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in the proximal renal tubule,12 but now known to involve also a more distal site in the nephron,9 13 probably including the loop of Henle in the deeper cortex and medulla of the kidney. Alterations in G.F.R. or aldosterone secretion cannot account for this natriuresis after E.c.F. expansion, so other factors must be involved, including the stillunidentified "natriuretic" hormone.14 However, in the dog rendered chronically oedematous by thoracic caval constriction, natriuresis does not follow E.C.F. expansion, and proximal tubular reabsorption is normal.9 In the low-output failure produced by chronic valvular lesions in the dog, work with radioactive krypton suggests that sodium retention is associated with a redistribution of intrarenal blood-flow, with reduced flow to the superficial cortical nephrons and a relative increase of flow to the deeper cortex and outer medulla.8 These observations have not been confirmed by investigations using radioactive microspheres,15 but the differences may be connected with anaesthesia 16 as well as with the peculiarities of the peritubular circulation. 17 18 If heart-failure does lead to redistribution of intrarenal blood-flow towards the medulla, for which there is already some evidence in man,19 this may perhaps improve oxygen delivery to the medulla (which even in health has a very low P0220) and so fuel the aerobic demands of sodium reabsorption 14 in the loop of Henle. An increase in medullary blood-flow would also reduce the sodium concentration of the medullary interstitium, so favouring sodium reabsorption8 and accounting for the reduction in maximal concentrating ability which is found in heart-failure. It is tempting to suggest that, in cor pulmonale, despite the normal cardiac output there is a similar redistribution of blood-flow towards the medulla, compensating for any impairment of oxygen delivery which might result from the arterial hypoxaemia. The development of oedema with only a little gain in body-weight6 suggests that body fluids can be redistributed during an exacerbation of cor pulmonale. Pitting ankle oedema becomes detectable only when the leg volume increases by about 10%,and in idiopathic orthostatic oedema pitting may develop when the body-weight rises by about 2 kg, whereas the leg volume may then only increase by some 500 ml. 22 There is normally a strong resistance to flow of fluid between two sites

sorption

Oedema in Cor Pulmonale IN the blue and bloated bronchitic with an exacerbation of cor pulmonale, the cause of oedema remains obscure but the functional abnormalities are becoming cleared. 12 arterialhypoxaemia is combined with hypercapnia and acidosis, although the acidosis is rarely profound. Despite a raised pulmonary arterial pressure the cardiac output is usually normal,2so that the pulmonary vascular resistance is very high. Plasma volume and hxmatocrit are raised, and renal blood-flow is reduced although glomerular filtration-rate (G.F.R.)2 and aldosterone secretion3 may well be normal. Total body-water, exchangeable sodium, and the volume of extracellular fluid (E.C.F.) are all increased when oedema is present,4but surprisingly some patients put on only a little weight as oedema develops.66 Nonetheless, weight usually falls considerably when a diuresis is induced by bed rest, along with controlled oxygen, bronchodilators, and antibiotics, with or without diuretic drugs. The pulmonary arterial pressure then also falls progressively, the cardiac though not always to normal, whereas 2 remains normal output throughout. Even in animals7-1O with experimentally induced congestive heart-failure the mechanisms of sodium retention are still debated, and none of the techniques can reproduce the combination of hypoxia, hypercapnia, and normal cardiac output which characterises human cor pulmonale. In the normal dog an expansion of E.C.F. such as occurs in cor pulmonale would induce natriuresisll-originally thought to result from inhibition of sodium reab1. 2.

Aber, G. M., Bishop, J. M. Clin. Sci. 1965, 28, 511. Abraham, A. S., Cole, R. B., Green, I. D., Hedworth-Whitty, R. B., Clarke, S. W., Bishop, J. M. Circulation Res. 1969, 24, 51. 3. Cox, J. R., Davies-Jones, G. A. B., Leonard, P. J. Clin. Sci. 1964, 26, 177. 4. Farber, S. J., Soberman, R. J. J. clin. Invest. 1956, 35, 779. 5. Cox, J. R., Howard, P., Speight, C. J., Pearson, C. J., Hobson, N. Clin. Sci. 1971, 41, 55. 6. Campbell, R. H. A., Brand, H. L., Cox, J. R., Howard, P. ibid. 1975, 49, 323. 7.

