Roles of NO and oxygen radicals in tubuloglomerular feedback in SHR

The spontaneously hypertensive rat (SHR) has enhanced tubuloglomerular feed back (TGF) responses and diminished buffering by juxtaglomerular apparatus (JGA)-derived nitric oxide (NO) despite enhanced expression of NO synthase (NOS) isoforms in the JGA. We tested the hypothesis that the enhanced TGF r esponse is due to inactivation of NO by oxygen radicals(O-2(-)). SHR had si gnificantly (P < 0.05) greater expression of the peroxynitrate reaction pro duct, nitrotyrosine, in renal cortex. A membrane-permeant, metal-independen t superoxide dismutase mimetic, tempol, was used to test the functional rol e of O-2(-). Maximum TGF responses, assessed from changes in proximal stop- flow pressure (P-SF) during orthograde loop of Henle (LH) perfusion of arti ficial tubular fluid (ATF), were enhanced in SHR [Wistar-Kyoto rat (WKY) 8. 8 +/- 0.4(n = 30 nephrons) vs. SHR 10.8 +/- 0.4 mmHg(n = 39 nephrons), P < 0.001]. TGF responses of SHR were unresponsive to microperfusion of 7-nitro indazole (7-NI, 10(-4) M), which is an inhibitor of neuronal NOS (nNOS) [WK Y 8.3 +/- 0.3 to 10.8 +/- 0.4 (n = 8, P < 0.001) vs. SHR 10.0 +/- 0.7 to 10 .5 +/- 0.8 mmHg (n = 8; not significant)]. Microperfusion of tempol (10-4 M ) into the efferent arteriole (EA) supplying the peritubular capillaries (P TC) blunted TGF. The response to tempol was significantly (P < 0.05) greate r in SHR [Delta TGF in WKY 19 +/- 6% (n = 10) vs. SHR 32 +/- 3% (n = 10)]. Microperfusion of the NO donor compound S-nitroso-N-acetyl-penicillamine (S NAP, 10(-7)-10(-4) M) via the LH blunted TGF, but the sensitivity of the re sponse was impaired significantly (P < 0.05) in SHR nephrons. PTC perfusion of tempol (10(-4) M) normalized the response to loop perfusion of both SNA P and 7-NI in SHR nephron to levels in WKY (during tempol, Delta P-SF with 7-NI in WKY 8.9 +/- 0.6 to 11.4 +/- 0.8; n = 12 vs. SHR 9.5 +/- 0.5 to 12.5 +/- 0.4 mmHg; n = 16). In conclusion, TGF responses are enhanced in SHR, i n part due to a diminished role for NO from nNOS in blunting TGF due to enh anced O-2(-) formation. O-2(-) in the JGA enhances TGF responses by inactiv ation of locally generated NO.