Effect of carbonic anhydrase inhibition on GFR and renal hemodynamics in adenosine-1 receptor-deficient mice

The reduction of glomerular filtration rate (GFR) caused by inhibitors of carbonic anhydrase (CA) is thought to be initiated by activation of the tubuloglomerular feedback (TGF) mechanism. We determined the effect of the CA inhibitor benzolamide (Bz) on renal hemodynamics in adenosine-1 receptor (A1AR) knockout mice that have been shown previously to lack a TGF response. In A1AR(+/+) mice, Bz (150 mug plus 2 mug/min) reduced RBF by 19.8% (from 829 +/- 42 to 666 +/- 44 mul/min; n=7), and GFR by 19.8% (from 396 +/- 43 to 324 +/- 46 mul/min; n=9, P=0.001). In A1AR(-/-) mice, RBF fell by 15.9 % (from 809 +/- 24 to 680 +/- 40 mul/min; n=7), and GFR by 21.1% (from 358 +/- 27 to 287 +/- 32 mul/min; n=10, P=0.0003; NS compared with A1AR(+/+)). The absence of TGF responses both before and during Bz infusion in A1AR(-/-) mice was confirmed by micropuncture. Following angiotensin II-receptor blockade with candesartan, Bz did not alter RBF (1.4 +/- 0.2 vs. 1.4 +/- 0.15 ml/min in A1AR(+/+), and 1.4 +/- 0.22 vs. 1.39 +/- 0.2 ml/min in A1AR(-/-) n=5/genotype) while GFR changed by -8.9 % in A1AR(+/+) mice (n=7), and by -1% in A1AR(-/-) mice (n=9; NS compared with A1AR(+/+)). Bz caused a significant rise of plasma renin concentration in both A1AR(+/+) and A1AR(-/-) mice. Our data show that the absence of a functional TGF mechanism does not prevent the reduction in GFR or RBF caused by CA inhibition. Acute angiotensin II receptor blockade, on the other hand, diminishes the effect of CA inhibition on GFR and RBF. The causes for the GFR reduction appear to be complex and include an effect of the renin-angiotensin system.