Knox, Franklyn G.

We examined whether phosphonoformate (PFA) can cause phosphaturia through its direct action on brush-border membrane (BBM) in vivo. Infusion of PFA or of parathyroid hormone (PTH) to thyroparathyroidectomized rats caused a marked increase in fractional excretion of phosphate without changes in excretion of Na+ or of GFR. The PFA-induced phosphaturia was not accompanied by an increase in urinary adenosine-3',5'-cyclic monophosphate (cAMP); moreover, PFA added in vitro did not influence the PTH-sensitive adenylate cyclase and cAMP-phosphodiesterase in proximal convoluted tubules. In BBM vesicles (BBMV) from rats with PFA-elicited phosphaturia, neither the rate of Na+-Pi symport nor Na+-dependent binding of [14C]PFA on BBMV was changed, whereas in BBMV from PTH-infused rats the Vmax of Na+-Pi symport decreased. PFA is almost completely ultrafiltrable; no metabolic transformation of PFA was detected after [14C]PFA exposure to rat renal cortical slices, homogenate, or to blood. We conclude that PFA causes phosphaturia by direct inhibition of Na+-Pi symport across BBM in proximal tubules, acting from the luminal side. Thus PFA (foscarnet) has a unique direct mechanism of phosphaturic effect, via its action on Pi reabsorption in proximal tubules in vivo.

The objective of the present study was to examine the effect of direct expansion of the renal interstitial volume on sodium reabsorption by proximal tubules of superficial and deep nephrons in the absence of systemic extracellular volume expansion. Renal interstitial volume expansion was achieved by injection of 50 microliter of 2.5% albumin in 0.9% saline into the renal interstitium via a polyethylene matrix that was chronically implanted in the interstitium of the rat kidney. Renal interstitial volume expansion increased renal interstitial hydrostatic pressure from 3.8 +/- 0.5 to 6.8 +/- 1.1 mmHg, P less than 0.05 (n = 5 rats). Fractional reabsorption of sodium by the superficial late proximal tubule decreased from 45.7 +/- 5.6 to 34.2 +/- 5.4%, P less than 0.05, and by the proximal tubule and descending limb of Henle's loop of deep nephrons it decreased from 73.9 +/- 2.9 to 57.2 +/- 6.3%, P less than 0.05 (n = 8 rats). Thus expansion of the renal interstitial volume increased renal interstitial hydrostatic pressure and decreased sodium reabsorption by the proximal tubules of superficial and deep nephrons.

The purpose of this study was to investigate the hypothesis that changes in renal perfusion pressure may be transmitted to the renal interstitium and cause alterations in renal interstitial hydrostatic pressure and sodium excretion. A method that utilizes a chronically implanted polyethylene matrix that allows for direct continuous measurement of renal interstitial hydrostatic pressure, and agrees well with subcapsular measurement in rats, was developed. Renal interstitial hydrostatic pressure, fractional excretion of sodium, and urine flow rate were 3.0 +/- 0.3 mmHg, 0.35 +/- 0.13%, and 19.44 +/- 3.00 microliter/min, respectively, when renal perfusion pressure was 101 +/- 0.8 mmHg. When renal perfusion pressure was increased to 123 +/- 0.9 mmHg renal interstitial hydrostatic pressure, fractional excretion of sodium, and urine flow rate increased significantly to 5.8 +/- 0.6 mmHg, 1.29 +/- 0.29%, and 50.76 +/- 8.83 microliter/min, respectively, in anesthetized male Sprague-Dawley rats. These changes occur despite a well-autoregulated glomerular filtration rate and renal blood flow. In conclusion, increasing renal perfusion pressure caused a significant increase in renal interstitial hydrostatic pressure as measured directly by the implanted polyethylene matrix method and was associated with a significant increase in sodium excretion.

