Abstract 216: Mechanism of Pressure-Natriuresis: Evidence That Na+/K+-ATPase is a Renal Extracellular Cyclic Guanosine 3’,5’-Monophosphate Receptor
Pressure-natriuresis (P-N) is the main compensatory mechanism by which the kidney excretes sodium (Na+) in response to an increase in blood pressure. Extracellular renal interstitial (RI) cyclic guanosine 3’,5’-monophosphate (cGMP) modulates P-N by binding to an unidentified receptor on the basolateral membrane of renal proximal tubule cells and activating the Src tyrosine kinase signaling cascade. In this study, we hypothesized that the cGMP receptor is the extracellular domain of Na+/K+-ATPase (NKA). In uninephrectomized Sprague Dawley rats, the renal perfusion pressure (RPP) was increased from 110 to 140 mmHg by ligating the infrarenal aorta, celiac, and mesenteric arteries, in a standard P-N model. In response to increased RPP, urinary Na+ excretion (UNaV) increased from 0.35±0.065 to 2.19±0.31 umol/min (P<0.0001; N=14). Rostafuroxin, a digitoxigenin derivative that specifically displaces ouabain binding from NKA without inhibiting NKA pump activity, significantly decreased UNaV in a dose-dependent manner, from 2.19±0.31 to 1.38±0.18 (P<0.05; N=8) and to 0.34±0.080 umol/min (P<0.0001; N=6), at RI infusion rates of 2.4 and 12 ng/kg/min, respectively. In contrast, at higher infusion rates, of 60 and 120 ng/kg/min, rostafuroxin increased UNaV to 2.49±0.45 (P=0.60; N=8) and to 3.68±0.49 umol/min (P<0.05; N=8), respectively. Thus, rostafuroxin is a pharmacologic agent with NKA antagonist/agonist activity, depending on dose. To show that cGMP-induced natriuresis depends upon NKA binding, we microinfused cGMP directly into the RI compartment of uninephrectomized Sprague Dawley rats without changing the RPP. We compared UNaV in the second hour period of a 2-hour RI microinfusion of vehicle (0.66±0.086 umol/min; N=5), to rostafuroxin 12 ng/kg/min (0.69±0.11 umol/min; P=0.81; N=6), cGMP 72 ng/kg/min (3.41±0.57 umol/min; P<0.005; N=7), or cGMP together with rostafuroxin (0.64±0.21 umol/min; P=0.93; N=6). The rostafuroxin dose that abolished P-N also nullified the natriuretic response to cGMP. In summary, RI microinfusion of rostafuroxin blocked both pressure- and cGMP-induced natriuresis. These data provide strong evidence that the extracellular domain of NKA serves as a receptor for RI cGMP, which mediates P-N.
- © 2012 by American Heart Association, Inc.