). Thus, no conclusion can be drawn from the composition of serum lipids to their levels in the vessel wall. Provided that the proportion of linoleic acid in adipose tissue is representative of that in the arterial wall, the inverse relationship between serum triglycerides and depot fat could be important. In contrast to our results a negative correlation between linoleic acid in adipose tissue and systolic as well as diastolic blood pressure has been described recently (2s). But no data were available concerning linoleic acid in the serum of the same subjects. Thus, it is uncertain whether there was an inverse relationship between serum and depot fat as in the present study. 608
Arachidonicacid, the direct 2 series prostaglandinprecursor, was not measured by the authors (28). In our study it remained normal in serum of hypertensivepatients and decreasedsignificantly only in adipose tissue of overweighthypertensives, The changes in linoleic acid occur independentlyof arachidonicacid and consequentlylinoleic acid cannot only be seen in view of its precursorfunction for the arachidonicacid cascade. Augmented linoleic acid in serum triglycerideshas been discussed as a sign of its increasedturnover associatedwith an enhanced need for l?TJl?A in the early stage of essentialhypertension (10). Since PUFA are readily oxidized as substratestheir sufficientavailabilityis an importantprerequisitefor naintaininf;the enerLy balance in stress and during physical exertion (23,30) as well as in essentialhypertension(10). Indeed, an increasedrelease of linoleic acid from serum triglycerideshas been observed after heparin injectionin patients with essentialhypertension(31). This remains to be shown during catecholamine-induced lipolysis in peripheral tissues of hypertensivesubjects. An altered desaturationof linoleic acid caused by a change inA6-desaturase activity should also be considered.This has been likewise described in the diabetic state (32). On the other hand, in diabetic patients an increase of systolic blood pressure vas correlatedwith a decrease of arachidonicacid in adipose tissue, linoleic acid being unchanged (33). Thus, more subtle mechanisms includingenzyme defects associatedwith the synthesis of arachidonicacid from linoleic acid might be involved. For example,reduced delta-6-desaturaseactivity could produce a higher linoleic acid level, coupledwith a therapeuticresponse to an increasedlinoleic acid intake which would compensatefor reduced enzyme function. One would thereforehave the apparent paradox of a high level of linoleicacid associatedwith a dietary effect on blood pressure of this fatty acid. Recently, this has been discussedmore in detail (34-36). It is unlikely that valid conclusionscan be drawn from studies in spontaneouslyhypertensiverats (SRR) which are recommendedas a suitable model for essentialhypertension(37). The proportionof PUFA on the whole is much higher in rats than in human beings.Nevertheless,in serum and liver triglycerides lC,38), serum cholesterolesters (39), and renal phospholipids t40) the percentageof linoleic acid is decreasedwhereas arachidonic acid is increased in SHR with sustainedhypertensionwhen comparedto normotensivecontrols.
609
~SffeCi- COUid '3e ~ObSf.?lXed '07 ijO&Surprisirq:ly, ii0 kypo-tensive natal f:cedin;_; of a linoleic acid-rich diet in SHR (39).On the o-tiler hand, the prenatal start of its feedin{; resulted in a si;nificantly lowr blood pressure 91 the i-dietary,:roups (41). Consequently, comparison betJ/eenXT? and pat5.entswith essential Pqertension is of uncertain -valuefrom the metabolic point of v 1. CX.
