REINFORCING FEEDBACK LOOP OF RENAL CYCLIC GMP AND INTERSTITIAL HYDROSTATIC PRESSURE IN PRESSURE-NATRIURESIS

摘要

This study addresses the hypothesis that renal interstitial (RI) cyclic guanosine 3′5′-monophosphate (cGMP), a modulator of pressure-natriuresis (P-N), exerts its effect through a relationship with renal interstitial hydrostatic pressure (RIHP). Increasing renal perfusion pressure (RPP) in Sprague-Dawley rats led to increases in RIHP (5.2 ± 0.6 to 10.9 ± 1.6 mm Hg; P<0.01), UNaV (0.062 ± 0.009 to 0.420 ± 0.068 μmol/min/g; P<0.01), and RI cGMP (3.5 ± 0.8 to 9.5 ± 1.7 fmol/min; P<0.01), and these effects were blocked by partial renal decapsulation. Infusion of cGMP into the RI compartment of decapsulated animals restored natriuresis (0.067 ± 0.010 to 0.310 ± 0.061 μmol/min/g; P<0.01). These changes were independent of changes in glomerular filtration rate (GFR). Artificially increasing RIHP in normotensive animals increased RI cGMP (4.1 ± 0.6 to 6.9 ± 0.7 fmol/min; P<0.01) and UNaV (0.071 ± 0.013 to 0.179 ± 0.039 μmol/min/g; P<0.05). Co-infusion of organic anion transport-inhibitor probenecid, or soluble guanylyl cyclase inhibitor ODQ, abolished these effects. Infusion of cGMP into the RI compartment of normotensive animals increased RIHP (6.7 ± 0.4 to 10.3 ± 0.9 mm Hg; P<0.001). Exogenous RI cGMP delivery did not affect total, cortical, or medullary renal blood flow. These studies suggest that extracellular RI cGMP is required for the natriuresis observed after increases in RPP and RIHP, and that cGMP acts via a tubule mechanism. The results support an intra-renal positive-feedback loop wherein RI cGMP increases RIHP, which in turn increases RI cGMP, contributing to the reinforcement of P-N.