The Role of Prostaglandins in Human Hypertension

The Role of Prostaglandins in Human Hypertension Michael C. Smith, MD, and Michael J. Dunn, MD • A large body of evidence supports the concept that prostaglandins (PG) are importantly involved in arterial pressure regulation. Various PGs, especially PGE 2 and prostacyclin (PGI 2 ) may influence blood pressure through control of vascular tone, sodium excretion, and renin release. Inhibition of PG synthesis by nonsteroidal antiinflammatory drugs (NSAID) augments the vasoconstrictor response to exogenous pressors such as angiotensin II, arginine vasopressin (AVP), and fludrocortisone. The acute administration of NSAID to either normotensive or untreated hypertensive subjects results in an increase in arterial pressure and peripheral resistance; long-term administration, however, is associated with little or no change in blood pressure, possibly because of a reduction in cardiac output. Although NSAID have little influence on blood pressure in normotensive subjects or untreated hypertensives, inhibition of PG synthesis blunts or abolishes the antihypertensive effect of most antihypertensive agents. NSAID antagonize the vasodepressor action of diuretics, fi-adrenoreceptor antagonists, vasodilators, and converting enzyme inhibitors. Consequently, potent NSAID should be used with caution, if at all, during treatment of hypertensive patients. Numerous studies have examined renal PG production in essential hypertension (EH). The majority have demonstrated reduced basal and stimulated urinary PGE 2 excretion in EH compared to normotensive subjects, but there is substantial overlap. Nevertheless, renal PGE 2 synthesis is significantly decreased in approximately one-third of patients with EH. A recent innovative approach to arterial pressure regulation has focused on dietary supplementation with polyunsaturated fatty acids (PUFA), especially linoleic acid and eicosapentaenoic acid. Several groups have demonstrated that long-term dietary supplementation with PUFA reduces blood pressure in both normotensive individuals and in patients with EH. The beneficial effect of PUFA supplementation may be related to enhanced synthesis of vasodilator or natriuretic PGs. © 1985 by The National Kidney Foundation, Inc. INDEX WORDS: Prostaglandins; hypertension; blood pressure.

T

HE REGULATION of arterial pressure is complex and the pathogenesis of essential hypertension (EH) is incompletely understood. In the past, investigative efforts regarding the pathogenesis of EH have focused primarily on the potential role of vasoconstrictor substances. Recent studies, however, have suggsted that reduced synthesis of vasodilator or natriuretic compounds may be etiologically related to EH. In this regard the role of prostaglandins (PGs) has received considerable attention. 1-3 This brief review will summarize the data for and against the hypothesis that PGs are involved in arterial pressure regulation in both normotensive and hypertensive man. Four major lines of evidence will be reviewed: (1) the ability of endogenous PGs to modulate the vasoconstrictor response to exogenous pressors; (2) the effect of nonsteroidal antiinflammatory drugs From the Department of Medicine, Case Western Reserve University, School of Medicine, Divisions of General Internal Medicine and Nephrology, University Hospitals of Cleveland. This work was supported in part by grants from the National Institutes of Health, HL 00762 and HL 02563. Address reprint requests to Michael C. Smith, MD, University Hospitals of Cleveland, 2065 Adelbert Rd, Cleveland, OH 44/06. © 1985 by The National Kidney Foundation, Inc. 0272-6386/85/020A32-08$03.00/0

A32

(NSAID) on arterial pressure in normotensive and treated and untreated hypertensive subjects; (3) renal PG production in EH; and (4) the effect of polyunsaturated fatty acids (PUFA) on blood pressure. MECHANISM OF PG ACTION ON BP CONTROL

