Blunted tubuloglomerular feedback by absence of angiotensin type 1A receptor involves neuronal NOS

To define the role of angiotensin type 1A (AT(1A)) receptor in modulating tubuloglomerular feedback signals and to determine its relationship to neuronal NO synthase (nNOS), the diameter of the afferent arterioles of wild-type and AT(1A) receptor-deficient mice was measured by the blood-perfused juxtamedullary nephron technique. The afferent arteriolar diameter of wild-type and AT(1A) receptor-deficient mice averaged 16.7 -0.6 (n=9) and 16.8+/-0.7 mum (n=9), respectively. In the wild-type mice, addition of 10 tmol/L acetazolamide to the blood perfusate exerted a biphasic afferent arteriolar constriction, with the initial response and sustained response averaging 47.2+/-3.8% and 33.9+/-3.3%, respectively. In AT(1A) receptor- deficient mice, the initial response and sustained response averaged 51.6+/-3.6% and 9.5+/-1.3%, respectively, and the sustained response was significantly attenuated compared with that of wild-type mice. Inhibition of nNOS with 10 mumol/L S-methyl-L-thiocitruiline significantly decreased the afferent arteriolar diameter of AT(1A) receptor-deficient mice, from 15.1+/-1.2 to 5.0+/-0.3 mum (n = 7), and the decrease was significantly greater than that observed in wild-type mice (from 15.9+/-1.2 to 10.6+/-1.3 mum; n=8). During nNOS inhibition, the initial and sustained afferent arteriolar constrictor responses to acetazolamide in wild-type mice averaged 54.4+/-6.4% and 44.8+/-11.3%; respectively, and were similar to those in AT(1A) receptor- deficient mice (53.2+/-6.4% and 59.5+/-4.4%, respectively). These results suggest that AT(1A) receptors enhance tubuloglomerular feedback-mediated afferent arteriolar constriction, at least in part, through reducing the counteracting modulation by nNOS.