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

Abstract

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 microg plus 2 microg/min) reduced RBF by 19.8% (from 829+/-42 to 666+/-44 microl/min; n=7), and GFR by 19.8% (from 396+/-43 to 324+/-46 microl/min; n=9, P=0.001). In A1AR(-/-) mice, RBF fell by 15.9 % (from 809+/-24 to 680+/-40 microl/min; n=7), and GFR by 21.1% (from 358+/-27 to 287+/-32 microl/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.

Adenosine A1 Receptor Antagonist Blunts Urinary Potassium Excretion, but Not Renal Hemodynamic Effects, Induced by Carbonic Anhydrase Inhibitor in Rats

“…An earlier study demonstrated that the CAI benzolamide induced a similar magnitude decrease of GFR and RBF in both A1ARϪ/Ϫ knockout and wild-type mice, despite the absence of TGF responses in the A1ARϪ/Ϫ knockout mice (Hashimoto et al, 2004a). Our data, using pharmacological blockade of A1AR, are consistent with these findings.…”

“…Our renal hemodynamic data in rats obviously differ from that of Hashimoto et al (2004a) in mice. However, our results are in general agreement with Deng et al (2002), who reported that in the rat, angiotensin-converting enzyme inhibitor treatment did not block the RBF decrease induced by benzolamide.…”

“…Our data, using pharmacological blockade of A1AR, are consistent with these findings. Interestingly, Hashimoto et al (2004a) also found that acute AT1 angiotensin receptor blockade significantly attenuated renal hemodynamic responses to benzolamide in both groups of mice, indicating that activation of the RAS may be responsible for the CAI-induced RBF response.…”

“…Based on the work by Hashimoto et al (2004a) described above, we designed an experiment in which we treated rats with the ARB L158809 for 1 week and examined the response to AZ. Contrary to our expectation, we found that the decrease of RBF in response to AZ was not attenuated by ARB treatment.…”

Adenosine and Kidney Function

“…It was observed, however, that the absence of a functional TGF mechanism did not prevent the reduction in GFR or renal blood flow caused by carbonic anhydrase inhibition. On the other hand, acute angiotensin II receptor blockade diminished the effect of carbonic anhydrase inhibition on GFR and renal blood flow in either genotype (119). The authors concluded that TGF activation is not necessary for the decline in GFR caused by carbonic anhydrase inhibitors and that the GFR reduction appears to be the consequence of a combination of an angiotensin II-dependent reduction in renal plasma flow and a diuresis-induced increase in P PT .…”