The yet obscure negative correlation between the percentage of linoleic acid in serum tri@ycerides and depot fat of patients with essential hypertension warrants further observations to clarify the causal relationship. ACKNOWLEDGEXE3TT U. Sauck and ldissU. Eichentopf The authors are grateful to 1::iso for slrilfultechnical assistance. REFERERCES 1. Grose Jil,Lebel I.$,Gbeasoor EN. Diminished urinary,prostacyclin metabolite in essential 'ngpertension. Cl-inSci 59: 121 s, 1980. 2. VeberYC, Siess W, Scherer B. Possible significance of renal prostaglandins in essential hypertension. Clin Exper Hypestens 2: 741, 1980. 3. Tan S, Sweet P, T!ulrom PJ. Impaired renal production of prostaglandin E : a newly identified lesion in human essential 'nyper?ension. Prostaglandins 15: 139, 1978. 4. Galli C, Agradi E, Petroni A, Socini A. %odulation of prosta:landin production in tic,dJ_,uesby dietary essential fatty acids. Acta f.IedStand (Suppl): 642, 171 1980. 5. Iwcpeinen 0, Karvonen NJ, Pekkarinen M, Miettinen N, Elosuo R, Paavilainen E. Dietary prevention of coronary heart disease: The Finnish I'bentalHospital Study. Int J Epidemiol 8: 99, 1979. 6. Iacono JN, W.rshall MW, Dougherty RM, Wheeler NA, Backin JF, Canary JJ. Reduction in blood pressure associated with high polyunsaturated fat diets that reduce cholesterol in man. l?reventiveiYed 4: 426, 1975. 7. Comberg HU, iieydenS, Hames CG. Hypotensive effect of dietary prostaglandin precursor in hypertensive man. Prostaglandins 15: 193, 1978. 9 Vereroesen AJ, Fleischman AI, Comberg BIT,Keyden s, L. I-lames CG. The influence of increased linoleate on essential hypertension in man. hcta Biol Ned Germ 37: 879,
19713.
610
9. MichailovML, Baumann R. Uber die Veranderungendes Triglyxeridspiegelsim Friihstadium der jugendlichenIQpertonie. Dt Gesundh Wesen 30: 734, 1975. 10. Singer P, Voigt S, Godicke W, Pfeiffer D, Baumann R. The fatty acid pattern of serum triglyceridesand FFA in patients with essentialhypertensionof differentstages, athletes, and normal subjects. Cor et Vasa 22: 327, 1980. CC, Il. Bijttcher CFJ, Boelsma van Houte E, ter Haar-Romeny-Wachter Woodford FP, van Gent CM. Lipid and fatty acid composition of coronaryand cerebral arteries at differentstages of atherosclerosis. Lancet 2: 1162, 1960. 12. Schrade W, Biegler R, BijhleE. Fatty-aciddistributionin the lipid fractions of healthy persons of differentage, patients with atherosclerosisand patientswith idiopathicbyperlipidaemia. J AtherosclerRes 1: 47, 1961. 13. KingsburyKJ, Morgan DbI,Aylott C, Burton P, Emmerson R, Robinson PJ. A comparisonof the polyunsaturatedfatty acids of the plasma cholesterylesters and subcutaneous depot fats of atheromatousand normal people. Clin Sci 22: 161, 1962. 14. Singer P, Gnauck G, Honigmann G, SchliackV, L<er J. The fatty acid compositionof triglyceridesin arteries, depot fat and serum of amputateddiabetics. Atherosclerosis 28: 87, 1977. 15. Singer P, Gnauck G, Honigmann G, SchliackV. Das Fettsauremuster der Triglyzeridebei schwerer diabetischerMakroangiopathie. Dt Gesundh Wesen 33: 2179, 1978. 16. Royer ME, Ho H. A simplifiedsemiautomatedassay for plasma triglycerides. Anal Biochem 29: 405, 1969. 17. DAB 7 - DeutschesArzneibuch,7 th Ed. Akademie-Verlag, Berlin, 1972. 18. Singer P, Voigt S, Moritz V, Baumann R. The fatty acid pattern of triglyceridesand FFA in serum of spontaneouslyhypertensive rats (SHR). Atherosclerosis33: 227, 1979. 19. ten Hoor F. Cardiovasculareffects of dietary linoleic acid. N'utrMetab 24 (Suppl 1): 162, 1980. 20. Dayton S, Hashimoto S, Dixon W, Pearce ML. Compositionof lipids in human serum and adipose tissue during prolonged feeding of a diet high in unsaturatedfat. J Lipid Res 7: 103, 1966. 21. HeffernanAGA. Fatty acid compositionof adipose tissue in normal and abnormal subjects. Am J Clin Nutr 15: 5, 1964. 22. Scott RF, Lee KI!,Kim DN, Morrison ES, Goodale F. Fatty acids of serum and adipose tissue in six groups eating natural diets containing7 to 40 per cent fat. Am J Clin Nutr 14: 280, 1964.
