1219

’ hypertension, the latter that autonomic overactivityraises pressure and that the kidney maintains hyperten-sion thereafter. Stepwise interaction of the two was not

. discussed.

Requests for reprints should be addressed to A. F. L.

REFERENCES

1. Conway, J. Circulation Res. 1970, 26, suppl. 1, 43.2. Julius, S., Pascual, A. V., London, R. Circulation, 1971, 44, 413.3. Cuche, J. L., Kuchel, O., Barbeau, A., Langlois, Y., Boucher, R., Genest,

J. Circulation Res. 1974, 35, 281.4. Friedman, M., Selzer, A., Rosenblum, H. J. Am. med. Ass. 1941, 117, 92.5. Schalekamp, M. A. D. H., Schalekamp-Kuyken, M. P. A., Birkenhager, W.

H. Clin. Sci. 1970, 38, 101.6. Schalekamp, M. A. D. H., Birkenhager, W. H., Kolsters, G., Lever, A. F.

in Hypertension: Current Problems (edited by A. Distler and H. P.Wolff); p. 133. Stuttgart, 1974.

7. Ledingham, J. M. Practitioner, 1971, 207, 5.8. Brown, J. J., Lever, A. F., Robertson, J. I. S., Schalekamp, M. A. D. Lancet,

1974, ii, 320.9. Richardson, D. W., Honour, A. J., Fenton, G. W., Stott, F. H., Pickering,

G. W. Clin. Sci. 1964, 26, 445.10. Armitage, O., Rose, G. A. ibid. 1966, 30, 325.11. Pickering, G. W. High Blood Pressure. London, 1968.12. Miall, W. E., Chinn, S. Clin. Sci. molec. Med. 1973; 45, 23s.13. Floyer, M. A. Clin. Sci. 1951, 10, 405:14. Thal, A. P., Grage, T. B., Vernier, R. L. Circulation, 1963, 27, 36.15. Jerums, G., Doyle, A. E. Clin. Sci. 1969, 37, 79.16. Lebel, M., Schalekamp, M. A., Beevers, D. G., Brown, J. J., Davies, D. L.,

Fraser, R., Kremer, D., Lever, A. F., Morton, J. J., Robertson, J. I. S.,Tree, M., Wilson, A. Lancet, 1974, ii, 308.

17. Brunner, H. R., Sealey, J. E., Laragh, J. H. Circulation Res. 1973, 32,suppl. 1, 99.

18. Beevers, D. G., Brown, J. J., Cuesta, V., Davies, D. L., Fraser, R., Lebel,M., Lever, A. F., Morton, J. J., Oelkers, W., Robertson, J. I. S., Schale-kamp, M. A., Tree, M. J. Steroid Biochem. 1975, 6, 779.

19. Tarazi, R. C., Frohlich, E. D., Dustan, H. P. New Engl. J. Med. 1968, 278,762.

20. Schalekamp, M. A., Beevers, D. G., Kolsters, G., Lebel, M., Fraser, R., Bir-kenhager, W. H. Lancet, 1974, ii, 310.

21. Engelman, K., Portnoy, B., Sjoerdsma, A. Circulation Res. 1970, 27, suppl.1, 141.

22. Louis, W. J., Doyle, A. E., Anavekar, S. N. Chua, K. G. Clin. Sci. molec.Med. 1973, 45, 119s.

23. Geffen, L. B., Rush, R. A., Louis, W. J., Doyle, A. E. Clin. Sci. 1973, 44,421.

24. Korner, P. I., Shaw, J., Uther, J. B., West, M. J., McRitchie, R. J., Richards,J. G. Circulation, 1973, 48, 107.

25. Frohlich, E. D., Tarazi, R. C., Dustan, H. P. Am. J. med. Sci. 1969, 257,9.

26. Ibrahim, M. M., Tarazi, R. C., Dustan, H. P., Bravo, E. L. Am. Heart J.1974, 88, 724.

27. Lorimer, A. R., MacFarlane, P. W., Provan, G., Duffy, T., Lawrie, T. D.V. Cardiovasc. Res. 1971, 5, 169.

28. Esler, M. D., Nestel, P. J. clin. Sci. 1973, 44, 213.29. Brod, J. in Neural and Psychological Mechanisms in Cardiovascular Disease

(edited by A. Zanchetti), p. 93. Milan, 1972.30. Brown, J. J., Fraser, R., Lever, A. F., Morton, J. J., Robertson, J. I. S.,

Schalekamp, M. A. in "An International Textbook on Hypertension"(edited by J. Genest); (in the press).

