Published Online
on September 10, 2007

A more recent version of this article appeared on November 1, 2007

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Submitted on May 1, 2007
Revised on May 21, 2007

Extracellular Renal Guanosine Cyclic 3'5'-Monophosphate Modulates Nitric Oxide– and Pressure-Induced Natriuresis

Farah Ahmed; Brandon A. Kemp; Nancy L. Howell; Helmy M. Siragy; and Robert M. Carey^*

From the Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health Sciences Center, Charlottesville.

^* To whom correspondence should be addressed. E-mail: rmc4c{at}virginia.edu.

Abstract—This study addresses the hypothesis that NO- and pressure-induced natriuresis are inhibited when guanosine cyclic 3',5'-monophosphate (cGMP) is prevented from being transported outside its renal synthesizing cells in vivo. Rats received a renal interstitial (RI) infusion of NO donor S-nitroso-N-acetylpenicillamine (SNAP) or SNAP+organic anion transporter inhibitor probenecid (PB) or SNAP+PB+cGMP. SNAP alone increased U_NaV (P<0.05 at 1 hour and P<0.005 at 2 hours). In contrast, SNAP failed to increase U_NaV when coinfused with PB, but cGMP coinfused with SNAP+probenecid restored the natriuretic response. SNAP alone increased RI cGMP (P<0.05) during the second experimental period. PB abolished the increase in RI cGMP in response to SNAP (P<0.01), but cGMP levels were restored by coinfusion with cGMP. PB also abolished SNAP-induced increases in fractional excretion of Na⁺ (FE_Na) and lithium (FE_Li) (both P<0.01). PB also abolished the rise in RI cGMP and natriuresis induced by raising renal perfusion pressure (RPP) from 100 to 160 mm Hg in rats subjected to a standard pressure-natriuresis protocol and the natriuretic response was rescued by coinfusion with cGMP. RI administration of phosphodiesterase type V (PDE V) reduced both RIcGMP and U_NaV in parallel (both P<0.01) without altering RIcAMP. The data demonstrate that export of cGMP from its renal synthesizing cells into the extracellular RI compartment is critical for the natriuretic action of NO donor SNAP or increased RPP and that RI cGMP controls basal Na⁺ excretion. Extracellular cGMP modulates NO- and pressure-induced natriuresis.

Key words: sodium • cyclic GMP • nitric oxide • pressure-natriuresis • kidney • interstitial fluid • probenecid

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