Davis, J. O. in Handbook of Physiology: section 2 (Circulation); vol. III. Am.Physiol. Soc., Washington., 1965. 8. Sparks, H. V., Kopald, H. H., Carriere, S., Chirmoskey, J. G., Kinoshita, M., Barger, A. C. Am. J. Physiol. 1972, 223, 840. 9. Levy, M. J. clin. Invest. 1972, 51, 922. 10 Schneider, E. G., Dresser, T. P., Lynch, R. E., Knox, F. G. Am. J. Physiol. 1971, 220, 952. 11. de Wardener, H. E., Mills, J. H., Clapham, W. F., Hayter, C. J. Clin. Sci. 1961, 21, 249.

12. Dirks, J. W., Cirksena, W., Berliner, R. J. clin. Invest. 1965, 44, 1160. 13. Stein, J. H., Reineck, H. J. Physiol. Rev. 1975, 55, 127. 14. de Wardener, H. E. in Handbook of Physiology, Section 8 (Renal Physiology); Chap. XXI. Am. Physiol. Soc., Washington, 1973. 15. Stein, J. H., Boonjarern, S., Wilson, C. B., Ferris, T. F. Circulation Res. 1973, 32, 33. 16. Warren, D. J., Ledingham, J. G. G. Clin. Sci. mol. Med. 1975, 48, 61. 17. Herd, J. A. Circulation Res. 1973, 32, 72. 18. Jones, L. G., Herd, J. A. Am. J. Physiol. 1974, 226, 886. 19. Kilcoyne, M. M., Schmidt, D. H., Cannon, P. J. Circulation, 1971, 43/44, 2. New Engl. J. Med. 1963, 269, 115. 20. Leonhardt, K. O., Landes, 21. Drury, A. N., Jones, N. W. Heart, 1927, 14, 55. 22. Streeten, D. H., Dalakos, T. G., Souma, M., Fellerman, H., Clift, C. V., Schletter, F. E., Stevenson, C. T., Speller, P. P. Clin. Sci. mol. Med. 1973, 45, 347.

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in the subcutaneous tissues,23 but this resistance suddenly falls when the interstitial volume is expanded by even a small amount, which can suffice to raise the normally negative interstitial pressure to atmospheric, after which a further big increase in tissue volume causes little further rise in interstitial pressure as oedema becomes evident. 23 24 Thus subclinical oedema, which has already produced a rise in body-weight, may become overt after only a small redistribution of total body-water. The reduced compliance of calf veins in patients with heart-failure25 may also be a consequence of subclinical cedema, for it cannot all be attributed to venoconstriction from the increased sympathetic tone which is a feature of congestive failure in man. These new observations emphasise the sterility of any semantic debate as to whether cor pulmonale is merely another form of heart-failure, for at least in physical terms the right ventricle in this condition is performing superbly,26 pumping a normal output against a pressure load which may be three or five times normal. In some cases of cor pulmonale in the bronchitic, salt and water retention may arise from mechanisms very similar to those in the dog with experimental chronic caval constriction. Clinicians have long known that the jugular venous pressure is not invariably raised in all patients with oedematous cor pulmonale,2’ and in some patients caval angiography has shown the flow of blood from the abdomen to the thorax to be inhibited during inspiration, despite the large pressure differential between these two cavities.2g This observation, which like so much in this story still puzzles physiologists, leads one to wonder whether lymphatic flow in the thoracic duct may also be trapped as it passes through the diaphragm, so adding to the factors producing cedema in the lower limbs. Although many of these physiological problems of cor pulmonale in the bronchitic remain unsolved, it is now well-recognised that this complication heralds a serious prognostic phase in chronic bronchitis.29-31However, reversal of at least some of these functional abnormalities-such as pulmonary hypertension and secondary polycythaemia-may yet prove possible, by long-term domiciliary oxygen therapy32-34 which may improve both the duration and the quality of life for these

patients. 23. Guyton, A. C., Granger, H. J., Taylor, A. E. Physiol. Rev. 1971, 51, 527. 24. Snashall, P. D., Boother, F. A. Clin. Sci. mol. Med. 1974, 46, 241. 25. Zelis, R. J. clin. Invest. 1974, 54, 219. 26. Berglund, E. Bull. Physiopath. Resp. 1972. 8, 1417. 27. Campbell, E. J. M., Short, D. S. Lancet, 1960, i, 1184. 28. Nakhjaran, F. K., Palmer, W. H., McGregor, M. M. Circulation, 1966, 33, 8. 29. Renzetti, A. D., McClement, J. H., Litt, B. Am. J. Med. 1966, 41, 115. 30. Burrows, B., Earle, R. H. New Engl. J. Med. 1969, 280, 397. 31. Kok-Jensen, A., Sorensen, E., Damsgaard, T. Scand. J. resp. Dis. 1974, 55, 120. 32. Neff, T. A., Petty, T. L. Ann. intern. Med. 1970, 72, 621. 33. Stark, R. D., Finnegan, P., Bishop, J. M. Br. med J. 1973, iii, 467. 34. Leggett, R. J., Cooke, N., Leitch, A. G., Clancy, L., Kirby, B., Flenley, D. C. Clin. Sci. mol. Med. 1975, 49, 10 p.

