The influence of cardiovascular and antiinflammatory drugs on thiazide-induced hemodynamic and saluretic effects
- 147 Downloads
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.
KeywordsThiazide 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.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
- 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.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
- 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
- 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
- 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.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.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
- 18.Epstein M (1991) Calcium antagonists and the kidney. Implications for renal protection. Am J Hypertension 4:482S–486SGoogle Scholar
- 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
- 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
- 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
- 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.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.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
- 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.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.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
- 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
- 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.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
- 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