Prostaglandins influence blood pressure through both direct and indirect effects on vascular resistance. Because most PGs, except prostacyclin (PGI z), undergo extensive pulmonary metabolism they function primarily as local hormones or autocoids. Although PGI z does not undergo substantial pulmonary degradation, it is produced at insufficient rates to function as a circulating hormone. 4 Table 1 summarizes the mechanisms by which the various PGs influence vascular tone. Prostacyclin, PGE z and PGD z directly dilate resistance vessels whereas thromboxane Az (TxA z) and PGF Za constrict blood vessels. Prostaglandins also exert indirect control of vascular resistance by virtue of their ability to regulate sodium excretion, renin secretion, and sympathetic tone. 13 Thus, it is apparent that PGs can have both antihypertensive (vasodilator, natriuretic, and antiadrenergic) and prohypertensive (vasoconstrictor and renin stimulatory) effects. The sum total of these actions, Hypertension and the Kidney: Proceedings of a Symposium

A33

PROSTAGLANDINS IN HUMAN HYPERTENSION

Table 1.

PG and Vascular Resistance

1. Vasodilator 2. Vasoconstrictor 3. Natriuretic 4. Renin stimulatory 5. Antiadrenergic

35

PGb; PGE 2 ; PGD 2 TxA 2 ; PGF2a PGE 2 ; PGI 2 ; PGD 2 PGI 2 ; PGE 2 ; PGD 2 PGE 2 ;PGI 2

however, is to reduce vascular tone since inhibition of PG synthesis by NSAID tends to increase blood pressure, whereas infusion of PGI 2 , PGE 2 or maneuvers to increase endogenous PG production decrease arterial pressure. 1.3.5.6

30

25

Increase 20

of

mean BP (mmHg)

15

10

PGs MODULATE THE VASOCONSTRICTOR EFFECT OF EXOGENOUS PRESSORS

5

There is a large body of evidence that supports the concept that PGs are important in modulating the pressor response to exogenous and, by inference, endogenous vasoconstrictors. Since PGE 2 and PGI 2 are important vasodilatory autocoids and pressors such as angiotensin II stimulate PG production, it was reasonable to hypothesize that inhibition of PG synthesis would augment the hypertensive action of vasoconstrictor compounds. Negus et al examined the effect of indomethacin administration on the pressor response to an infusion of angiotensin II in normal volunteers. 7 Inhibition of PG synthesis significantly increased the pressor response to angiotensin II over a dose range of 200 to 1,000 ng/min (Fig 1). Other workers have confirmed these results. 8 Moreover, this effect is not restricted to angiotensin II; the pressor response to fludrocortisone and AVP is also augmented by NSAID. The addition of either indomethacin or ibuprofen significantly enhances the hypertensive response to long-term fludrocortisone administration in normal subjects. 9 Glanzer and his coworkers have shown that administration of arginine vasopressin (AVP) to normotensive subjects results in a slight initial increase in arterial pressure accompanied by a transient increase in peripheral resistance and decline in cardiac output. 10 After 10 to 15 minutes, BP, peripheral resistance, and cardiac output return to preinfusion levels despite continued administration of AVP. On the other hand, when AVP is infused into subjects treated with indomethacin, arterial presisure shows little change. However, peripheral resistance remains significantly increased and cardiac output substantially reduced throughout the infusion of AVP.lO Thus, the sustained increase in vas-

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Fig 1. The increase in mean arterial pressure in response to an infusion of angiotensin II in ten normal subjects during the control period and after the administration of 150 mg of indomethacin over the prior 16 hours. 'P < 0.035; "P < 0.01. (Reprinted with permission,1)

cular resistance is counterbalanced by a decline in cardiac output and BP remains at control levels. Taken together these results suggest an important role for endogenous PGs in modulating the pressor action of vasoactive compounds. EFFECTS OF CYCLO-OXYGENASE INHIBITORS ON CONTROL OF BP

The acute effects of cyclo-oxygenase inhibition on BP differ from the chronic effects in both normotensive and untreated hypertensive subjects. When indomethacin is administered acutely to normal man there is a significant increase in arterial pressure and vascular resistance and a variable decrease in cardiac output. 11.12 The increment in peripheral resistance is offset by a reduction in cardiac output that apparently moderates the hypertensive response. Hermiller and his colleagues investigated both the acute and longerterm hemodynamic response to indomethacin administration in subjects with pulmonary hypertension. 12 A single oral dose of 50 mg of indomethacin resulted in a significant increase in arterial pressure and vascular resistance and a decrease in cardiac index (Fig 2). However, over the next 16 hours continued inhibition of PG synthesis was associated with normalization of BP. Vascular resistance increased further but was offset by a simulta-