31. Birkenhager, W. H., Schalekamp, M. A. D. H., Krauss, X. H., Kolsters, G.,Schalekamp-Kuyken, M. P. A., Kroon, B. J. M., Teulings, F. A. G., Eur.J. Clin. Invest. 1972, 2, 115.

32. Schalekamp, M. A., Kolsters, G., Zaal, G., Birkenhager, W. H., Padfield, P.L., Beevers, G., Brown, J. J., Lever, A. F., Robertson, J. I. S. in Hyper-tension: Its Nature and Treatment (edited by D. M. Burley, G. F. B. Bird-wood, J. H. Fryer, and S. H. Taylor); p. 147. Horsham, 1975.

33. Brown, J. J., Cuesta, V., Davies, D. L., Lever, A. F., Morton, J. J., Padfield,P. L., Robertson, J. I. S., Trust, P., Bianchi, G., Schalekamp, M. A. D.Lancet, i, 1219.

34. Miller, N. E., Dicara, L. V., Solomon, H., Weiss, J. M., Dworkin, B. Circula-tion Res. 1970, 26, suppl. 1, 3.

35. Henry, J. P., Stephens, P. M., Santisteban, G. A. ibid. 1975, 36, 156.36. Hallback, M. Acta physiol. scand, 1975, 93, 455.37. Patel, C., North, W. R. S. Lancet, 1975, ii, 93.38. Kristt, D. A., Engel, B. T. Circulation, 1975, 51, 370.39. Wheatley, D., Balter, M., Levine, J., Lipman, R., Bauer, M. L., Bonato, R.

Br. J. Psychiat 1975, 127, 327.40. Dahl, L. K., Heine, M. Circulation Res. 1975, 36, 692.41. Bianchi, G., Fox, U., DiFrancesco, G. F., Bardi, U., Radice, M. Clin. Sci.

molec. Med. 1973, 45, 135s.42. Goldblatt, H. Physiol. Rev. 1947, 27, 120.43. Borst, J. G G., Borst-de-Geus, A. Lancet, 1963, i, 677.44. Guyton, A. C., Cowley, A. W., Coleman, T. G., Liard, J. F., McCaa, R. E.,

Manning, R. D., Norman, R. A., Young, D. B. in Mechanisms of Hyper-tension (edited by M. P. Sambhi), p. 16. Amsterdam, 1973.

45. Folkow, B. in Pathophysiology and Management of Arterial Hypertension(edited by G. Berglund, L. Hansson, and L. Werko); p. 95. Göteborg1975.

MECHANISM OF RENAL HYPERTENSION

J. J. BROWND. L. DAVIESJ. J. MORTON

J. I. S. ROBERTSON

V. CUESTAA. F. LEVER

P. L. PADFIELDP. TRUST

M.R.C. Blood Pressure Unit, Western Infirmary,Glasgow G11 6NT

G. BIANCHI

Ospedale Maggiore di Milano, Ospedale Policlinico, Istitutodi Clinica Medica, 1 Padiglione Granelli, Universita Degli

Studi di Milano, 20122 Milano, Italy

M. A. D. SCHALEKAMP

Academische Ziekenhuis Rotterdam, Rotterdam-3002,The Netherlands

Summary Renal hypertension of the two-kidneytype is divided into three stages. In the

first, hypertension results from the vasoconstrictor effectof angiotensin II. This persists to some extent in thesecond phase but there is in addition a slow-developingpressor effect, also resulting from angiotensin II and

probably attributable to sodium. In the first two phasesremoval of the abnormal kidney corrects the hyperten-sion. This fails in the third phase because changes in theopposite kidney maintain hypertension. Renin and

angiotensin are probably not involved at this stage.