611
Lo,li‘an 'i" Xiemersma RA, Thomson I,:, Oliver KF, Olsson AGr A-J> Y~;,'a.lldS.US G, Rijssner S, Kaijscr L, Callmer E, Carlson LAY heart Loci;crble L Lutz '$'.Risk: factors for i.c;ch.aemic Edinbur,~-:i-,z~tocm!oi!ns-hldy. :di.sease in Aormal men a;_ed;+I;,. Lance-t; I:
24
949,
19X.
I?, Gnauck G, Uoni;mann G, S-talcP, Schliack V, Xettler LB, LXu-rtrock p, Thoclke ;;. The fatty acid pattern of adipose tissue and liver triglycerides accordin:;to fat droplet size in liver parenchymal cells o-fdiabetic subjects. Diabetolosia 10: 4.55, 1374. G, Schliack V. Triglyceride 25* Singer P, Gnnuck G, Iioni,T;nann fatty acid pattern in xanthomas, liver, adipose tissue and serum of subjects with hyperlipoproteinaemia. Act hPed Solon 20: 113, 1979. 26. Singer P, Honi,zmann G, Schliack V. Decrease of eicosapentaenoic acid in fatty liver o;^diabetic subjects. Prostar;landins and 1,ledicine5: I-33,1380. G, Thoelke Ii,Schliack V. 27. Slnl;erP, Gnauck G, :IoniC;mann The fatty acid pattern of triglycerides in liver, adipose tissue and serum of diabetics with hyperlipoproteinaemia before and durin;: clofibrate treatment. Act Diabetol Lat 15: 40, 1378. 28. Oster F, Arab L, Schellenber g B, Heuck CC? lllordasini R, Schlierf G. Blood pressure and adipose tissue linoleic acid. Res Exp k:ed 175: 237, 1379. 29. Carlsten A, iiallgren B, Jagenburg R, Svanborr;A, Werko L. Arterial concentration of free fatty acids and free amino acids in healthy human individuals at rest and at different work loads. Stand J Clin Lab Invest 14: 185, 1962. Some immediate 30. Xurter R, Swale J, Peyman XA, Carnett C"$?lii. 2nd long-term effects of exercise on the plasma lipids. Lancet II: 671, 1972. Voigt S, Singer P, Ffeiffer D. Das Verhaltea individueller 31. Fettsguren der Trislyzeride und freien Fettsguren nach Heparininjektion bei essentieller Hypertonic. 3. Dresdner Lipidsymposium (VEB Berlin-Chemie ed) Berlin 1379. Benjamin W. Synthesis of arachi32. Friedmann I;, Sellhorn .!&, donic acid from linoleic acid in viva in diabetic rats. Israel J Ked Sci 2: 677, lSG6. 33. Sinf;erP, IIonizmann G, Schliack V. Zur Leberverfettung und Petts%urezusanmensetzun,~ der Leber- und Fettgewebstriglyzeride von Diabeti!:errtohne und nit arterieller Ii;rpertoniel Dt Gesundh ?!esen 36: lG93, 1381. 34. Darcet Ph, Driss P, Nendy F, Delhaye ;T. Exploration du m&t-a. bolisme ?es acides eras des lipides totaux plasmatiques e> de l'qP +eSation plaquettaire d'une population d'hommes ages a l'aide d'une alimentation er?richicen acide alinol&nique. Ann ETut-r Alicl 34: 277, lpm. ‘.
i3in.y~~
612
35.