The present study tested the hypothesis that the presence of renal prostaglandin E2 (PGE2) is necessary for full natriuretic response to increased renal interstitial hydrostatic pressure (RIHP) during increased renal perfusion pressure (RPP). In control untreated pentobarbital-anesthetized dogs (n = 7), fractional excretion of sodium (FENa) was 1.17 +/- 0.48, 1.07 +/- 0.24, and 2.69 +/- 0.57% at RPP of 90, 122, and 148 mmHg, respectively. These changes in FENa were associated with effective renal blood flows (ERBF) of 1.43 +/- 0.20, 1.49 +/- 0.23, and 1.99 +/- 0.40 ml.min-1.g kidney wt-1, respectively. Similarly, glomerular filtration rate (GFR) was 0.53 +/- 0.10, 0.71 +/- 0.10, and 0.72 +/- 0.14 ml.min-1.g kidney wt-1, respectively. Treatment with indomethacin, a cyclooxygenase inhibitor, significantly lowered FENa to 0.45 +/- 0.13, 0.77 +/- 0.21, and 1.19 +/- 0.59% at RPP of 91, 121, and 146 mmHg, respectively. Additionally, indomethacin treatment lowered ERBF (0.51 +/- 0.15, 0.52 +/- 0.10, and 0.85 +/- 0.21 ml.min-1.g kidney wt-1) and GFR (0.28 +/- 0.09, 0.34 +/- 0.09, and 0.47 +/- 0.09 ml.min-1.g kidney wt-1) at low, middle, and high RPP, respectively. PGE2 replacement (n = 6) into renal artery at 0.01 microgram.min-1.kg body wt-1 returned FENa, ERBF, and GFR to control levels over the same range of RPP, whereas prostacyclin (PGI2) infusion (n = 7) at the same dose did not. RIHP was 4.2 +/- 1.2, 4.2 + 0.5, and 7.5 +/- 1.7 mmHg with increasing RPP in control untreated group and increased to similar levels with indomethacin treatment and during PGE2 or PGI2 replacement.(ABSTRACT TRUNCATED AT 250 WORDS)

The objective of these experiments was to study pressure natriuresis in the Wistar-Kyoto (WKY) and the spontaneously hypertensive rat (SHR) during acute bilateral renal decapsulation, a maneuver that partially blocks the increase in renal interstitial hydrostatic pressure (RIHP). In control WKY rats (n = 7), at renal perfusion pressure (RPP) of 105 +/- 0.7 and 125 +/- 1.1 mmHg, RIHP increased from 4.4 +/- 0.4 to 7.2 +/- 0.7 mmHg (P less than 0.05) and fractional excretion of sodium (FENa) increased from 0.23 +/- 0.05 to 1.32 +/- 0.14% (P less than 0.05). Acute bilateral renal decapsulation (n = 6) blunted the increase in RIHP observed when RPP was increased in control WKY rats and abolished the pressure natriuretic and diuretic response. When RPP was allowed to increase from 106 +/- 0.8 to 130 +/- 2.2 mmHg in the WKY rats with decapsulated kidneys, RIHP increased from 3.8 +/- 0.5 to 4.3 +/- 0.4 mmHg but FENa did not significantly change (0.31 +/- 0.12 to 0.43 +/- 0.13%). In control SHRs (n = 7), at RPPs of 135 +/- 0.8 and 163 +/- 3.0 mmHg, RIHP was 4.4 +/- 0.4 and 5.0 +/- 0.6 mmHg (NS) and FENa was 0.41 +/- 0.10 and 0.82 +/- 0.17% (P less than 0.05). Renal decapsulation in the SHR did not affect the blunted relationships between RPP, RIHP, and FENa; at RPPs of 135 +/- 0.3 and 162 +/- 2.9 mmHg (n = 7), RIHP was 4.4 +/- 0.6 and 4.7 +/- 0.5 mmHg (NS) and FENa was 0.43 +/- 0.10 and 0.95 +/- 0.22% (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract —Elevation of renal interstitial hydrostatic pressure (RIHP) by direct renal interstitial volume expansion increases sodium excretion. This natriuretic response is blunted by the nonspecific inhibition of the cyclooxygenase (COX) enzymes. The present study tested the hypothesis that the natriuretic response to increased RIHP during direct renal interstitial volume expansion is dependent on COX-1 but not COX-2. RIHP and fractional excretion of sodium (FE Na ) were measured before and after direct renal interstitial volume expansion in control rats (n=7), rats infused with the COX-1 inhibitor piroxicam (n=6, 1.5 mg/kg), and rats infused with the COX-2 inhibitors NS-398 (n=5, 1.5 mg/kg) and meloxicam (n=6, 0.3 mg/kg). In control animals, direct renal interstitial volume expansion significantly increased RIHP (Δ2.3±0.5 mm Hg, P <0.05) and FE Na (Δ1.1±0.3%, P <0.05). Likewise, in animals infused with NS-398 or meloxicam, direct renal interstitial volume expansion significantly increased RIHP (Δ1.8±0.6 mm Hg, P <0.05, and Δ1.7±0.3 mm Hg, P <0.05) and FE Na (Δ1.5±0.4%, P <0.05, and Δ1.1±0.3%, P <0.05), respectively. In contrast, infusion of piroxicam significantly blunted the natriuretic response to direct renal interstitial volume expansion (ΔFE Na 0.3±0.2%), even though RIHP was increased (Δ1.9±0.6 mm Hg, P <0.05). Infusion of piroxicam but not NS-398 or meloxicam blunted the natriuretic response to increased renal interstitial hydrostatic pressure, suggesting that the natriuretic response to increased blood pressure may be preserved during inhibition of COX-2.