INTRODUCTION

THE mechanism of renal hypertension is disputed. Ithas long been suspected that excess renin is releasedfrom an abnormal kidney, but peripheral plasma con-centrations of renin are not always increased 1 andremoval of the abnormal kidney does not always reduceblood-pressure.3 These observations can be reconciledby separating the two-kidney form of renal hypertension(two-kidney hypertension results from unilateral renal-artery constriction with the opposite kidney untouched;in one-kidney hypertension the opposite kidney is

removed) into three stages (fig. 1). Our concern here iswith the mechanism of the second; the first and third arediscussed elsewhere.5-7

PHASE I AND TRANSITION TO PHASE II

Constriction of a main renal artery in the dog raises

Fig. I-Arbitrary subdivision of two-kidney hypertension into 3 phases onbasis of arterial pressure, plasma renin and angiotensin H, and reduc-tion of blood-pressure on removing the renal lesion.

1220

blood-pressure within minutes. Plasma concentrations ofrenin and angiotensin n also rise and the concentrationsreached are probably sufficient to account for the hyper-tension by acute vasoconstriction.1 6 8 This is phase i.

After a few days renin decreases but hypertension per-sists or worsens; 1 2 8 9 for a given plasma-renin concen-tration blood-pressure is now higher than in normal

dogs acutely infused with renin.’ Similarly, the regres-sion of arterial pressure and plasma-angiotensin-n con-centration is higher in patients with chronic renal hyper-tension than in normal subjects acutely infused withangiotensin n (fig. 2).’ 10 This is phase n (fig. 1). Itcontrasts with phase i where, in the dog, the two regres-sions are the same.6

Phase n is also characterised by correction of hyper-tension on removal of the renal lesion (fig. 1). When

PLASMA ANGIOTENSIN II CONCENTRATION pq ml

Fig. 2-Relation of arterial pressure with venous (0) and arterial () plas-ma-angiotensin-II in normal subjects before and during infusion ofangiotensin II.Comparison with venous plasma-angiotensin-II in patients with

renal hypertension’ (A) malignant and benign with ([]) or without (A)renal failure.

Mean B.P.(mm Hg)

Fig. 3-Relation of arterial pressure and plasma-angiotensin-II in patientswith renal hypertension before and after technically successful sur-gery,Patient with the highest pressure and angiotensin had a renin-sec-

reting tumour. The regressions for hypertensive and normal subjectsare taken from fig. 2. before surgery; after surgery.

hypertension is corrected surgically in man the abnor-mal relation of angiotensin ii and pressure is correctedas well (fig. 3). When blood-pressure does not fall the ab-normality persists.’ The return to normal is slow. Fig.4 shows the effect of infusing angiotensin 11 on threeoccasions in a hypertensive woman with renal arterythrombosis. Pre-operatively, angiotensin and arterial

pressure were abnormally related before and during in-fusion of angiotensin. Nine days after nephrectomy,pressure and angiotensin ii had fallen but their relationwas still abnormal with the lower end of the first curveclose to the upper end of the second. After sixteen weeksthe relation was more nearly normal. This suggests arapid component reducing pressure along the axis A-B(fig. 4) and a slow component shifting the axis from Bto C. As described, the onset of renal hypertension in thedog is characterised by the reverse; a rapid componentshifting pressure along an axis equivalent to D and aslow component shifting the axis from D to E.

Fig. 4-3 studies (A, B, and C) of arterial pressure and plasma-angiotensin-n before and during angiotensin infusion in a patient with renal arterythrontbotit and severe hypertension.Study A was done before operation, study B 9 days after operation,

study C 16 wk after operation. The lower regression (E) is for normalsubjects infused with angiotensin, the upper for renal hypertension(from fig. 2).

Fig. 5-Relation between the fall of mean arterial pressure following infu-sion of saralasin and plasma-angiotensin-II before infusion in patientswith renal hypertension.Data from Brown et al.11

1221

Mechanism of Rapid ComponentIntravenous infusion of saralasin," a competitive

antagonist of the acute pressor effect of angiotensin 11,12 reduces arterial pressure in renal hypertension to anextent which is closely related to basal plasma-angioten-sin-n concentration (fig. 5). This suggests that the vaso-constrictor action of angiotensin ii persisting in phase uis related to the plasma concentration of angiotensin nand that when angiotensin is normal the effect is smallor negligible.Mechanism of Slow Component

Angiotensin may also produce the slow component.Apart from its pressor effect, angiotensin raises blood-pressure gradually when infused at a low but constantrate.13 A renin-secreting tumour also produces persis-tently increased angiotensin n. A patient of this typestudied by us10 14 had hypertension, increased

angiotensin n, and an abnormal relation of angiotensinand pressure which reversed when excision of theaffected kidney restored normal blood-pressure (figs. 2and 3).