Horrobin DF. A new concept of lifestyle-related cardiovascular disease: The importance of interactions between cholesterol, essential fatty acids, prostaglandin El and thromboxane A2. Xed Hypotheses 6: 785, 1980. 36. Horrobin DF. Loss of delta-6-desaturase activity as a !:eg factor in aging. h?ed Hypotheses 7: 1211, 19Sl. 37. Yamori Y. Pathogenesis of spontaneous hypertension as a model for essential hypertension. Jay Circulat J 41: 259, 1977. 38. Singer P, mirth M, GiidickeI!:, Koritz V, Baumann R. Lipid levels and fatty acid pattern of triglycerides in liver of spontaneously hypertensive rats (SIB). Acta Biol I;ed Germ 41: in press, 1982. 33. Singer P, FAoritzV, Fijrster D, Voigt S, ii'irth !;I, Naumann E, Zimontkowski S. Effect of linoleic acid-rich diet on blood pressure, lipids, catecholamines, and dopamine-B-bydroqlase 9n spontaneously hypertensive rats (SRR). Acta Biol I:'Ied Germ 41: 215, 1982. 40. Singer I?,Wirth K, Koritz V. Unpublished data. 41. Uoffmann P, Poenicke I:,Fakr A, FijrsterVJ,Llarkov ChK. Influence of dietary polyunsaturated fatty acids (~[TE‘I~) on blood pressure, platelet agreGability and prostaslandin (PG) biosynthesis in spontaneously hypertensLve rats (SUR). p 211 in Prostaglandins and Thromboxancs (W Fijrster ed) VEB G Fischer, Jena, 1981.
613
INVERSE RELATIONSHIPBETKEEN LINOLKIC ACID IN SERUM AND IN ADIPOSE TISSUE OF PATIENTS WITB ESSENTIAL KyPERTr;MSION. Peter Singer, SiegfriedVoigt and Wolfgang Godicke. Central Institutefor CardiovascularResearch,Academy of Sciences of the GDR, Wiltbergstr.50, DDR-1115 Berlin-Buch,GDR. (reprint requests to PS). ABSTRACT In patientswith labile essentialhypertensionwithout and with overweightas well as in normotensivecontrolsthe fatty acid pattern of serum triglyceridesand subcutaneousadipose tissue was estimated by gas liquid chromatography.In serum triglyceridesof hypertensiveslinoleic acid was increasedbut appeared decreased in depot fat. This inverse relationshipcould not be found for arachidonicacid. Correspondingly,the C 18:2/C 20:4-ratiowas higher in serum triglyceridesthan in adipose tissue. Only in depot fat of overweighthypertensives the percentageof arachidonicacid was decreasedwhen compared to subjectswith normal body weight. Linolenic acid remainedunchanged in serum triglyceridesbut decreasedsignificantlyin adipose tissue of hypertensivepatients.Eicosapentaeaoicacid was increasedin serum triglyceridesand depot fat of patients with essentialhypertensionof normal body weight. The results are discussedwith respect to the possible pathogenesisof essentialhypertensionand the hypotensivepotency of dietary linoleic acid which has been described in patientswith high blood pressure. INTRODUCTIO1T A deficiencyof renal prostaglandinsof the I and E series has been described in essentialhypertension(1-3). On the other hand, a high intake of dietary essentialfatty acids (EFA) leads to their accumulationand to enhancedprostaglandinformation in tissues (4,5). In small groups of patientswith labile essential hypertensiona blood pressure loweringeffect of a linoleic acid-richdiet was believedto be due to an increasedprostaglandin synthesis (6-8). This appears paradoxicalbecause in the early stages of the disease linoleic acid levels in serum
:_.iy”.&
are
Ii<_
$1
but become low i.rr sustained k&ypertension ./'?,lO:i _
It 1x3s Ieen reported -:-1-, at :)oijnlnsaturatcd :!