A34

SMITH AND DUNN INDOMETHACIN (no 7)

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neous decline in cardiac index which nullified any effect on BP. Given these data it is not surprising that chronic administration of indomethacin or other NSAID have little effect on BP in normotensive and untreated hypertensive patients. 13 -11 Although several studies have demonstrated a small increment in BP from 5 to 12 mm Hg, 18-20 the majority have not shown any significant change in BP. It is most likely that this lack of effect is due to chronic depression of cardiac output, however, reduced renin secretion or altered baroreceptor function may also playa role. Although changes in arterial pressure are negligible when NSAID are given to most normotensive and untreated hypertensive subjects, BP generally increases when NSAID are combined with antihypertensive therapy. Virtually all studies have

Fig 2. The response of blood pressure, vascular resistance, and cardiac index to acute and repeated administration of indomethacin in seven subjects with primary pulmonary hypertension. 'P < .05 v baseline. (Modified and reprinted with permission. 12)

shown that inhibition of PG production significantly blunts or abolishes the depressor response to antihypertensive agents.2.14.11-19.21-24 Watkins et al demonstrated that the addition of indomethacin to either propranolol or bendrofluazide significantly increased both systolic and diastolic blood pressure (Fig 3). These and other results are summarized in Table 2. Indomethacin in doses ranging from 75 to 200 mg daily reduced the antihypertensive effect of diuretics, J3-adrenoreceptor antagonists, vasodilators, and centrally acting (Xagonists. Although the changes in blood pressure were variable, and in some cases small, occasional authors have noted increments in arterial pressure exceeding 30 mm Hg systolic and 25 mm Hg diastolic with the addition of indomethacin to antihypertensive therapy. 19.22 However, the prohypertensive action of NSAID in treated hypertensives is

PROSTAGLANDINS IN HUMAN HYPERTENSION

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not uniform. For example, Abe and his coworkers noted that indomethacin interfered with the antihypertensive effect of captopril only in subjects with low renin hypertension. 2 In addition, Mills and his associates found that although indomethacin attenuated the antihypertensive response to a variety of agents, aspirin in a dose of 1,950 mg/ d had no effect on arterial pressure. 19 Consequently, aspirin may be preferable when NSAID are required in treated hypertensive patients. The mechanism of the prohypertensive effect of NSAID in patients receiving antihypertensive therapy is unknown. It seems quite unlikely that these diverse agents all stimulate PG production as their mode of action. 25 Rather, it is more reasonable to speculate that by eliminating the vasodilator, natriuretic, and antiadrenergic effects of the PGs (Table 1) NSAID make it more difficult for antihypertensive therapy to alter the balance of cardiovascular forces in favor of a reduction in BP. In this regard, some studies have noted decreased sodium excretion and weight gain when NSAID were added to an antihypertensive regimen. '4.22 Table 2.

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Unfortunately, although total peripheral resistance may have increased, this important hemodynamic parameter was not measured in any of the studies summarized in Table 2. . PG PRODUCTION IN ESSENTIAL HYPERTENSION

Because PGs are autocoids and the kidney is central in BP regulation most studies that have examined PG synthesis in human EH have measured urinary PGE 2 excretion. Until recently there was agreement in the literature that urinary PGE 2 excretion was diminished in EH. However, several studies have been unable to confirm these early results and suggest that renal PG synthesis may be normal in EH or dependent on age, sex, renin status and sodium intake. Table 3 summarizes most of the relevant studies regarding urinary PG excretion in EH.20.26-33 In many studies mean values for both basal and furosemide stimulated urinary PGE 2 excretion have been reduced in EH compared to normotensive controls.26-28.34 Although mean PGE 2 excretion is decreased, there is sub-

