Objective: 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.
Methods: 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.
Results: 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 approximately 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 Ca(2+) channel blocker amlodipine (5 mg) on GFR and HCT-induced Na(+) excretion equalled that obtained with the AT(1) blocker, yet with this treatment K(+) excretion rose in proportion to Na(+) excretion. The beta-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 beta-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.
Conclusion: In conclusion, AT(1) receptors, as well as the Ca(2+) 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, beta-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.