European Journal of Clinical Pharmacology

, Volume 62, Issue 11, pp 885–892 | Cite as

The influence of cardiovascular and antiinflammatory drugs on thiazide-induced hemodynamic and saluretic effects

  • H. Knauf
  • M. A. Bailey
  • G. Hasenfuss
  • E. Mutschler
Clinical Trials



Thiazide diuretics are known to induce a transient fall of the glomerular filtration rate (GFR), which, in turn, reduces tubular Na+ load. This tubuloglomerular feedback (TGF) curtails the natriuretic effect of this class of diuretics. Cardiovascular and antiinflammatory therapeutics may interfere with TGF and thereby influence the effect of thiazides once co-administration is clinically indicated.


The effects on GFR and saluresis of hydrochlorothiazide (HCT; 25 mg) monotherapy were measured in healthy volunteers and compared to those obtained during co-administration of the thiazide and a second therapeutic.


In the presence of the ACE inhibitor enalapril (10 mg), the transient fall in the GFR induced by HCT was almost abolished, and Na+ excretion increased by ∼30 % as compared to HCT monotherapy. K+ excretion, however, remained unchanged. Similar results were obtained with the AT II type 1 receptor antagonist candesartan (8 mg): GFR remained stable, Na+ excretion rose by 35 % and K+ excretion was not changed. The effect of the Ca2+ channel blocker amlodipine (5 mg) on GFR and HCT-induced Na+ excretion equalled that obtained with the AT1 blocker, yet with this treatment K+ excretion rose in proportion to Na+ excretion. The β-blockers propranolol (80 mg) or bisoprolol (5 mg) reduced GFR but maintained TGF. HCT-induced Na+ excretion was significantly reduced in the presence of a β-blocker, whereas K+ excretion was not changed. The inhibition of cyclooxygenase by diclofenac (50 mg) or rofecoxib (25 mg) significantly reduced the diuretic/natriuretic effect of HCT, but K+ excretion was unchanged, and TGF was still demonstrable.


In conclusion, AT1 receptors, as well as the Ca2+ channels in the smooth muscle cells of the afferent arteriole, are considered prerequisites for TGF function; their blockade increases the diuretic/natriuretic efficacy of thiazide diuretics. In contrast, β-blockers and COX inhibitors do not interfere directly with TGF. These first dose effects reflect the primary response of the kidney to the drugs. They cannot, however, predict the benefits of long-term treatment.


Thiazide diuretics Tubuloglomerular feedback ACE inhibitors AT1 receptor antagonists Ca2+ channel blockers β-blockers NSAIDs 



The generous support of Hexal, Merck, Pfizer and Takeda is gratefully acknowledged.


