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1 Division of Nephrology and Hypertension, Georgetown University Medical Center, Washington, District of Columbia 20007; and 2 Second Department of Internal Medicine, University of Tokyo, Tokyo, Japan
The spontaneously
hypertensive rat (SHR) has enhanced tubuloglomerular feedback (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 response is due to inactivation of NO by oxygen radicals
(O
2). SHR had significantly (P < 0.05) greater expression of the peroxynitrate reaction product,
nitrotyrosine, in renal cortex. A membrane-permeant, metal-independent superoxide dismutase mimetic, tempol, was used to
test the functional role of O2.
Maximum TGF responses, assessed from changes in proximal stop-flow
pressure (PSF) during orthograde loop of Henle (LH)
perfusion of artificial 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-nitroindazole (7-NI, 104 M), which
is an inhibitor of neuronal NOS (nNOS) [WKY 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 (104 M) into
the efferent arteriole (EA) supplying the peritubular capillaries (PTC)
blunted TGF. The response to tempol was significantly (P < 0.05) greater in SHR [
TGF in WKY 19 ± 6% (n = 10)
vs. SHR 32 ± 3% (n = 10)]. Microperfusion of the NO
donor compound
S-nitroso-N-acetyl-penicillamine (SNAP,
107-104
M) via the LH blunted TGF, but the sensitivity of the response was
impaired significantly (P < 0.05) in SHR nephrons. PTC
perfusion of tempol (104 M) normalized
the response to loop perfusion of both SNAP and 7-NI in SHR nephron to
levels in WKY (during tempol, PSF 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, in part due to a diminished role for NO from nNOS in
blunting TGF due to enhanced O2
formation. O2 in the JGA enhances TGF
responses by inactivation of locally generated NO.
7-nitroindazole; superoxide dismutase; tempol; S-nitroso-N-acetyl-penicillamine; nitrotyrosine; nitric oxide synthase
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