Acetazolamide as a potent chloride-regaining diuretic: short- and long-term effects, and its pharmacologic role under the ‘chloride theory’ for heart failure pathophysiology

  • 124 Accesses


According to the “chloride theory” for heart failure (HF) pathophysiology, manipulation of the serum chloride concentration is an important therapeutic target. This study determined the short- and long-term effects of acetazolamide (Diamox), a potential chloride-regaining diuretic, on peripheral blood, serum electrolytes, and renal function. Effects of low-dose Diamox (250–500 mg/day) were evaluated in 30 HF patients for whom Diamox was added as de-novo/add-on decongestion therapy for acutely worsening HF (n = 18) or as modification therapy for serum hypochloremia in stable HF ( < 100 mEq/L; n = 12). Peripheral hematologic tests were performed at baseline, and at short- ( ≤ 10 days) and long-term ( ~ 60 days) time-points. In all 30 study patients of both groups, the serum chloride concentration increased in the short-term and even further over the long-term. The serum potassium concentration constantly decreased throughout the study period. Both the blood urea nitrogen and serum creatinine concentrations increased in the short-term, but returned to baseline levels over the long-term. Responders to Diamox (n = 13; defined by HF resolution and body weight loss ≥ 1 kg) in the decongestion group exhibited reduced serum b-type natriuretic peptide levels and a markedly increased serum chloride concentration, but the hemoglobin/hematocrit and serum creatinine concentrations did not change after treatment. In conclusion, acetazolamide is a potent candidate “chloride-regaining diuretic” for treating HF patients under the “chloride theory”. Its effect to enhance the serum chloride concentration occurred within 10 days and persisted for at least ~ 60 days. Plasma volume and renal function were preserved under adequate diuretic treatment with acetazolamide.

This is a preview of subscription content, log in to check access.

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 99

This is the net price. Taxes to be calculated in checkout.


  1. 1.

    Cody RJ, Covit AB, Schaer GL, Laragh JH, Sealey JE, Feldschuh J (1986) Sodium and water balance in chronic congestive heart failure. J Clin Invest 77:1441–1452

  2. 2.

    Volpe M, Tritto C, DeLuca N, Rubattu S, Rao MAE, Lamenza F, Mirante A, Enea I, Rendina V, Mele AF, Trimarco B, Condorelli M (1993) Abnormalities of sodium handling and of cardiovascular adaptations during high salt diet in patients with mild heart failure. Circulation 88(1):1620–1627

  3. 3.

    Sica DA (2006) Sodium and water retention in heart failure and diuretic therapy: basic mechanisms. Cleve Clin J Med 73(suppl 2):S2–S7

  4. 4.

    Testani JM, Hanberg JS, Arroyo JP, Brisco MA, ter Maaten JM, Wilson FP, Bellumkonda L, Jacoby D, Tang WHW, Parikh CR (2016) Hypochloraemia is strongly and independently associated with mortality in patients with chronic heart failure. Eur J Heart Fail 18:660–668

  5. 5.

    Hanberg JS, Rao V, ter Maaten JM, Laur O, Brisco MA, Wilson FP, Grodin JL, Assefa M, Broughton JS, Planavsky NJ, Ahmad T, Bellumkonda L, Tang WHW, Parikh CR, Testani JM (2016) Hypochloremia and diuretic resistance in heart failure: mechanistic insights. Circ Heart Fail 9:e003180

  6. 6.

    Kataoka H (2017) Vascular expansion during worsening of heart failure: effects on clinical features and its determinants. Int J Cardiol 230:556–561

  7. 7.

    Kataoka H (2019) Biochemical determinants of changes in plasma volume after decongestion therapy for worsening heart failure. J Card Fail 25:213–217

  8. 8.

    Kataoka H (2017) Proposal for heart failure progression based on the “chloride theory”: worsening heart failure with increased vs. non-increased serum chloride concentration. ESC Heart Fail 4:623–631

  9. 9.

    Kataoka H (2017) The “chloride theory”, a unifying hypothesis for renal handling and body fluid distribution in heart failure pathophysiology. Med Hypotheses 104:170–173

  10. 10.