The Effect of Inhibition of PG Synthesis on Antihypertensive Therapy

Reference

Antihypertensive Regimen

19751a

Furosemide Propranolol; pindolol Thiazide; propranolol Thiazide; propranolol Prazosin Captopril:j: Mixed§ Mixed Atenolol

Patak, Durao, 197721 Lopez-Ovejero, 197814 Watkins, 198022 Rubin, 198023 Abe, 1981 2 Wing, 1981 24 Mills, 198219 Salvetti, 198317

90

asp 18" 14/13t 7 16/9

8 10 16/6 9/2 11/7

"Change in mean arterial pressure; mm Hg. tChange in systolic/diastolic pressure; mm Hg. :j:Low renin hypertension only. §Diuretics; {J-adrenoreceptor antagonists; methyldopa; vasodilators; clonidine.

NSAID

Indomethacin, Indomethacin, Indomethacin, Indomethacin, Indomethacin, Indomethacin, Indomethacin, Indomethacin, Indomethacin,

200 mg/d 100 mg/d 200 mg/d 100 mg/d 100 mg/d 75 to 150 mg/d 75 mg/d 75 mg/d 200 mg/d

A36

SMITH AND DUNN

Table 3. Renal PG Excretion in Human Essential Hypertension Observation

Reference

Abe,

.L Basal and stimulated urine

197726

PGE 2 ' Tan, 197827 Weber, 197928

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Grose, 1980 29

.L Basal urine 6-keto-

Ruilope, 198220

.L Basal urine PGE 2 in low renin

urine PGE 2

prostaglandin F,o t patients Normal basal Normal basal .L Basal urine patients .L Basal urine

Lebel, 198230 Campbell, 198231 Rathaus, 198332 Sato, 198333

urine PGE 2 urine PGE 2 PGE 2 in low renin PGE 2 in females

'Furosemide stimulation. tStable metabolite of PGI 2 .

stantial overlap among patients with EH and normal subjects. 27.34 Despite this lack of clear cut separation, Tan and his colleagues found that one-third of their subjects with EH had profoundly reduced urinary PGE2 excretion (Fig 4). More recent investigations have stratified subjects according to a variety of parameters and have found decreased urinary PG excretion only in subsets of EH. In these studies renal PG production has been found to be normal,30.31 decreased in low renin EH,20.32 reduced in females under the age of 40,33 or only decreased in females on an extremely low sodium intake. 31 Given the heterogeneity of EH, these findings are not surprising. Nevertheless, they provide support for the concept that renal un1100 ~~

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derproduction of PGE2 results in reduced sodium excretion and contributes to the genesis or maintenance of hypertension in at least a subset of patients with EH . Measurements of circulating PGs in EH are more difficult to interpret. Some workers have found increased plasma concentration of PGEl5.36 while one group has reported reduced plasma levels of 6-keto-prostaglandin F 1a (6-keto-PGF 1a), the stable metabolite of PG1 2.37 Safar and colleagues found that increased plasma PGE2 concentrations were directly related to vascular resistance. 35 These data suggest that increased vascular PG production might occur in EH in response to an increased total peripheral resistance. On the other hand, decreased vascular PGI 2 synthesis could directly result in an increase in arterial pressure. 37 With these apparently discrepant results, further investigation is required to clarify the role of systemic PG production in EH. THE EFFECTS OF PUFA ON BP

PUFA are the precursors of PG synthesis and act as substrate for the enzyme fatty acid cyclo-oxygenase (Fig 5). Prostaglandins with 1, 2, and 3 double bonds belong to the monoenoic, dienoic, and trienoic series, respectively. Arachidonic acid, the precursor of the normally prevalent dienoic PGs, is not ingested as such but is synthesized from the 18 carbon fatty acid linoleic acid. In addition, linoleic acid may be converted to dihomo gamma linolenic acid and subsequently to monoenoic PGs. The trienoic PGs are synthesized from eicosapentaenoic acid or its precursor linolenic acid. Whereas sunflower oil and safflower oil are the most abundant sources of linoleic acid, fish oils such as cod liver oil are the predominant sources of eicosapentaenoic acid. Eicosapentaenoic acid is converted to PGE3 and PGI3, both active vasodilator PGs, and to TxA3 a relatively inactive vasoconstrictor. Further, eicosapentaenoic acid competes with arachidonic acid for fatty acid

