Nitric oxide stimulates guanylate cyclase and regulates sodium
transport in rabbit proximal tubule.
Roczniak, Agnes, and Kevin D. Burns.
Departments of Medicine and Physiology, the University of Ottawa
and Ottawa General Hospital, Ottawa, Ontario, Canada
APStracts 2:0127F, 1995.
The proximal tubule contains the target for nitric oxide (NO), soluble
guanylate cyclase, and has the capacity for NO production. Inhibition
of renal NO synthesis reduces fractional excretion of lithium,
suggesting an inhibitory effect of NO on proximal tubule Na+
transport. The present studies determined direct effects of donors of
NO in rabbit proximal tubule. In both freshly isolated proximal
tubule segments and in primary cultures of proximal tubule cells,
sodium nitroprusside (SNP) and S-nitroso-N-acetylpenicillamine (SNAP)
caused dose-dependent increases in cyclic guanosine monophosphate
(cGMP). SNAP was more potent than SNP in stimulating cGMP: this was
associated with an enhanced production of nitrite, the stable end
-product of NO. In rabbit proximal tubule cells, SNP or SNAP (10-3 M)
significantly inhibited the activity of the apical Na+-H+ exchanger,
determined by assay of amiloride-sensitive 22Na+ uptake (%
inhibition: SNP: 34.90 +/- 5.52%; p < 0.001; SNAP: 30.77 +/-
8.20%; p < 0.002). To determine the role of cGMP in mediating
these effects, proximal tubule cells were incubated with the
membrane-permeable analogue, 8-BrcGMP. Na+-H+ exchange was
significantly inhibited by 8-BrcGMP (10-3 M) (% inhibition: 32.40 +/-
9.06%; p < 0.05). The inhibitor of soluble guanylate cyclase,
LY-83583, caused partial inhibition of SNP-stimulated cGMP
generation, and partly blocked the inhibitory effect of SNP on Na+-H+
exchange. Protein kinase A (PKA) activity was not stimulated by SNP,
indicating that potential cross-activation of PKA by cGMP did not
mediate the effects of NO-donors. These data indicate that NO
stimulates soluble guanylate cyclase in rabbit proximal tubule, and
causes inhibition of Na+-H+ exchange. This is at least partly
mediated by generation of cGMP. We conclude that NO is an important
autocrine or paracrine factor directly regulating Na+ transport in
the proximal tubule.
Received 4 January 1995; accepted in final form 12 July 1995.
APS Manuscript Number F1-5.
Article publication pending Am. J. Physiol. (Renal Fluid Electrolyte
Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 10 August 1995.