    Hilton JG, Kalinsky H (1951) Potentiation of diuretic action of mercuhydrin by ammonium chloride. J Clin Invest 30:1105–1110

  11. 11.

    Friedberg C, Taymor R, Minor JB, Halpern M (1953) The use of Diamox, a carbonic anhydrase inhibitor, as an oral diuretic in patients with congestive heart failure. N Engl J Med 248:883–889

  12. 12.

    Leaf A, Schwartz WB, Relman AS (1954) Oral administration of a potent carbonic anhydrase inhibitor (“Diamox”): I. Changes in electrolyte and acid-base balance. N Engl J Med 250:759–764

  13. 13.

    Relman AS, Leaf A, Schwartz WB (1954) Oral administration of a potent carbonic anhydrase inhibitor (“Diamox”): II. Its use as a diuretic in patients with severe congestive heart failure. N Engl J Med 250:800–804

  14. 14.

    Rubin AL, Thompson HG Jr, Braveman WS, Luckey EH (1955) The management of refractory edema in heart failure. Ann Intern Med 42:358–368

  15. 15.

    Khan MI (1980) Treatment of refractory congestive heart failure and normokalemic hypochloremic alkalosis with acetazolamide and spironolactone. Can Med Assoc J 123:883–887

  16. 16.

    Caramelo C, Albalate M, Tejedor A, Alcázar TR, Baldoví S, Pérez AG, Marín M (2008) Actuality of the use of acetazolamide as a diuretic: usefulness in refractory edema and in aldosterone-antagonist-related hyperkalemia. Nefrologia 28:234–238

  17. 17.

    Kassamali R, Sica DA (2011) Acetazolamide: a forgotten diuretic agent. Cardiol in Rev 19:276–278

  18. 18.

    Kataoka H (2018) Treatment of hypochloremia with acetazolamide in an advanced heart failure patient and importance of monitoring urinary electrolytes. J Card Cases 17:80–84

  19. 19.

    Kataoka H (2018) Comparison of changes in the plasma volume and renal function between acetazolamide vs conventional diuretics: understanding their mechanical differences according to the chloride theory. Eur Heart J 39:40–41 (abstract)

  20. 20.

    Ghali JK, Tam SW (2010) The critical link of hypervolemia and hyponatremia in heart failure and the potential role of arginine vasopressin antagonists. J Cardiac Fail 16:419–431

  21. 21.

    Kataoka H, Takada S (2000) The role of thoracic ultrasonography for evaluation of patients with decompensated chronic heart failure. J Am Coll Cardiol 35:1638–1646

  22. 22.

    Kataoka H (2012) Ultrasound pleural effusion sign as a useful marker for identifying heart failure worsening in established heart failure patients during follow-up. Congest Heart Fail 18:272–277

  23. 23.

    Udelson JE, Orlandi C, Ouyang J, Krasa H, Zimmer CA, Frivold G, Haught H, Meymandi S, Macarie C, Raef D, Wedge P, Konstam MA, Gheorghiade M (2008) Acute hemodynamic effects of tolvaptan, a vasopressin V2 receptor blocker, in patients with symptomatic heart failure and systolic dysfunction: an international, multicenter, randomized, placebo-controlled trial. J Am Coll Cardiol 52:1540–1545

  24. 24.

    Kataoka H, Yamasaki Y (2016) Strategy for monitoring decompensated heart failure treated by an oral vasopressin antagonist with special reference to the role of serum chloride: a case report. J Card Cases 14:185–188

  25. 25.

    ter Maaten JM, Valente MA, Damman K, Hillege HL, Navis G, Voors AA (2015) Diuretic response in acute heart failure: pathophysiology, evaluation, and therapy. Nat Rev Cardiol 12:184–192

  26. 26.

    Pitt B, Ferreira JP, Zannad F (2017) Mineralocorticoid receptor antagonists in patients with heart failure: current experience and future perspectives. Eur Heart J Cardiovasc Pharmacother 3:48–57

  27. 27.