‘atty3cids (IUFA) arterial wall ?.ncreascwith. the severity zf athe3. n lipids of the rosclerosis (11) whereas :Lnthe se~fim a decrease of :'UFA has been observed (12,13). From these and other data it :i.s r:leari,hat no conclusions can be drawn from the fatty acid ;,attern of serum l.ipids concernin::the composit~.onof the tissues (14,15). Considering our previous findings in serum of hypertensive subjects (10) the question arises as to whether an inverse relationship of PUFA also exists between serum and tissues in mild forms of essential hypertension. The present study is based on a comparison between the fatty acid pattern of subcutaneous adipose tissue obtained from biopsy specimens and that of serum triglycerides of hypertensive patients. FJATERIAL &?D I'JETHODS In 11 normotensive probands with normal glucose tolerance and serum lipids; in 15 patients with labile essential hypertension of stage I according to the WHO classification, with body weight, carbo'hydratetolerance and serum lipids within normal range; as well as in 9 overweight hy-pertensives the fatty acid pattern of serum triglyceride s was estimated by gas liquid chromatography. Some clinical and biochemical data of the patients are summarized in Table 1. TABLE 1: CLINICAL AND BIOCHEXUCAL DATA (MEAN*-xD>OF NORJ~OTENSIVE CONTROLS (I), HYPERTENSIVE PATIEXTS WITH NORMAL BODY WEIGHT (II) AND OVERWEIGHT (III)
(n$ll) Ace
(years)
Body weight Body height Systolic BP (kl?a) Diastolic BP &Pa) Triglycerides (mmol/l) Cholesterol (mmol/l)
37.6 25.5 67.8 f8.5 170 +-5 17.1 to.8 11.1 20.6 1.4710.24 5.5721.37
(rz5) 35.4 $11.8 73.6 z.8 175 ; 21.2 z 1.5 12.5 + 0.8 1.50$-0.28 5.60+-1.05
III @=9> 35.0 29.5 93.2 $7.8 173 25 22.2 22.1 12.4 Cl.2 1.53io.20 5.8621.33
The diagnosis of essential hypertension was based on clinical examination, on haemodynamic and laboratory data as well as on radiological methods to exclude secondary i‘orms of hypertension. All atients were kept on a standard diet and did not receive any grm es for at least 3 weeks before the study. Body
604
weight had remained unchanged during the previous 2 months. Dlood
samples were withdrawn in a supine position following an overnight fast 30 minutes after Fnsertinca venous needle. From the majority of the subjects subcutaneousadipose tissue could be obtained for analyses of the fatty acid pattern. The clinical and biochemicaldata of these patientswere similar to the total groups. The specimens of the normotensivesubjectswere taken from the anterior abdominalwall durin,-cholecystectomyor herniotomy.Adipose tissue of hypertensivepatients (150-200rns) was obtainedusing an intracutaneousanaesthesia(procaine1 ;;) and a small infraumbilicalincision (0,5-1,Ocm) in the linea alba. In preliminarystudies no influenceof lxocaine on the Patty acid pattern of adipose tissue could be observed. Serum triglycerideswere determinedusing the modified method of Royer and Ko (E), serum cholesteroland glucose tolerance after oral glucose load (50 e;)accordingto DAD 7 (17). Gas liquid chromatof;raphy of triglycerides was carried out by the method which has been described earlier in detail (18). Statistical analyses were performed usins Student's t-test.
RFSULTS my gas liquid chromatography24 fatty acids could be identified from which the most importantare listed in Tables 2 and 3. A striking finding is the significantincrease of linoleic acid in serum triglycerides(Table 2) associatedwith its significantly lower percentage in adipose tissue of patients with essentialhypertension (Table 3) when compared to nornotensive controls. This likewise occured in overweight hypertensives. Therefore, although the percentage of linoleic acid in serum triglycerides and depot fat was similar in the control subjects, it was significantly
higher in serum triglyceridesthan in adipose tissue of all patients with hypertension(compareTable 2 and 3). A similar alteration in serum and adipose tissue, however, could not be proved for arachidonic acid which is formed by desaturationand elongationfrom linoleic acid. Only in depot fat of overweighthypertensivesubjectswas its proportionsicnificantlylower than in normotensivesand hypertensiveswith normal body weight. When comparedto serum triglyceridesarachidonic acid was higher in adipose tissue of all subjects studied. Correspondingly,the C 18:2/C 20:4-ratiowas lower in subcutaneous fat than in serum triglycerideswithout major differencesbetween the groups~ No correlationbetween linoleic or arachidonicacids and the blood pressure level could be found.
