1080 lar and unipolar disorder in females. It may also provide relevant neuroendocrine information after antidepressant treatment in subgroups of affectively ill patients. Departments of Psychiatry and Biochemistry, Free University of Brussels, Erasme and Brugmann University Hospitals, Brussels, Belgium
FISH
J. MENDLEWICZ P. LINKOWSKI H.BRAUMAN
Unilever Research, 3130 AC Vlaardingen, Netherlands
et al.’ suggested dietary enrichment with acids for the prevention of arterial thrombosis and atherosclerosis. A major natural source of (n-3) fatty acids is linseed oil, which contains about 50% (9, 12, 15)-linolenic acid (18:3 n-3; ot-LA). By desaturation and chain elongation oc-LA is metabolised to eicosapentaenoic acid (20:5 n-3; EPA) which can also be taken up directly from certain fish oils. EPA is the precursor of platelet thromboxane A3 (TXA3) which, unlike TXAz which is derived from arachidonic acid (20:4 n-6; AA), has no aggregating power.’ In the vessel wall EPA should be metabolised to prostaglandin 3 (PGI3) which might be as effective an anti-aggregating substance as PGl2 (prostacyclin), derived from AA. Dyerberg et al. reasoned that increasing tissue EPA might shift the thromboxane-prostacyclin balance towards a less thrombogenic state. We have found that diets rich in cod liver oil, linseed oil, and sunflower-seed oil all lower the tendency to arterial thrombosis in rats, in contrast to hardened coconut oil. With the cod liver and linseed oil diets this change coincided with a significantly reduced production of platelet thromboxanes (measured as malondialdehyde) and vascular prostacyclin (measured as unstable platelet aggregation inhibiting substance). Sunflowerseed oil, on the other hand, had no such effect. 2.3 The lower prostaglandin production upon feeding (n-3) fatty acids could be explained on the basis of the fatty-acid spectra of platelet and vessel wall lipids as well as by the fact that EPA is a poor substrate for the production of cyclic prostaglandin endoperoxides,4,s the precursor of thromboxanes and prostacyclin. We suggest that the low thrombogenicity of linseed oil and cod liver oil diets is primarily due to the fact that the platelets of animals fed these oils cannot produce sufficient thromboxanes to maintain the platelet-aggregation reaction after the initial stimulus has gone. As a result of this low thrombotic tendency of the platelets, diminished production of vascular PGI-like material is without consequences. The thrombogenicity of cod-liver oil is further decreased because this oil induces the expression of a plasma factor which inhibits blood coagulation induced by vascular damage.2 Although linseed and cod liver oil are at least as antithrombotic as sunflower-seed oil,2 one cannot predict from our animal data that the effect of these oils would be beneficial in man. Feeding (n-3) fatty acids causes major changes in the composition of cardiac lipids which have important consequences for cellular metabolism and lead to cardiac necrosis.6,7 Moreover, a large intake of (n-3) fatty acids may be respon-
SIR,-Dyerberg
(n-3) fatty
Dyerberg J, Bang HO, Stoffersen E, Moncada S, Vane JR. Eicosapentaenoic acid and prevention of thrombosis and atheroclerosis? Lancet 1978; ii:
117-19. 2. Hornstra G, Hemker HC. Clot
SiR,-You accept (Oct. 6, p. 725) uncritically that radioactive xenon wash-out techniques measure regional cerebral blood-flow. The many assumptions that have to be made are so unlikely to be fulfilled that the whole concept of a picture of cerebral blood-flow based on xenon washout may be invalid. The method can be written in its simplest form as follows: cerebral blood-flow (CBF)=volume (V) rate of washout ()), where V=volume of distribution and i, is the washout rate (not the partition coefficient as in some publications). The assumption is that the xenon is diffused throughout the brain, but there is, for example, no evidence for or against the uptake of xenon by neuroglia or capillary endothelium. The theory requires rapid influx of xenon and rapid simultaneous efflux of xenon in proportion to blood-flow. There is no evidence for this. This assumption is valid for the washout of xenon from muscle by capillary flow, but, unlike the muscle capillaries, the capillaries of the brain have no pores.’ Xenon is highly lipid soluble and is likely to persist in the blood-brain barrier through which it must pass. To correct for some of these effects, V is multiplied by a partition coefficient (P) which is different for white and grey matter but has not been measured for neuroglia. Usually a "mean" partition coefficient is set at, for example, 1.1.2 This may be satisfactory for normal brain but may not be appropriate for asymmetrical brain disease such as epilepsy or cerebrovascular disorder. The equation is then rewritten: CBF=VxPx ml/min. Since neither V nor P is known, a method of eliminating V was devised whereby cerebral perfusion (CP) instead of CBF was derived. With CP=CBF/unit weight of tissue (W) the equation becomes: CP=VxPxVW. Since W/V is density (p, g/ml) CP=P x Vp ml/min/g, and for p= 1, CP=P x X. Thus incorporating density in g/ml and putting it to equal unity has units of ml/min/g to cerebral perfusion, yet onlyits measured whose units --: "per min". Thus the assumptions of constancy of V and P are essential to the interpretation of the results ofin terms of cerebral perfusion. It can thus be appreciated that xenon washout does not measure regional CBF when a washout curve is obtained over a region of the brain. Further, since CP=Pxa and since P is not measured, there is no way of distinguishing the one from the other. Metabolic activity may well affect P, which is approximated by the partition of xenon between lipid and water. Metabolic activity in the capillary endothelium, blood-brain barrier, and brain cells burns sugar and creates water. Thus the lipid/water ratio intracellularly must alter with metabolic activity. Indeed a relation between CP and oxygen consumption has been demonstratedIt is just as likely, therefore that the localisations of function summarised in your editorial are primarily due to changes in metabolic activity alone or changes in both metabolic activity and flow. The xenon washout technique cannot indicate the proportion of each.
given
6. 7.
promoting effect of platelet-vessel wall inter-
Influence of dietary fats and relation to arterial thrombus formain rats. Hæmostasis 1979; 8: 211-26. 3. Ten Hoor F, De Deckere EAM, Haddeman E, Hornstra G, Quadt JFA. Dietary manipulation of prostaglandin and thromboxane synthesis in heart, aorta and blood platelets of the rat. Adv Prostagl Thrombox Res (in action: tion
press). 4. Hornstra G, Christ-Hazelhof E, Haddeman E, Nugteren DH, Teen Hoor F. Fish oil feeding lowers thromboxane and prostacyclin formation by rat platelets and aorta and does not result in the production of PGI3. Unpublished. 5. Needleman P, Raz A, Minkes MS, Ferrendelle JA, Sprecker H. Triene prostaglandins: prostacyclin and thromboxane biosynthesis and unique biological properties. Proc Nat Acad Sci USA 1979; 76: 944-48.
G. HORNSTRA E. HADDEMAN F. TEN HOOR
IMAGES OF BRAIN FUNCTION
OILS, PROSTAGLANDINS, AND ARTERIAL THROMBOSIS
1.
sible for yellow-fat disease, a generalised disorder of fatty depots observed in a wide variety of animals.8 It would be premature to urge the widespread use of (n-3) fatty acid diets.
Gudbjarnason S. Prostaglandins and polyunsaturated fatty acids in heart muscle. J Mol Cell Cardiol 1975; 7: 443-49. Gudbjarnason S, Oskarsdottir G. Modification of fatty acid composition of rat heart lipids by feeding cod liver oil. Biochem Biophys Acta 1977; 487:
10-15. 8. Ruiter A,
Jongbloed AW, Van Gent CM, Danse LHJC, Metz SHM. The indietary mackerel oil on the condition of organs and on blood lipid compisition in young growing pigs. Am J Clin Nutr 1978; 31: fluence of
2159-66. 1. Olendorf WH. Molecular criteria for blood brain barrier penetration. In: Deblanc HJ, Sorensen JA, eds. Non invasive brain imaging. New York: Society of Nuclear Medicine, 1975: 17-23. 2. Wilkinson IMS, Bull JWD, Du Boulay GH, Marshall J, Ross Russell RW, Symon L. Regional blood flow in the normal cerebral hemisphere. J Neurosurg Psychiat 1969; 32: 367-78. 3. Lassen NA. Cerebral blood flow and oxygen consumption in man. Physiol Rev 1959; 39: 183-238.