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A37

PROSTAGLANDINS IN HUMAN HYPERTENSION

Table 4. Reference

Subjects

Vergroesen, 197838 Stern, 198039 Rao, 1981 40 Sanders, 1981 41 Iacono, 19825 Puska, 19836 Mortensen, 198342 Lorenz, 198343

EW EH EH Nt EH;N EH;N N N

Effect of PUFA on BP Fatty Acid

~BP

.l.l.l.l.l.l.l.l-

Sunflower oil Linoleic Cod liver oil PIS = 1; linoleic:j: PIS = 1; linoleic Eicosapentaenoic Cod liver oil

BP BP BP BP BP BP BP BP

• Essential hypertension. tNormotensive subjects. :j:Polyunsaturated/saturated ratio plus i linoleic acid.

significant increments in urinary 6-keto-PGF J" excretion and modest increases in urine PGE 2 .44 Fish oil supplements, rich sources of eicosapentaenoic acid, have effects on blood pressure similar to those of dietary supplementation with linoleic acid. Lorenz and colleagues determined the effect of dietary supplementation with 40 mLid cod liver oil on BP under basal conditions and during the infusion of norepinephrine and angiotensin 11.43 They found a significant reduction in upright systolic blood pressure and systolic pressure during norepinephrine infusion (Fig 6). There were no significant changes in urinary excretion of PGE 2 or PGF 2". Therefore, ifthe reductions in BP were related to changes in renal PG synthesis, they may have been due to increases in trienoic PG production. The possible synergistic action of linoleic or eicosapentaenoic acid with diuretics or other antihypertensive agents has not been examined.

cyclo-oxygenase and can reduce synthesis of the dienoic PGs. The net effect, then, of dietary supplementation with eicosapentaenoic acid would be predicted to increase the ratio of vasodilator/vasoconstrictor PGs. With this background several groups have attempted the novel approach of reducing BP by dietary supplementation with PUFA. Table 4 summarizes the major studies which have manipulated dietary PUFA by supplementation with linoleic acid, eicosapentaenoic acid, or an increase in the polyunsaturated/saturated fat ratio. All of these reports agree that such dietary modification significantly reduces BP both in normal subjects and in patients with EH. Most studies found reductions in systolic and diastolic pressure ranging from 5 to 10 mm. 5 ,6.38·43 The mechanism by which dietary supplementation with linoleic acid decreased BP is unclear but it is tempting to theorize that it may relate to enhanced production of dienoic PGs. Although none of the studies in Table 4 documented increased synthesis of PGs, Epstein and coworkers have shown than an infusion of 10% safflower oil (77 % linoleic acid) in normal subjects results in

ACKNOWLEDGMENT Sharon Nash provided excellent secretarial assistance in the preparation of this manuscript.