605
TABLE 2: SEmCTBD PATTY ACIDS (EJEA&D) IN SERUM TRIGLYCEKCDES PATIBRTS OF I\TORMOTERSIVECOHTROLS (I , hliYI?ERTENSIVB 'VI'ITPH IJORMAL BODY VEIGI-IT(II AXD OTJ-ERWBIGXT(III)
(r&l) %4 %4:1 cl6 '16:l Cl3
2.0 0.2 26.2 1.1
'18:l '18:2 '18:3 '20:4
50.6 11.9 1.1 1.2 0.3 0.4 0.4
'20:5 '22:4 '22:5
'18:2 zz p/s
to.9 20.1 22.1 ++ to.8 ++
3.5 t0.c t3.1 +-1.9 f-k 20.7 to.7 to.2 -I-+ +-0.4 to.4
9.9 t4.7 0.50%0.11 l-1
II (n=lT) 1.7 0.7 21.1 3.1 3.3 48.0
+o.y %.7 22.7 Q.4 l-ic-o.7 24.8
14.2 1.1 1.4 1.2 0.3 0.3
+2.7 to.7 to.9 +-0.2++ 4-0.2 LO.4
10.1 f-7.2 0.7420.16
III (n=?r;) 1.2 0.7 20.6 1.9
3.5 51.5 15.3 0.9 1.1 0 .i 0.4 0.6
to.7 -1-: %.4 t3.2 f-k f-l.0
to.9 22.6 +-2.4-t-+ to.3 to.2 +-0.1-k to.1 to.3
13.9 +4.5 0.70~0.11 +-t-
' Significance between group I and group 111; ++ = P< 0.01, -k = PLL0.05. Alpha-Linolenic acid (C 18:3, n-6) remained uncharqed in serum triglycerides but decreased significantly in depot fat of hyper tensive patient s with a further fall when they were obese. In comparison to serum triglycerides it was 6enerall.yhigher in adipose tissue of all subjects. On the other hand, eicosapentaenoic acid which is formed by desaturation and elongation from alpha-linolenic acid appeared significantly increased in serum triglycerides and deot fat only in patients vith essential hypertension of normal g ody weight.
606
FATTY ACIDS IN SUBCUTANEOUSADIPOSE TISSUE OF TABIZ 3: SFJiECTED NORWTENSlXE CONTROLS (I), HYPERmTSIVE PATIENTS WITH NORMAL BODY WEIGHT (II) AND OVERWEIGfIT (III) III (&)
(d6, c14 %4:1 % '16:l '18 %8:1 '18:2 '18:3 '20:4 '20:5 '22:4 '22:5 %8:2 Tzi
P/S
2.2
to.4
0.2
+0.1
2.6
20.4
+-2.7 0.8 +-0.5 ++ 3.2
+2.4
51.6 24.0 11.2 +1.9 -I4.1 to.9 -I3.4 $-1.6 -I-
to.5 -I0.3 to.1 21.3 t1.4
to.5
0.3
c-o.1
21.9 +-1.8
20.9
2.5
Lo
4.3
3.2
4.6
21.1
54.1
f2.4
8.6
to.9
51.0 8.9
‘42.1
++
il.7
3.2
+0.3 ++ 3.4 21.2 ++ 0.4 b.2
+0.1
0.3
to.2
0.1
to.2
0.3 0.1
3.3
22.5
2.G 50.9 +
2.0
2.3
0.2
0.80t0.24
@=9)
20.1 to.1
fi-
0.5620.12
2.5
++I
i-f
io.5 1.8 to.7 0.3 +-0.1 0.3 to.1 0.1 to.1
++ +c
4.8
3.2
-I-+
0.49+-0.09
++
' Significancebetween group I and group III; = P< 0.05. ++ = PL0.01, -IIn serum triglyceridesof the controlsthe polyunsaturate/ saturate (p/s) ratio was lower than in adipose tissue. Like linoleic acid it increasedin serum triglyceridesbut decreased in depot fat of both hypertensivegroups resulting in an inverse relationshipbetween controls and patientswith high blood pressure. Palmitic acid was lower in serum triglyceridesof hypertensive patients but remained unchanged in adipose tissue. Palmitoleic acid was significantlyincreasedin serum and adipose tissue of hypertensivepatientswith lower percentagein serum triglyceridesof obese hypertensives.Oleic acid appeared siGni-, ficantly higher in depot fat of hypertensiveswith overwei&t in comparisonto normotensivecontrols and hypertensivepatients with normal weight. 607
Although several fatty ac!_ds c ;:atienCs “1, i’._1I.1.1et;sen-L i.a1. 1up?c0Ktr~~l~; "tC ;ension are si~_;nificantly different Crcm ~iOiXlOtC!Xi~~e interpretation will be focused on li.noleicand.arnchidonic acids which are of particular relevance to SlOOci pressure l?e:,Qlc3t!.0Ti :6,7,13).
