European Journal of Clinical Pharmacology

, Volume 34, Issue 4, pp 323–331 | Cite as

A randomized cross-over study of enalapril in congestive heart failure: Haemodynamic and hormonal effects during rest and exercise

  • I. P. Mulligan
  • A. G. Fraser
  • V. Tirlapur
  • M. J. Lewis
  • R. G. Newcombe
  • A. H. Henderson
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Summary

We performed a randomized double-blind placebo controlled cross-over study of enalapril in 16 patients with chronic congestive heart failure, to assess haemodynamic and hormonal effects at rest and on exercise. Acute effects were measured 4 h after enalapril 10 mg, and chronic effects after 6 weeks treatment with enalapril 10–20 mg per day.

Exercise tolerance, assessed by the duration of a maximal bicycle ergometer test, was not altered by enalapril. Mean blood pressure was reduced after enalapril, at rest and on exercise, acutely by 7% and 8% respectively, and chronically by 14% and 16%. Systemic vascular resistance was reduced by 16% at rest both acutely (NS) and chronically (p<0.05). The resting pulmonary capillary wedge pressure was reduced by 28% with chronic treatment. In the acute study, total body oxygen consumption on exercise was 26% higher after enalapril. Chronically, resting oxygen consumption was reduced by 13% after enalapril, with mixed venous oxygen saturation increasing by 16%.

In the acute study enalapril increased plasma renin activity at rest and on exercise by 181% and by 189%, and reduced aldosterone by 49% (NS) and 39% (p<0.05), and these effects were sustained after 6 weeks. Enalapril increased antidiuretic hormone concentrations at rest acutely by 73% (NS) and chronically by 34% (p<0.05) but not on exercise; the increase in the acute study correlated with plasma enalaprilat levels (r=0.66, p<0.05). Enalapril did not alter plasma catecholamine concentrations.

Patients preferred enalapril to placebo, and radiographic heart size was reduced during chronic treatment. There were no serious adverse effects.

We conclude that enalapril is an effective angiotensin converting enzyme inhibitor of clinical value in chronic heart failure, but study design and methods of assessment of benefit can have a major influence on the results of pharmacological studies in such patients.

Key words

enalapril congestive heart failure haemodynamic-/hormonal effects plasma renin/-aldosterone antidiuretic hormone 
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References