It is not clear how angiotensin ii produces the slowcomponent. Retention of sodium and water may be in-volved : infusion of angiotensin at low dose has thiseffect’s and, as sodium is retained, less angiotensin isneeded to maintain a constant increase of pressure; 16sodium retention occurs in the dog during transitionfrom phase i to phase III 9 and increasing dietary sodiumin normal dogs enhances the pressor response to angio-tensin 11.17 Thus, sodium retention produced by angio-tensin may raise the regression of angiotensin andarterial pressure from that found in angiotensin-infusednormal subjects towards that found in chronic renalhypertension (fig. 2). A shift of this sort occurs whensodium intake is increased in normal’8 and anephric’9subjects.Abnormal Equilibrium of Renin and SodiumThe rentention of sodium during transition to phase

II is transient’ 9 but the relation of renin and sodium

probably remains abnormal after equilibrium is reachedin animals20 and in hypertensive patients with renalartery stenosis7 or chronic renal failure .21 22 In one-kid-

ney hypertension the sodium retention is more markedand dependence of hypertension on sodium is greater; intwo-kidney hypertension the rise of renin is more

marked and dependence of hypertension on renin is

greater.20 23 24 This probably occurs because more

sodium and water is lost from the untouched than fromthe clipped kidney25 26 and, with the untouched kidneypresent, equilibrium shifts towards sodium loss with in-creased renin. When hypertension is acute, or severe, theshift may be so marked as to produce sodium depletionwith further stimulation of renin, angiotensin n, andaldosterone.27 28

Interaction of Angiotensin II and SodiumWe are less certain of the way in which angiotensin

11 and sodium interact to raise blood-pressure. Fivemechanisms which may be directly or indirectly involvedare discussed elsewhere in more detail. In brief, they in-volve the phenomenon of autoregulation,29 30 a struc-tural change of small blood-vessels,3l increased re-

sponse of vascular smooth muscle,32 decreasedcompliance or distensibility of the interstitial space,33

and an action of angiotensin on the central nervous sys-tem.34

PHASE III

Phase III develops when removal of the abnormal kid-ney fails to reduce blood-pressure (fig. 1). This occurs inman and animals3 4 and there is clear evidence thatchanges produced in the opposite kidney are respon-sible.3 4 35 The same process probably accounts for theoccasional failure of technically successful surgery toreduce blood-pressure in Conn’s syndrome, phæochro-mocytoma, and Cushing’s syndrome.7 35 It may alsomaintain pressure in the late stages of essential hyper’-tension. 16-31 Renin probably plays no part in phase III.

Requests for reprints should be addressed to A. F. L.

REFERENCES

1. Bianchi, G., Tenconi, L. T., Lucca, R. Clin. Sci. 1970, 38, 741.2. Brown, T. C., Davis, J. O., Olichem, M. J., Johnston, C. I. Circulation Res.

1966, 18, 475.3. Floyer, M. A. Clin. Sci. 1951, 10, 405.4. Thal, A. P., Grage, T. B., Vernier, R. L. Circulation, 1963, 27, 36.5. Cuesta, V., Bianchi, G., Brown, J. J., Caravaggi, A. M., Davies, D. L.,

Deheneffe, J., Fraser, R., Lever, A. F., Morton, J. J., Oelkers, W., Robert-son, J. I. S., Schalekamp, M. A. Proc. int. Soc. Nephrol. (in the press).

6. Caravaggi, A. M., Bianchi, G., Brown, J. J., Lever, A. F., Morton, J. J.,Powell-Jackson, J. D., Robertson, J. I. S., Semple, P. F. Circulation Res.1976 (in the press).

7. Brown, J. J., Fraser, R., Lever, A. F., Morton, J. J., Robertson, J. I. S.,Schalekamp, M. A. in An International Textbook on Hypertension(edited by J. Genest); 1976.

8. Miller, E. D., Samuels, A. I., Haber, E., Barger, A. C. Am. J. Physiol. 1975,228, 448.

9. Liard, J. F., Cowley, A. W., McCaa, R. E., McCaa, C., Guyton, A. C. Circu-lation Res. 1974, 34, 549.

10. Beevers, D. G., Brown, J. J., Cuesta, V., Davies, D. L., Fraser, R., Lebel,M., Lever, A. F., Morton, J. J., Oelkers, W., Robertson, J. I. S., Schalek-amp, M. A., Tree, M. J. Steroid Biochem. 1975, 6, 779; Beevers, D. G.,Brown, J. J., Fraser., R., Lever, A. F., Morton, J. J., Robertson, J. I. S.,Semple, P. F., Tree, M. Kidney International, 1975, 8, suppl. 1, 181.

