Nitric oxide synthase in the JGA of the SHR: expression and role in tubuloglomerular feedback.

The spontaneously hypertensive rat (SHR) has an enhanced tubuloglomerular feedback (TGF) and a diminished buffering by juxtaglomerular apparatus (JGA)-derived NO. We examined the hypothesis that these effects are due to decreases in nitric oxide synthase (NOS) expression or limited availability of L-arginine or tetrahydrobiopterin (BH(4)). SHR had significantly (P < 0.05) greater mRNA abundance (by RT-PCR) or protein (by Western analysis) for neuronal NOS (nNOS, or type I) and endothelial cell NOS (ecNOS, or type III) in renal cortex or isolated glomeruli, respectively. There was prominent expression of ecNOS in glomerular endothelium and nNOS in macula densa. Maximal TGF responses, assessed from changes in proximal stop-flow pressure during orthograde loop of Henle (LH) perfusion, were greater in SHR [Wistar-Kyoto (WKY), 8.1 +/- 0.3 (n = 46) vs. SHR, 10.3 +/- 0.3 mmHg (n = 57); P < 0.001]. Unlike WKY, TGF responses of SHR were unresponsive to microperfusion of the nNOS inhibitor, 7-nitroindazole (7-NI, 10(-4) M) [WKY, 9.5 +/- 0.5 to 13.2 +/- 0.7 (n = 13, P < 0.001) vs. SHR, 11.8 +/- 0.7 to 12.5 +/- 0.6 mmHg (n = 19, not significant)], or to L-arginine (10(-3) M) [WKY, 7.7 +/- 0.8 to 6.3 +/- 0.4 (n = 10, P < 0.05) vs. SHR, 10.4 +/- 0.7 to 10.6 +/- 0.7 mmHg (n = 10, not significant)]. Neither BH(4) (10(-4) M) nor sepiapterin (10(-4) M), its stable precursor, modified TGF responses in WKY or in SHR, nor did they restore a response to microperfusion of 7-NI in SHR. In conclusion, there is a diminished role for NO from nNOS in blunting of TGF in SHR which cannot be ascribed to limited NOS expression or availability of substrate or BH(4).