In general, a higher percentaGe of linoleic acid in serum triglycerides compared to adipose tissue has been described (15,20-23). On the other hand, no differences between linoleic acid in adipose tissue and arterial wall obtained from amputated patients could be ascertained in vivo (14). On the contrary, srachidonic and eicosapentaenoic acids were at the same level in triglycerides of serum and of the vessel wall, but were si.;nificantly lower in adipose tissue. Thus, from previous results the percentage of linoleic acid in adipose tissue appears comparable to that in triglycerides of the arterial wall. It remains? however, questionable whether this can be transferred to hypertensive subjects. No comparison seems possible between cholesterol esters of the depot fat and the vessel wall since their quantity is necligible in the former. The intention of the present paper was to find a rational base for the hypotensive effect of linoleic acid-rich diets. Such an effect might seen paradoxical in patients with essential hypertension because an already high percentage of this fatty acid as well as an increased p/s-ratio in the serum triglycerides of l,ypcrtensives have been found, at least in the early stage of the disease. Linoleic acid levels are normal in sustained hypertension 9,lO). The simultaneous finding of its lower level in adipose tand possibly in arterial) tissue represents a possible explanation of its effect on lowering blood pressure. Accordingly, a dietary increase of linoleic acid has been postulated as a desirable intervention to reduce cardiovascular risk (5,2O). The fatty acid -pattern of serum lipids does not reflect the composition of the tissues (14,15). Moreover, it differs from one tissue to another (4,24,25), in various functional or pathological states within one and the same organ (26) or in several tissues treated with the same drug (27). Thus, no conclusion can be drawn from the composition of serum lipids to their levels in the vessel wall. Provided that the proportion of linoleic acid in adipose tissue is representative of that in the arterial wall, the inverse relationship between serum triglycerides and depot fat could be important. In contrast to our results a negative correlation between linoleic acid in adipose tissue and systolic as well as diastolic blood pressure has been described recently (2s). But no data were available concerning linoleic acid in the serum of the same subjects. Thus, it is uncertain whether there was an inverse relationship between serum and depot fat as in the present study. 608
Arachidonicacid, the direct 2 series prostaglandinprecursor, was not measured by the authors (28). In our study it remained normal in serum of hypertensivepatients and decreasedsignificantly only in adipose tissue of overweighthypertensives, The changes in linoleic acid occur independentlyof arachidonicacid and consequentlylinoleic acid cannot only be seen in view of its precursorfunction for the arachidonicacid cascade. Augmented linoleic acid in serum triglycerideshas been discussed as a sign of its increasedturnover associatedwith an enhanced need for l?TJl?A in the early stage of essentialhypertension (10). Since PUFA are readily oxidized as substratestheir sufficientavailabilityis an importantprerequisitefor naintaininf;the enerLy balance in stress and during physical exertion (23,30) as well as in essentialhypertension(10). Indeed, an increasedrelease of linoleic acid from serum triglycerideshas been observed after heparin injectionin patients with essentialhypertension(31). This remains to be shown during catecholamine-induced