11. Brown, J. J., Brown, W. C. B., Fraser, R., Lever, A. F., Morton, J. J.,Robertson, J. I. S., Agabiti-Rosei, E., Tree, M., Trust, P. M. in TheEffects of Antihypertensive Therapy (edited by M. Sambhi). Amsterdam(in the press).

12. Pals, D. T., Masucci, F. D., Sipos, F., Denning, G. S. Circulation Res. 1971,29, 664.

13. Dickinson, C. J., Yu, R. ibid. 1967, 21, suppl. 2, 157,14. Brown, J. J., Fraser, R., Lever, A. F., Morton, J. J., Robertson, J. I. S., Tree,

M., Bell, P. R. F., Davidson, J. K., Ruthven, I. S. Lancet, 1973, ii, 1228.15. De Bono, E., Lee, G. De J., Mottram, F. R., Pickering, G. W., Brown, J.

J., Keen, H., Peart, W. S., Sanderson, P. H. Clin. Sci. 1963, 25, 123.16. Ames, R. P., Borkowski, A. J., Sicinski, A. M., Laragh, J. H. J. clin. Invest.

1965, 44, 1171.17. Bianchi, G., Brown, J. J., Lever, A. F., Robertson, J. I. S., Roth, N. Clin.

Sci. 1968, 34, 303.18. Oelkers, W., Brown, J. J., Fraser, R., Lever, A. F., Morton, J. J., Robertson,

J. I. S. Circulation Res. 1974, 34, 69.19. Deheneffe, J., Cuesta, V., Briggs, D., Brown, J. J., Fraser, R., Lever, A. F.,

Morton, J. J., Robertson, J. I. S., Tree, M. ibid. (in the press).20. Tobian, L., Coffee, K., McCrea, P. Am. J. Physiol. 1969, 217, 458.21. Ledingham, J. M. Jl R. Coll. Physns, 1971, 5, 103.22. Schalekamp, M. A., Beevers, D. G., Briggs, J. D., Davies, D. L., Fraser, R.,

Lebel, M., Lever, A. F., Medina, A., Morton, J. J., Robertson, J. I. S.,Tree, M. Am. J. Med. 1973, 55, 379.

23. Swales, J. D., Thurston, H., Queiroz, E. P., Medina, A. J. Lab. clin. Med.1972, 80, 539.

24. Gavras, H., Brunner, H. R., Vaughan, E. D., Laragh, J. H. Science, 1973,180, 1369.

25. Kramer, P., Ochwadt, B. Pflügers Arch. ges. Physiol. 1972, 332, 332.26. Brown, J. J., Peart, W. S., Owen, K., Robertson, J. I. S., Sutton, D. Br. med.

J. 1960, ii, 327.27. Barraclough, M. A. Am. J. Med. 1966, 40, 265.28. Möhring, J., Möhring, B., Naumann, H. J., Philippi, A., Homsy, E., Orth,

H., Dauda, G., Kazda, S., Gross, F. Am. J. Physiol. 1975, 228, 1847.29. Ledingham, J. M., Cohen, R. D. Lancet, 1963, ii, 979.30. Guyton, A. C., Coleman, T. G. Circulation Res. 1969, 24, suppl. 1, 1.31. Folkow, B. Clin. Sci. 1971, 41, 1.32. Tobian, L., Binion, J. T. J. clin. Invest. 1954, 33, 1407.33. Lucas, J., Floyer, M. A. Clin. Sci. molec. Med. 1974, 47, 1.34. Ferrario, C. M., Gildenberg, P. L., McCubbin, J. W. Circulation Res. 1972,

30, 257.35. Pickering, G. W. High Blood Pressure. London, 1968.36. Ledingham, J. M. Practitioner, 1971, 207, 5.37. Brown, J. J., Lever, A. F., Robertson, J. I. S., Schalekamp, M. A. D. Lancet,

1974, ii, 320.38. Brown, J. J., Lever, A. F., Robertson, J. I. S., Schalekamp, M. A. D. ibid.

1976, i, 1217.