  1. 1.
    Schnermann J, Briggs JP (2000) Function of the juxtaglomerular apparatus: control of glomerular hemodynamics and renin secretion. In: Seldin DW, Giebisch G (eds) The Kidney: physiology and pathophysiology, 3rd edn. Lippincott and Wilkins, Philadelphia, pp 945–980Google Scholar
  2. 2.
    Cassin S, Vogh B (1966) Effect of hydrochlorothiazide on renal blood flow and clearance of para-amino-hippurate and creatinine. Proc Soc Exp Biol Med 122:970–973PubMedGoogle Scholar
  3. 3.
    Hropot M, Fowler N, Karlmark B, Giebisch G (1985) Tubular action of diuretics: distal effects on electrolyte transport and acidification. Kidney Int 28:477–489PubMedGoogle Scholar
  4. 4.
    Knauf H, Cawello W, Schmidt G, Mutschler E (1994) The saluretic effect of the thiazide-diuretic bemeticide in relation to the glomerular filtration rate. Eur J Clin Pharmacol 46:9–13PubMedCrossRefGoogle Scholar
  5. 5.
    Okusa MD, Ellison DH (2000) Physiology and pathophysiology of diuretic action. In: Seldin DW, Giebisch G (eds) The Kidney: physiology and pathophysiology, 3rd edn. Lippincott and Wilkins, Philadelphia, pp 2877–2922Google Scholar
  6. 6.
    Friedman PA, Hebert SC (1997) Site and mechanism of diuretic action. In: Seldin D, Giebisch G (eds) Diuretic agents: clinical physiology and pathophysiology. Academic, New York, pp 75–113Google Scholar
  7. 7.
    Schlatter E (1993) Effects of various diuretics on membrane voltage of macula densa cells. Whole-cell-patch-clamp experiments. Pflügers Arch 423:74–77PubMedCrossRefGoogle Scholar
  8. 8.
    Greger RF (1995) Loop diuretics. In: Greger RF, Knauf H, Mutschler E (eds) Diuretics, Handb Exp Pharm 117. Springer, Berlin Heidelberg New York, pp 221–274Google Scholar
  9. 9.
    Braam B, Mitchell KD, Koomans HA, Navar LG (1993) Relevance of tubuloglomerular feedback mechanisms in pathophysiology. J Am Soc Nephrol 4:1257–1274PubMedGoogle Scholar
  10. 10.
    Knauf H Mutschler E (1990) Saluretic effects of the loop diuretic torasemide in chronic renal failure. Interdependence of electrolyte excretion. Eur J Clin Pharmacol 39:337–343PubMedCrossRefGoogle Scholar
  11. 11.
    Navar LG (1997) Renal hemodynamic effects of diuretics. In: Seldin DW, Giebisch G (eds) Diuretic agents: clinical physiology and pharmacology. Academic, New York, pp 135–169Google Scholar
  12. 12.
    Vallon V (2003) Tubuloglomerular feedback and the control of glomerular filtration rate. News Physiol Sci 18:169–174PubMedGoogle Scholar
  13. 13.
    Leary WP, Reyes AJ, van der Byl K, Acosta-Barrios NT (1985) Effects of captopril, hydrochlorothiazide and their combination on timed urinary excretion of water and solutes. J Cardiovasc Pharmacol 7 (Suppl 1):56–62Google Scholar
  14. 14.
    Leary WP, Reyes AJ, van der Byl K (1992) Interactions between different diuretics and between diuretics and other drugs on renal excretion in man: mechanism and clinical implications. Prog Pharmacol Clin Pharmacol. 9:317–360Google Scholar
  15. 15.
    Cleland JGF (1997) Interaction between ACE inhibitors and diuretics. In: Seldin DW, Giebisch G (eds) Diuretic agents: clinical physiology and pharmacoloogy. Academic, New York, pp 321–334Google Scholar
  16. 16.
    Opie LH (1987) Calcium channel antagonists, part I: Fundamental properties: mechanisms, classification, sites of action. Cardiovasc Drugs Ther 1:411–430PubMedCrossRefGoogle Scholar
  17. 17.
    Zanchetti A, Leonetti G (1990) Natriuretic effects of calcium antagonists. Clinical implications. Drugs 40 (Suppl 2):15–21PubMedCrossRefGoogle Scholar
  18. 18.
    Epstein M (1991) Calcium antagonists and the kidney. Implications for renal protection. Am J Hypertension 4:482S–486SGoogle Scholar
  19. 19.
    Bauer JH, Reams GP (1987) Beta-adrenergic antagonists and the kidney. In: Brenner BM, Stein JH (eds) Pharmacotherapy of renal disease and hypertension. Churchill Livingstone, New York, pp 223–254Google Scholar
  20. 20.
    Leary WP, Reyes AJ, van der Byl K (1984) Effect of hydrochlorothiazide plus sotalol on urinary electrolyte excretion in normal subjects. S Afr Med J 66:680–681PubMedGoogle Scholar
  21. 21.
    Schrier RW (1988) Pathogenesis of sodium and water retention in high and low output cardiac failure, cirrhosis, nephrotic syndrome, and pregnancy. N Eng J Med 318:1065–1074CrossRefGoogle Scholar
  22. 22.
    Seldin DW (1990) Sodium balance and fluid volume in normal and in edematous states. In: Seldin DW, Giebisch G (eds) The regulation of sodium and chloride balance. Raven, New York, pp 261–292Google Scholar
  23. 23.
    Skorecki KL, Brenner BM (1982) Body fluid homeostasis in congestive heart failure and cirrhosis with ascites. Am J Med 72:323–338PubMedCrossRefGoogle Scholar
  24. 24.
    Better OS, Schrier RW (1983) Disturbed volume homeostasis in patients with cirrhosis of the liver. Kidney Int 23:303–311PubMedGoogle Scholar
  25. 25.
    Keller E, Hoppe-Seyler G, Schollmeyer P (1981) Influence of hepatic cirrhosis and end-stage renal disease on pharmacokinetics and pharmacodynamics of furosemide. Eur J Clin Pharmacol 20:27–33PubMedCrossRefGoogle Scholar
  26. 26.
    Kirchner KA (1997) Effect of prostaglandin inhibition on the action of diuretic agents. In: Seldin DW, Giebisch G (eds) Diuretic agents: clinical physiology and pharmacology. Academic, New York pp 247–258Google Scholar