FISH
J. MENDLEWICZ P. LINKOWSKI H.BRAUMAN
Unilever Research, 3130 AC Vlaardingen, Netherlands
et al.’ suggested dietary enrichment with acids for the prevention of arterial thrombosis and atherosclerosis. A major natural source of (n-3) fatty acids is linseed oil, which contains about 50% (9, 12, 15)-linolenic acid (18:3 n-3; ot-LA). By desaturation and chain elongation oc-LA is metabolised to eicosapentaenoic acid (20:5 n-3; EPA) which can also be taken up directly from certain fish oils. EPA is the precursor of platelet thromboxane A3 (TXA3) which, unlike TXAz which is derived from arachidonic acid (20:4 n-6; AA), has no aggregating power.’ In the vessel wall EPA should be metabolised to prostaglandin 3 (PGI3) which might be as effective an anti-aggregating substance as PGl2 (prostacyclin), derived from AA. Dyerberg et al. reasoned that increasing tissue EPA might shift the thromboxane-prostacyclin balance towards a less thrombogenic state. We have found that diets rich in cod liver oil, linseed oil, and sunflower-seed oil all lower the tendency to arterial thrombosis in rats, in contrast to hardened coconut oil. With the cod liver and linseed oil diets this change coincided with a significantly reduced production of platelet thromboxanes (measured as malondialdehyde) and vascular prostacyclin (measured as unstable platelet aggregation inhibiting substance). Sunflowerseed oil, on the other hand, had no such effect. 2.3 The lower prostaglandin production upon feeding (n-3) fatty acids could be explained on the basis of the fatty-acid spectra of platelet and vessel wall lipids as well as by the fact that EPA is a poor substrate for the production of cyclic prostaglandin endoperoxides,4,s the precursor of thromboxanes and prostacyclin. We suggest that the low thrombogenicity of linseed oil and cod liver oil diets is primarily due to the fact that the platelets of animals fed these oils cannot produce sufficient thromboxanes to maintain the platelet-aggregation reaction after the initial stimulus has gone. As a result of this low thrombotic tendency of the platelets, diminished production of vascular PGI-like material is without consequences. The thrombogenicity of cod-liver oil is further decreased because this oil induces the expression of a plasma factor which inhibits blood coagulation induced by vascular damage.2 Although linseed and cod liver oil are at least as antithrombotic as sunflower-seed oil,2 one cannot predict from our animal data that the effect of these oils would be beneficial in man. Feeding (n-3) fatty acids causes major changes in the composition of cardiac lipids which have important consequences for cellular metabolism and lead to cardiac necrosis.6,7 Moreover, a large intake of (n-3) fatty acids may be respon-
SIR,-Dyerberg
(n-3) fatty
Dyerberg J, Bang HO, Stoffersen E, Moncada S, Vane JR. Eicosapentaenoic acid and prevention of thrombosis and atheroclerosis? Lancet 1978; ii:
117-19. 2. Hornstra G, Hemker HC. Clot
SiR,-You accept (Oct. 6, p. 725) uncritically that radioactive xenon wash-out techniques measure regional cerebral blood-flow. The many assumptions that have to be made are so unlikely to be fulfilled that the whole concept of a picture of cerebral blood-flow based on xenon washout may be invalid. The method can be written in its simplest form as follows: cerebral blood-flow (CBF)=volume (V) rate of washout ()), where V=volume of distribution and i, is the washout rate (not the partition coefficient as in some publications). The assumption is that the xenon is diffused throughout the brain, but there is, for example, no evidence for or against the uptake of xenon by neuroglia or capillary endothelium. The theory requires rapid influx of xenon and rapid simultaneous efflux of xenon in proportion to blood-flow. There is no evidence for this. This assumption is valid for the washout of xenon from muscle by capillary flow, but, unlike the muscle capillaries, the capillaries of the brain have no pores.’ Xenon is highly lipid soluble and is likely to persist in the blood-brain barrier through which it must pass. To correct for some of these effects, V is multiplied by a partition coefficient (P) which is different for white and grey matter but has not been measured for neuroglia. Usually a "mean" partition coefficient is set at, for example, 1.1.2 This may be satisfactory for normal brain but may not be appropriate for asymmetrical brain disease such as epilepsy or cerebrovascular disorder. The equation is then rewritten: CBF=VxPx ml/min. Since neither V nor P is known, a method of eliminating V was devised whereby cerebral perfusion (CP) instead of CBF was derived. With CP=CBF/unit weight of tissue (W) the equation becomes: CP=VxPxVW. Since W/V is density (p, g/ml) CP=P x Vp ml/min/g, and for p= 1, CP=P x X. Thus incorporating density in g/ml and putting it to equal unity has units of ml/min/g to cerebral perfusion, yet onlyits measured whose units --: "per min". Thus the assumptions of constancy of V and P are essential to the interpretation of the results ofin terms of cerebral perfusion. It can thus be appreciated that xenon washout does not measure regional CBF when a washout curve is obtained over a region of the brain. Further, since CP=Pxa and since P is not measured, there is no way of distinguishing the one from the other. Metabolic activity may well affect P, which is approximated by the partition of xenon between lipid and water. Metabolic activity in the capillary endothelium, blood-brain barrier, and brain cells burns sugar and creates water. Thus the lipid/water ratio intracellularly must alter with metabolic activity. Indeed a relation between CP and oxygen consumption has been demonstratedIt is just as likely, therefore that the localisations of function summarised in your editorial are primarily due to changes in metabolic activity alone or changes in both metabolic activity and flow. The xenon washout technique cannot indicate the proportion of each.
given
6. 7.
promoting effect of platelet-vessel wall inter-
Influence of dietary fats and relation to arterial thrombus formain rats. Hæmostasis 1979; 8: 211-26. 3. Ten Hoor F, De Deckere EAM, Haddeman E, Hornstra G, Quadt JFA. Dietary manipulation of prostaglandin and thromboxane synthesis in heart, aorta and blood platelets of the rat. Adv Prostagl Thrombox Res (in action: tion
press). 4. Hornstra G, Christ-Hazelhof E, Haddeman E, Nugteren DH, Teen Hoor F. Fish oil feeding lowers thromboxane and prostacyclin formation by rat platelets and aorta and does not result in the production of PGI3. Unpublished. 5. Needleman P, Raz A, Minkes MS, Ferrendelle JA, Sprecker H. Triene prostaglandins: prostacyclin and thromboxane biosynthesis and unique biological properties. Proc Nat Acad Sci USA 1979; 76: 944-48.
G. HORNSTRA E. HADDEMAN F. TEN HOOR
IMAGES OF BRAIN FUNCTION
OILS, PROSTAGLANDINS, AND ARTERIAL THROMBOSIS
1.
sible for yellow-fat disease, a generalised disorder of fatty depots observed in a wide variety of animals.8 It would be premature to urge the widespread use of (n-3) fatty acid diets.
Gudbjarnason S. Prostaglandins and polyunsaturated fatty acids in heart muscle. J Mol Cell Cardiol 1975; 7: 443-49. Gudbjarnason S, Oskarsdottir G. Modification of fatty acid composition of rat heart lipids by feeding cod liver oil. Biochem Biophys Acta 1977; 487:
10-15. 8. Ruiter A,
Jongbloed AW, Van Gent CM, Danse LHJC, Metz SHM. The indietary mackerel oil on the condition of organs and on blood lipid compisition in young growing pigs. Am J Clin Nutr 1978; 31: fluence of
2159-66. 1. Olendorf WH. Molecular criteria for blood brain barrier penetration. In: Deblanc HJ, Sorensen JA, eds. Non invasive brain imaging. New York: Society of Nuclear Medicine, 1975: 17-23. 2. Wilkinson IMS, Bull JWD, Du Boulay GH, Marshall J, Ross Russell RW, Symon L. Regional blood flow in the normal cerebral hemisphere. J Neurosurg Psychiat 1969; 32: 367-78. 3. Lassen NA. Cerebral blood flow and oxygen consumption in man. Physiol Rev 1959; 39: 183-238.