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A38

SMITH AND DUNN

REFERENCES 1. Smith MC, Dunn MJ: Renal kallikrein, kinins and prostaglandins in hypertension, in Brenner BM, Stein J (eds): Hypertension, New York, Churchill Livingstone, 1981, pp 168-202 2. Abe K: The kinins and prostaglandins in hypertension. Clin Endocrinol Metab 10:577-605, 1981 3. Gerber JG : Indomethacin-induced rises in blood pressure. Ann Intern Med 99:555-558, 1983 4. Fitzgerald GA, Brash AR , Falardeau P, et al: Estimated rate of prostaglandin secretion into the circulation of normal man. J Clin Invest 68:1272-1275 , 1981 5. Iacono JM, Dougherty RM, Puska P: Reduction of blood pressure associated with dietary polyunsaturated fat. Hypertension 4(suppl III):III34-III42, 1982 6. Puska P, Nissinen A, Vartiainen E, et al: Controlled, randomised trial of the effect of dietary fat on blood pressure. The Lancet 1: 1-5, 1983 7. Negus P, Tannen RL, Dunn MJ : Indomethacin potentiates the vasoconstrictor actions of angiotensin II in normal man. Prostaglandins 12:175-180, 1976 8. Vierhapper H, Waldhausl W, Nowotny P: Effect of indomethacin upon angiotensin-induced changes in blood pressure and plasma aldosterone in normal man. Eur J Clin Invest 11 :85-89, 1981 9. Martin K, Zipser R, Horton R: Effect of prostaglandin inhibition in the hypertensive action of sodium-retaining steroids. Hypertension 3:622-678, 1981 10. Glanzer K, Priibing B, Diising R, et al: Hemodynamic and hormonal responses to 8-arginine-vasopressin in healthy man: Effects of indomethacin. Klin Wochenschr 60: 12341239, 1982 II. Nowak J, Wenmalm A: Influence of indomethacin and of prostaglandin E, on total and regional blood flow in man. Acta Physiol Scand 102:484-491 , 1978 12. Hermiller JB , Bambach D, Thompson MJ, et al : Vasodilators and prostaglandin inhibitors in primary pulmonary hypertension. Ann Intern Med 97:480-489, 1982 13. Donker AJM, Arisz L, Brentjens JRH: The effect of indomethacin on kidney function and plasma renin activity in man. Nephron 17:288-296, 1976 14. Lopez-Ovejero JA, Weber MA, Drayer JIM, et al: Effects of indomethacin alone and during diuretic or J3-adrenoreceptor-blockade therapy on blood pressure and the renin system in essential hypertension . Clin Sci 55 :203s-205s, 1978 15. Ylitalo P, Pitkiijiirvi T, Metsii-Ketelii T, et al: The effect of inhibition of prostaglandin synthesis on plasma renin activity and blood pressure in essential hypertension. Prostaglandins Med 1:479-488, 1978 16. Giillner HG, Gill JR, Bartter FC, et al: The role of the prostaglandin system in the regulation of renal function in normal women. Am J Med 69:718-724, 1980 17. Salvetti A, Pedrinelli R, Magagna A: The influence of indomethacin on some pharmacologic actions of atenolol, in Dunn MJ, Patrono C, Cinotti G (eds): Prostaglandins and the Kidney. New York, Plenum Medical Book Company, 1983, pp 287-295 18. Patak RV, Mookerjee BK, Bentzel CJ , et al: Antagonism of the effects of furosemide by indomethacin in normal and hypertensive man. Prostaglandins 10:649-659, 1975 19. Mills EH, Whitworth JA , Andrews J, et al: Non-ste-