  27. 27.
    Brater DC (1986) Drug-drug and drug-disease interactions with nonsteroidal anti-inflammatory drugs. Am J Med 80:(Suppl 1A) 62–77PubMedGoogle Scholar
  28. 28.
    Brater DC, Chennavasin P, Seiwell R (1980) Furosemide in patients with heart failure: shift in dose-response curve. Clin Pharmacol Ther 28:18–186CrossRefGoogle Scholar
  29. 29.
    Chennavasin P, Seiwell R, Brater DC (1980) Pharmacokinetic-dynamic analysis of the indomethacin-furosemide interaction in man. J Pharmacol Exp Ther 215:66Google Scholar
  30. 30.
    MacGregor GA, Markandu ND, Banks RA et al (1982) Captopril in essential hypertension: Contrasting effects of adding hydrochlorothiazide or propranolol. Br Med J 284:693–696Google Scholar
  31. 31.
    Weinberger MH (1985) Blood pressure and metabolic responses to hydrochlorothiazide, captopril and the combination in black and white mild-to-moderate hypertensive patients. J Cardiovasc Pharmacol 7 (Suppl 1):S22–S25Google Scholar
  32. 32.
    MacGregor GA, Banks RA, Markandu ND, Bayliss J, Roulston J (1983) Lack of effect of beta-blocker on flat dose response to thiazide in hypertension: efficacy of low-dose thiazide combined with beta-blocker. BMJ 286:1535–1538PubMedCrossRefGoogle Scholar
  33. 33.
    Cappuccio FP, Markandu ND, Singer DRJ, MacGregor GA (1993) Amlodipine and lisinopril in combination for the treatment of essential hypertension: efficacy and predictors of response. J Hypertens 11:839–847PubMedCrossRefGoogle Scholar
  34. 34.
    Hansson L, Zanchetti A, Carruthers SG et al (1991) Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the hypertension optimal treatment (HOT) randomised. Lancet 351:1755–1762CrossRefGoogle Scholar
  35. 35.
    ALLHAT (2002) The antihypertensive and lipid-lowering treatment to prevent heart attack trial. Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomised to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic. JAMA 288:2981–2997CrossRefGoogle Scholar
  36. 36.
    O’Connor CM, Bekin RN, Carson PE et al. for the PRAISE investigators (1995) Effect of amlodipine on mode of death in severe chronic heart failure. The PRAISE trial. Circulation 92 (Suppl):1–143Google Scholar
  37. 37.
    The CONSENSUS Trial Study Group (1987) Effects of enalapril on mortality in severe congestive heart failure: results on the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 314:1547–1552Google Scholar
  38. 38.
    Pfeffer MA, Braunwald E, Moy L et al (1992) Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. N Engl J Med 327:669–677PubMedCrossRefGoogle Scholar
  39. 39.
    The SOLVD Investigators (1992) Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 327:685–691CrossRefGoogle Scholar
  40. 40.
    Yusuf S, Pepine CJ, Garges L et al (1992) Effect of enalapril on myocardial infarction and unstable angina in patients with low ejection fractions. Lancet 340:1173–1178PubMedCrossRefGoogle Scholar
  41. 41.
    Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJV, Michelson EL, Olofsson B, Östergren J, Yusuf S (2003) Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet 362:759–766Google Scholar
  42. 42.
    Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJV, Michelson EL, Olofsson B, Östergren J (2003) Effects of candesartan in patients with chronic heart failure and preserved left-ventricular efection fraction: the CHARM-Preserved Trial. Lancet 362:777–781PubMedCrossRefGoogle Scholar
  43. 43.
    McMurray JJV, Östergren J, Swedberg K, Granger CB, Held P, Michelson EL, Olofsson B, Yusuf S, Pfeffer MA (2003) Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet 362:767–771Google Scholar
  44. 44.
    Granger CB, McMurray JJV, Yusuf S, Held P, Michelson EL, Olofsson B, Östergren J, Pfeffer MA, Swedberg K (2003) Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet 362:772–776PubMedCrossRefGoogle Scholar
  45. 45.
    Waagstein F, Hjalmarson A, Varnaysclas E et al (1975) β-blockers in dilated cardiomyopathy. Br Heart J 37:1022–1036PubMedGoogle Scholar
  46. 46.
    Engemeier RS, O’Connel JB, Walsh R et al (1985) Improvement in symptoms and exercise tolerance by metoprolol in patients with dilated cardiomyopathy: a double-blind, randomised, placebo-controlled trial. Circulation 72:536–546Google Scholar
  47. 47.
    Packer M (1993) How should physicians view heart failure? The philosophical and physiological evolution of the conceptual models of the disease. Am J Cardiol 71:3C–11CPubMedCrossRefGoogle Scholar
  48. 48.
    Buffin-Meyer B, Younes-Ibrahim M, El Mernissi G, Cheval L, Marsy S, Grima M, Girolami J, Doucet A (2004) Differential regulation of collecting duct Na+, K+-ATPase and K+ excretion by furosemide and piretanide: role of bradykinin. J Am Soc Nephrol 15:876–884PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • H. Knauf
    • 1
    • 5
  • M. A. Bailey
    • 2
  • G. Hasenfuss
    • 3
  • E. Mutschler
    • 4
    • 6
  1. 1.FreiburgGermany
  2. 2.Molecular Physiology, The Queen’s Medical Research InstituteUniversity of EdinburghEdinburghUK
  3. 3.Department of Cardiology and PulmologyGeorg-August UniversityGöttingenGermany
  4. 4.MainzGermany
  5. 5.Department of Medicine 1St. Berward-KrankenhausHildesheimGermany
  6. 6.Pharmacological InstituteUniversity of FrankfurtFrankfurtGermany

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