Mechanism of attenuated hydrochlorothiazide response during indomethacin administration

Indomethacin antagonizes the natriuretic and chloruretic response to hydrochlorothiazide in most studies. Neither the mechanism nor nephron site of this antagonism has been determined. To identify sites and potential mechanisms, cortical micropuncture was performed during hydrochlorothiazide treatment in control and indomethacin rats. Indomethacin reduced (P less than 0.005) FeCl from 5.20 +/- 0.49% to 2.26 +/- 0.49% (mean +/- SE). MAP, CIn, and plasma volume were not different between groups. SNGFR and fractional proximal fluid and chloride delivery were not different between groups. Fractional chloride delivery to early distal tubules was 10.8 +/- 0.4% in control but 6.2 +/- 0.3% in indomethacin rats (P less than 0.001). Calculated loop chloride reabsorption was greater in indomethacin than control rats during hydrochlorothiazide administration (41.0 +/- 1.6% vs. 34.3 +/- 2.3%; P less than 0.05). Fractional chloride delivery to late distal tubules was 7.8 +/- 0.7% in control and 4.6 +/- 0.3% in indomethacin rats (P less than 0.005), but distal tubule chloride reabsorption was not different between groups. Papillary tissue chloride was less in control than indomethacin rats during hydrochlorothiazide (P less than 0.05). Urinary PGE2 excretion was reduced (P less than 0.001) by indomethacin during hydrochlorothiazide. Thus indomethacin induced reductions in hydrochlorothiazide response result in part from increased chloride reabsorption in the loop segment. This suggests indomethacin antagonizes hydrochlorothiazide by reducing chloride delivery to hydrochlorothiazide's site of action in the distal tubule rather than by effects of indomethacin on hydrochlorothiazide pharmacokinetics.