BISMUTH AND ULCERS

compounds have been used in the treatment of dyspepsia for more than a century’ but over the years doubts have been expressed as to whether such compounds have any specific value. Although they are still regarded as a panacea in many countries, bismuth compounds have steadily decreased in popularity in Britain, and the United States, where some pharmacologists take the view that "there is little reason to recommend bismuth muth’s] continuance in a modern therapeutic armamentarium."2 Lately a new bismuth compound has been introduced, tripotassium dicitrato bismuthate, which is said to be an effective ulcer-healing agent,3 so it may be prudent to re-examine the various claims made for bisBISMUTH

muth. First advocated in the 1850s by Chambers in England and Kussmaul in Germany for use in the treatment of peptic ulcer, bismuth salts such as the carbonate were thought at one time to act as antacids. This belief has been clearly disproved by investigations which show that bismuth carbonate is virtually useless as an antacid. 4s Next it was suggested that bismuth salts might adhere specifically to ulcers or to the gastrointestinal mucosa, with the formation of a "protective layer against erosive chemical attack by acids or pepsin and against physical erosion by passage and movement of food"6-a view still cited today despite contrary evidence.’8 Another hypothesis is that bismuth compounds inhibit the proteolytic activity of gastric juice. Unfortunately, this hypothesis also has suffered a setback, since different investigations have shown, firstly, that the antipeptic activity of bismuth aluminate in vitro is no better than that of magnesium oxide or carbonate9 and, secondly, that this compound, when taken before meals in the recommended fashion, has no detectable effect on proteolytic activity in vivo.1O A background of extravagant claims unsupported by scientific evidence has perhaps produced a degree of scepticism about the actions and possible usefulness of new bismuth preparations such as tripotassium dicitrato bismuthate (T.D.B.) (available in the U.K. as ’DeNol’). The proceedings of a symposium on T.D.B., to which workers who had experience with this preparation were invited, was published lately,3 and some of the participants have also reported their results elsewhere.l’-’3 In the only study of gastric-ulcer healing in man, each of 10 patients with gastric ulcer showed endoscopic improvement on the bismuth compound, compared with only 5 of 10 treated with placebo.14 In each of the investigations on patients with duodenal-ulcer dis11 12 15-17 ulcer healing was significantly faster in ease 1. MacKenna, R. M. B. Liverpool med.-chir J. 1931, 39, 54. 2. Goodman, L. S., Gilman, A. The Pharmacological Basis of Therapeutics; p. 967. New York, 1970. 3. Postgrad. med. J. 1975, 51, suppl. 5. 4. Freezer, C. R. E., Gibson, C. S., Matthews, E. Guy’s Hosp. Rep. 1928, 78, 191. 5. Brindle, J. J. Pharm. Pharmac. 1953, 5, 692. 6. Wilson, T. R. Postgrad. med. J. 1975, 51, suppl. 5, p. 18. 7. Hurst, A. F., Stewart, M. J. Gastric and Duodenal Ulcer. London, 1929. 8. Alstead, S. Lancet, 1941, ii, 420. 9. Bateson, P. R. J. Pharm. Pharmac. 1958, 10, 123. 10. Matts, S. G. F., Swan, C. H. J., Kelleher, J. Br. med. J. 1965, i, 753. 11. Salmon, P. R., Brown, P., Williams, R., Read, A. E. Gut, 1974, 15, 189. 12. Moshal, M. G. S. Afr. med. J. 1975, 49, 1157. 13. Boyes, B. E., Woolf, I. L., Wilson, R. Y., Cowley, D. J., Dymock, I. W. Gut, 1974, 15, 833. 14. Boyes, B. E., Woolf, I. L., Wilson, R. Y., Cowley, D. J., Dymock, I. W. Post-

15.

grad. med. J. 1975, 51, suppl. 5, p. 29. Salmon, P. R. ibid. p. 26.