    Ferreira JP, Rossignol P, Machu J-L, Sharma A, Girerd N, Anker SD, Cleland JG, Dickstein K, Filippatos G, Hillege HL, Lang CC, ter Maaten J, Metra M, Ng L, Ponikowski P, Samani NJ, van Veldhuisen DJ, Zwinderman AH, Voors A, Zannad F (2017) Mineralocorticoid receptor antagonist pattern of use in heart failure with reduced ejection fraction: findings from BIOSTAT-CHF. Eur J Heart Fail 19:1284–1293

  28. 28.

    Grodin JL (2016) Pharmacologic approaches to electrolyte abnormalities in heart failure. Curr Heart Fail Rep 13:181–189

  29. 29.

    Urso C, Brucculeri S, Caimi G (2015) Acid-base and electrolyte abnormalities in heart failure: pathophysiology and implications. Heart Fail Rev 20:493–503

  30. 30.

    Wilcox CS (1983) Regulation of renal blood flow by plasma chloride. J Clin Invest 71:726–735

  31. 31.

    Yunos NM, Bellomo R, Hegarty C, Story D, Colin LH, Bailey M (2012) Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA 308:1566–1572

  32. 32.

    Thongprayoon C, Cheungpasitporn W, Cheng Z, Qian Q (2017) Chloride alterations in hospitalized patients: prevalence and outcome significance. PLoS ONE 12:e0174430

  33. 33.

    Tojima H, Kunitomo F, Kimura H, Tatsumi K, Kuriyama T, Honda Y (1988) Effects of acetazolamide in patients with the sleep apnea syndrome. Thorax 43:113–119

  34. 34.

    Javaheri S (2006) Acetazolamide improves central sleep apnea in heart failure: a double-blind, prospective study. Am J Respir Crit Care Med 173:234–237

  35. 35.

    Cowie MR, Gallagher AM (2017) Sleep disordered breathing and heart failure: what does the future hold? JACC Heart Fail 5:715–723

  36. 36.

    Imiela T, Budaj A (2018) Response to “acetazolamide and cardiac failure. Clin Drug Investig.

  37. 37.

    Shirakabe A, Hata N, Kobayashi N, Shinada T, Tomita K, Tsurumi M, Matsushita M, Okazaki H, Yamamoto Y, Yokoyama S, Asai K, Mizuno K (2012) Clinical significance of acid-base balance in an emergency setting in patients with acute heart failure. J Cardiol 60:288–294

  38. 38.

    Otaki Y, Watanabe T, Takahashi H, Hasegawa H, Honda S, Funayama A, Netsu S, Ishino M, Arimoto T, Shishido T, Miyashita T, Miyamoto T, Konta T, Kubota I (2013) Acidic urine is associated with poor prognosis in patients with chronic heart failure. Heart Vessels 28:735–741

  39. 39.

    Kataoka H (2018) Vasopressin antagonist-like effect of acetazolamide in a heart failure patient: a case report. Eur Heart J Case Rep 2(3):1–5

  40. 40.

    Vogiatzis I, Koulouris E, Sidiropoulos A, Giannakoulas C (2013) Acute pulmonary edema after a single oral dose of acetazolamide. Hippokratia 17:177–179

  41. 41.

    Zimmermann S, Achenbach S, Wolf M, Janka R, Marwan M, Mahler V (2014) Recurrent shock and pulmonary edema due to acetazolamide medication after cataract surgery. Heart Lung 43:124–126

  42. 42.

    Maisey DN, Brown RD (1981) Acetazolamide and symptomatic metabolic acidosis in mild renal failure. Br Med J 283:1527–1528

  43. 43.

    Margo CE (1986) Acetazolamide and advanced liver disease. Am J Ophthalmol 101:611–612

Download references

Author information

Correspondence to Hajime Kataoka.

Ethics declarations

Conflict of interest

The author declares that he has no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kataoka, H. Acetazolamide as a potent chloride-regaining diuretic: short- and long-term effects, and its pharmacologic role under the ‘chloride theory’ for heart failure pathophysiology. Heart Vessels 34, 1952–1960 (2019).

Download citation


  • Heart failure
  • Chloride
  • Diuretics
  • Acetazolamide
  • Diamox
  • Electrolyte