  1. 1.
    Kramer BL, Massie BM, Topic N (1983) Controlled trial of captopril in chronic heart failure: A rest and exercise haemodynamic study. Circulation 67: 807–816Google Scholar
  2. 2.
    Captopril Multicenter Research Group (1983) A placebo-controlled trial of captopril in refractory chronic congestive heart failure. J Am Coll Cardiol 2: 755–763Google Scholar
  3. 3.
    Cleland JGF, Dargie HF, Hodsman GP et al. (1984) Captopril in heart failure. A double-blind controlled trial. Br Heart J 52: 530–535Google Scholar
  4. 4.
    Sharpe DN, Murphy J, Coxon R, Hannan SF (1984) Enalapril in patients with chronic heart failure: A placebo-controlled, randomized, double-blind study. Circulation 70: 271–278Google Scholar
  5. 5.
    Jennings G, Kiat H, Nelson L, Kelly MJ, Kalff V, Johns J (1984) Enalapril for severe congestive heart failure. A double-blind study. Med J Aust 141: 723–726Google Scholar
  6. 6.
    Franciosa JA, Wilen MM, Jordan RA (1985) Effects of enalapril, a new angiotensin-converting enzyme inhibitor, in a controlled trial in heart failure. J Am Coll Cardiol 5: 101–107Google Scholar
  7. 7.
    Creager MA, Massie BM, Faxon DP et al. (1985) Acute and longterm effects of enalapril on the cardiovascular response to exercise and exercise tolerance in patients with congestive heart failure. J Am Coll Cardiol 6: 163–170Google Scholar
  8. 8.
    Cleland JGF, Dargie HJ, Ball SG et al. (1985) Effects of enalapril in heart failure: a double-blind study of effects on exercise performance, renal function, hormones, and metabolic state. Br Heart J 54: 305–312Google Scholar
  9. 9.
    McGrath BP, Arnolda L, Matthews PG et al. (1985) Controlled trial of enalapril in congestive cardiac failure. Br Heart J 54: 405–414Google Scholar
  10. 10.
    The Consensus Trial Study Group (1987) Effects of enalapril on mortality in severe congestive heart failure. N Engl J Med 316: 1429–1435Google Scholar
  11. 11.
    Packer M, Medina N, Yushak M (1985) Haemodynamic changes mimicking a vasodilator drug response in the absence of drug therapy after right heart catheterization in patients with chronic heart failure. Circulation 71: 761–766Google Scholar
  12. 12.
    Eriksson B-M, Persson B-A (1982) Determination of cate-cholamines in rat heart tissue and plasma samples by liquid chromatography with electrochemical detection. J Chromatography 228: 143–154Google Scholar
  13. 13.
    Menard J, Catt KJ (1972) Measurement of renin activity, concentration and substrate in rat plasma by radioimmunoassay of angiotensin I. Endocrinology 90: 422–430Google Scholar
  14. 14.
    Few JD, Chandry S, James VHT (1984) The direct determination of aldosterone in human saliva. J Steroid Biochem 21: 87–92Google Scholar
  15. 15.
    Aziz LA, Forsling ML, Woolf CJ (1981) The effect of intracerebroventricular injection of morphine on vasopressin release in the rat. J Physiol 311: 401–410Google Scholar
  16. 16.
    Hichens M, Hand EL, Mulcahy WS (1981) Radioimmunoassay for angiotensin converting enzyme inhibitors. Ligand Q 4: 43Google Scholar
  17. 17.
    Kelly JG, Doyle G, Donohue J et al. (1986) Pharmacokinetics of enalapril in normal subjects and patients with renal impairment. Br J Clin Pharmacol 21: 63–69Google Scholar
  18. 18.
    Hills M, Armitage P (1979) The two-period cross-over trial. Br J Clin Pharmacol 8: 7–20Google Scholar
  19. 19.
    Franciosa JA (1984) Exercise testing in chronic congestive hearte failure. Am J Cardiol 53: 1447–1450Google Scholar
  20. 20.
    Lipkin DP, Poole-Wilson PA (1986) Symptoms limiting exercise in chronic heart failure. Br Med J 292: 1030–1031Google Scholar
  21. 21.
    Weber KT, Kinasewitz GT, Janicki JS, Fishman AP (1982) Oxygen utilization and ventilation during exercise in patients with chronic cardiac failure. Circulation 65: 1213–1223Google Scholar
  22. 22.
    Lipkin DP, Canepa-Anson R, Stephens MR, Poole-Wilson PA (1986) Factors determining symptoms in heart failure: comparison of fast and slow exercise tests. Br Heart J 55: 439–445Google Scholar
  23. 23.
    Cleland JGF, Stirling KW, Henderson E, Dargie HJ (1986) Symptom limited exercise and respiratory gas exchange. Br Heart J 55: 519Google Scholar
  24. 24.
    Kugler J, Maskin C, Frishman WH, Sonnenblick EH, LeJemtel TH (1982) Regional and systemic metabolic effects of angiotensin-converting enzyme inhibition during exercise in patients with severe heart failure. Circulation 66: 1256–1261Google Scholar
  25. 25.
    Creager MA, Faxon DP, Weiner DA, Ryan TJ (1985) Haemodynamic and neurohumoral response to exercise in patients with congestive heart failure treated with captopril. Br Heart J 53: 431–435Google Scholar
  26. 26.
    Franciosa JA, Park M, Levine TB (1981) Lack of correlation between exercise capacity and indexes of resting left ventricular performance in heart failure. Am J Cardiol 47: 33–39Google Scholar
  27. 27.
    Francis GS, Goldsmith SR, Cohn JN (1982) Relationship of exercise capacity to resting left ventricular performance and basal plasma norepinephrine levels in patients with congestive heart failure. Am Heart J 104: 725–731Google Scholar
  28. 28.
    Cohn JN, Levine TB, Olivari MT et al. (1984) Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 311: 819–823Google Scholar
  29. 29.
    Bayliss J, Norell MS, Canepa-Anson R et al. (1985) Clinical importance of the renin angiotensin system in chronic heart failure: Double-blind comparison of captopril and prazosin. Br Med J 290: 1861–1865Google Scholar
  30. 30.
    Bayliss J, Canepa-Anson R, Norell MS, Poole-Wilson PA, Sutton G (1986) Vasodilatation with captopril and prazosin in chronic heart failure: Double-blind study at rest and on exercise. Br Heart J 55: 265–273Google Scholar
  31. 31.
    Riegger AJG (1985) Neurohumoral vasoconstrictor systems in heart failure. Eur Heart J 6: 479–489Google Scholar
  32. 32.
    Goldsmith SR, Francis GS, Cowley AW, Levine B, Cohn JN (1983) Increased plasma arginine vasopressin levels in patients with congestive heart failure. J Am Coll Cardiol 1: 1385–1390Google Scholar
  33. 33.
    Riegger AJG, Lieban G, Kochsiek K (1982) Antidiuretic hormone in congestive heart failure. Am J Med 72: 49–52Google Scholar
  34. 34.
    Davies R, Slater JDH, Forsling ML, Payne N (1976) The response of arginine vasopressin and plasma renin to postural change in normal man, with observations on syncope. Clin Science 51: 267–274Google Scholar
  35. 35.
    Schrier RW, Berl T, Anderson RJ (1979) Osmotic and nonosmotic control of vasopressin release. Am J Physiol 236: F321-F332Google Scholar
  36. 36.
    Simpson HCR, Zubillaga JE, Collier JG et al. (1986) Haemodynamic effects of vasopressin in man are related to posture. Clinical Science 70: 177–184Google Scholar
  37. 37.
    Cleland JGF, Dargie HJ, McAlpine H et al. (1985) Severe hypotension after first dose of enalapril in heart failure. Br Med J 291: 1309–1312Google Scholar

Copyright information

© Springer-Verlag 1988

Authors and Affiliations

  • I. P. Mulligan
    • 1
  • A. G. Fraser
    • 1
  • V. Tirlapur
    • 1
  • M. J. Lewis
    • 2
  • R. G. Newcombe
    • 3
  • A. H. Henderson
    • 1
  1. 1.Department of CardiologyUniversity of Wales College of MedicineCardiffWales, UK
  2. 2.Department of PharmacologyUniversity of Wales College of MedicineCardiffWales, UK
  3. 3.Department of Medical Computing & StatisticsUniversity of Wales College of MedicineCardiffWales, UK

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