roidal anti-inflammatory drugs and blood pressure. Aust NZ J Med 12:478-482, 1982 20. Ruilope L, Garcia Robles R, Barrientos A, et al: The role of urinary PGE, and renin-angiotensin-aldosterone system in the pathogenesis of essential hypertension. Clin Exper Hyper 4:989-1000, 1982 21. Durao V, Martins Prata M, Pires Goncalves LM: Modification of antihypertensive effect of J3-adrenoreceptor-blocking agents by inhibition of endogenous prostaglandin synthesis. The Lancet 2: 1005-1007, 1977 22 . Watkins J, Abbott EC, Hensby eN, et al: Attenuation of hypotensive effect of propranolol and thiazide diuretics by indomethacin. Br Med J 281:702-705, 1980 23 . Rubin P, Jackson G, Blaschke T: Studies on the clinical pharmacology of prazosin. II: The influence of indoemethacin and of propranolol on the action and disposition of prazosin. Br J Clin Pharmacol 10:33-39, 1980 24. Wing LMH, Bune AJC, Chalmers Jp, et aT: The effects of indomethacin in treated hypertensive patients. Clin Exp Pharmacal Physiol 8:537-541 , 1981 25 . Vlasses PH, Ferguson RK, Smith JB , et al : Urinary excretion of prostacyclin and thromboxane A, metabolites after angiotensin converting enzyme inhibition in hypertensive patients. Prostaglandins Leukotriens Med II: 143-150, 1983 26. Abe K, Yasujima M, Chiba S, et al: Effect of furosemide on urinary excretion of prostaglandin E in normal volunteers and patients with essential hypertension. Prostaglandins 14:513-521, 1977 27. Tan SY, Bravo E, Mulrow PJ : Impaired renal prostaglandin E, biosynthesis in human hypertensive states. Prostaglandins Med 1:76-85, 1978 28 . Weber PC, Scherer B, Held E, et al : Urinary prostaglandins and kallikrein in essential hypertension. Clin Sci 57 :259s261s, 1979 29 . Grose JH, Lebel M, Gbeassor FM: Diminished urinary prostacyclin metabolite in essential hypertension. Clin Sci 59: 121s-123s, 1980 30. Lebel M, Grose JH: Renal prostaglandins in borderline and sustained essential hypertension. Prostaglandins Leukotrienes Med 8:409-418, 1982 31. Campbell WB, Holland OB, Adams BY, et al: Urinary excretion of prostaglandin E" prostaglandin F,. and thromboxane B, innormotensive and hypertensive subjects on varying sodium intakes. Hypertension 4:735-741 , 1982 32. Rathaus M, Korzets Z, Bernheim J: The urinary excretion of prostaglandins E, and F,. in essential hypertension. Eur J elin Invest 13: 13-17, 1983 33. Sato K, Abe M, Seino M, et al: Reduced urinary excretion of prostaglandin E in essential hypertension. Prostaglandins Leukotrienes Med 11:189-197, 1983 34. Tan SY, Sweet P, Mulrow PJ: Impaired renal production of prostaglandin E,: A newly identified lesion in human essential hypertension. Prostaglandins 15: 139-159, 1978 35. Safar ME, Hornych AF, Levenson lA, et al: Central haemodynamic and plasma prostaglandin E, in borderline and sustained essential hypertensives before and after indomethacin. elin Sci 61 :323s-325s, 1981 36. London GM, Hronych A, Safar ME, et al: Plasma prostaglandins PGE, and PGF,., total effective vascular com-

PROSTAGLANDINS IN HUMAN HYPERTENSION pliance and renal plasma flow in essential hypertension. Nephron 32:118-124, 1982 37. Uehara Y, Ishii M, Ikeda T, et al: Plasma levels of 6keto-prostaglandin Fl. in normotensive subjects and patients with essential hypertension. Prostaglandins Leukotrienes Med 10:455-464, 1983 38. Vergroessen AJ, Fleishman AI, Comberg HU, et al: Influence of increased dietary linoleate on essential hypertension in man. Acta BioI Med Germ 37:879-883 , 1978 39. Stern B, Heyden S, Miller D, et al : Intervention study in high school students with elevated blood pressures. Nutr Metab 24:137-147,1980 40. Rao RH, Rao VB, Srikantia SG: Effect of polyunsaturated-rich vegetable oils on blood pressure in essential hypertension. Clin Exp Hypertens 3:27-32 , 1981

A39 41. Sanders TAB, Vickers M , Haines AP: Effect on blood lipids and haemostasis of a supplement of cod-liver oil, rich in eicosapentaenoic and docosahexaenoic acids , in healthy young men. Clin Sci 61:317-324,1981 42. Mortensen JZ, Schmidt EB , Nielsen AH, et al: The effect of N-6 and N-3 polyunsaturated fatty acids on hemostasis. blood lipids and blood pressure . Thromb Haemost 50:543546, 1983 43. Lorenz R, Spengler U, Fischer S, et aI: Platelet function, thromboxane formation and blood pressure control during supplementation of the western diet with cod liver oil. Circulation 67:504- 511,1983 44. Epstein M, Lifschitz M, Rappaport K: Augmentation of prostaglandin production by linoleic acid in man. Clin Sci 63:565-571, 1982