lipolysis in peripheral tissues of hypertensivesubjects. An altered desaturationof linoleic acid caused by a change inA6-desaturase activity should also be considered.This has been likewise described in the diabetic state (32). On the other hand, in diabetic patients an increase of systolic blood pressure vas correlatedwith a decrease of arachidonicacid in adipose tissue, linoleic acid being unchanged (33). Thus, more subtle mechanisms includingenzyme defects associatedwith the synthesis of arachidonicacid from linoleic acid might be involved. For example,reduced delta-6-desaturaseactivity could produce a higher linoleic acid level, coupledwith a therapeuticresponse to an increasedlinoleic acid intake which would compensatefor reduced enzyme function. One would thereforehave the apparent paradox of a high level of linoleicacid associatedwith a dietary effect on blood pressure of this fatty acid. Recently, this has been discussedmore in detail (34-36). It is unlikely that valid conclusionscan be drawn from studies in spontaneouslyhypertensiverats (SRR) which are recommendedas a suitable model for essentialhypertension(37). The proportionof PUFA on the whole is much higher in rats than in human beings.Nevertheless,in serum and liver triglycerides lC,38), serum cholesterolesters (39), and renal phospholipids t40) the percentageof linoleic acid is decreasedwhereas arachidonic acid is increased in SHR with sustainedhypertensionwhen comparedto normotensivecontrols.
609
~SffeCi- COUid '3e ~ObSf.?lXed '07 ijO&Surprisirq:ly, ii0 kypo-tensive natal f:cedin;_; of a linoleic acid-rich diet in SHR (39).On the o-tiler hand, the prenatal start of its feedin{; resulted in a si;nificantly lowr blood pressure 91 the i-dietary,:roups (41). Consequently, comparison betJ/eenXT? and pat5.entswith essential Pqertension is of uncertain -valuefrom the metabolic point of v 1. CX.
The yet obscure negative correlation between the percentage of linoleic acid in serum tri@ycerides and depot fat of patients with essential hypertension warrants further observations to clarify the causal relationship. ACKNOWLEDGEXE3TT U. Sauck and ldissU. Eichentopf The authors are grateful to 1::iso for slrilfultechnical assistance. REFERERCES 1. Grose Jil,Lebel I.$,Gbeasoor EN. Diminished urinary,prostacyclin metabolite in essential 'ngpertension. Cl-inSci 59: 121 s, 1980. 2. VeberYC, Siess W, Scherer B. Possible significance of renal prostaglandins in essential hypertension. Clin Exper Hypestens 2: 741, 1980. 3. Tan S, Sweet P, T!ulrom PJ. Impaired renal production of prostaglandin E : a newly identified lesion in human essential 'nyper?ension. Prostaglandins 15: 139, 1978. 4. Galli C, Agradi E, Petroni A, Socini A. %odulation of prosta:landin production in tic,dJ_,uesby dietary essential fatty acids. Acta f.IedStand (Suppl): 642, 171 1980. 5. Iwcpeinen 0, Karvonen NJ, Pekkarinen M, Miettinen N, Elosuo R, Paavilainen E. Dietary prevention of coronary heart disease: The Finnish I'bentalHospital Study. Int J Epidemiol 8: 99, 1979. 6. Iacono JN, W.rshall MW, Dougherty RM, Wheeler NA, Backin JF, Canary JJ. Reduction in blood pressure associated with high polyunsaturated fat diets that reduce cholesterol in man. l?reventiveiYed 4: 426, 1975. 7. Comberg HU, iieydenS, Hames CG. Hypotensive effect of dietary prostaglandin precursor in hypertensive man. Prostaglandins 15: 193, 1978. 9 Vereroesen AJ, Fleischman AI, Comberg BIT,Keyden s, L. I-lames CG. The influence of increased linoleate on essential hypertension in man. hcta Biol Ned Germ 37: 879,
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613