This study investigated the role of volume status and perfusion pressure on the hemodynamic response of cortical and medullary renal capillaries to systemic inhibition of nitric oxide. NG-Monomethyl-L-arginine (L-NMMA) was infused intravenously (15-mg/kg bolus and 500-micrograms.min-1.kg-1 infusion), and blood flow in cortical capillaries (QCC) and in descending (QDVR) and ascending vasa recta (QAVR) was measured by fluorescence videomicroscopy in euvolemic and volume-expanded anesthetized Munich-Wistar rats. L-NMMA in euvolemic rats decreased vasa recta blood flow (delta QDVR, 3.97 +/- 0.80 nL/min [P < .01]; delta QAVR, 1.90 +/- 0.39 nL/min [P < .01]; n = 6) and QCC (delta QCC, 0.57 +/- 0.15 nL/min [P < .01]; n = 7) despite increases in renal perfusion pressure (RPP). Fractional excretion of sodium (FENa) remained unchanged. In volume-expanded rats, L-NMMA decreased vasa recta blood flow when RPP increased (delta QDVR, 1.42 +/- 0.79 nL/min [P = .05]; delta QAVR, 1.95 +/- 0.34 nL/min [P < .001]; n = 9) or was held constant by partial aortic occlusion (delta QDVR, 1.19 +/- 0.45 nL/min [P < .05]; delta QAVR, 1.44 +/- 0.40 nL/min [P < .01]; n = 8). QCC was unchanged by L-NMMA when RPP increased (delta QCC, 0.27 +/- 0.20 nL/min; n = 8) but decreased significantly by 0.61 +/- 0.11 nL/min (P < .01, n = 8) when increases in RPP were prevented. FENa increased when RPP increased (delta FENa, 2.47 +/- 0.51%; P < .001) and was held constant (delta FENa, 2.64 +/- 0.46%; P < .001).(ABSTRACT TRUNCATED AT 250 WORDS)

Although urinary sodium excretion is positively influenced by acute changes in renal perfusion pressure, micropuncture studies show highly conflicting results concerning the response of superficial proximal tubule sodium reabsorption to changes in renal perfusion pressure. In the present study, the changes of superficial proximal reabsorption to decreased and increased renal perfusion pressure were determined in rats by an in vivo microperfusion method. In vivo microperfusion was selected as the method to determine the proximal sodium reabsorption because this method made it possible to deliver a constant fluid and electrolyte load to the proximal tubule without the influence of possible changes of glomerular filtration rate. Renal perfusion pressure was decreased from normal pressure by inflating a suprarenal aortic cuff and was increased from the normal level by the occlusion of celiac and mesenteric arteries and the infrarenal aorta. Although fractional excretion of sodium (FENa) in the urine was decreased from 1.24 +/- 0.23% to 0.45 +/- 0.11% (n = 7, p less than 0.01) when renal perfusion pressure was decreased from 125 +/- 6 to 99 +/- 3 mm Hg, absolute tubular reabsorption by the superficial proximal convoluted tubules was not increased (from 4.4 +/- 0.5 to 4.2 +/- 0.3 nl/min/mm, n = 22). When the renal perfusion pressure was elevated from 126 +/- 4 to 149 +/- 4 mm Hg, tubular reabsorption by the superficial proximal tubules was decreased from 4.1 +/- 0.3 to 2.5 +/- 0.3 nl/min/mm (n = 36, p less than 0.01) with an accompanying increase in FENa (from 1.28 +/- 0.24% to 2.29 +/- 0.37%, n = 9, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Flow of tubule fluid to the macula densa is part of a proposed feedback loop for autoregulation of glomerular filtration rate. In the present study, autoregulation of single nephron filtration rate was tested in the presence and the absence of flow to the macula densa in the rat. Filtration rates were measured at elevated arterial blood pressures caused by carotid occlusion and vagal section and at reduced renal perfusion pressures caused by partial aortic constriction. Measurements of single nephron filtration rate in the presence and the absence of flow to the macula densa were obtained by complete volume collections from the distal nephron beyond the macula densa and from the proximal tubule, respectively. Mean blood pressure was 130 ± 4 (SE) mm Hg for the initial collections, and renal perfusion pressure was 100 ± 1 mm Hg for the repeat collections (nine rats). Distal single nephron filtration rate was 42 ± 1 nliters/min at elevated perfusion pressure and 41 ± 1 nliters/min at reduced perfusion pressure; proximal single nephron filtration rate was 41 ± 1 nliters/min at elevated perfusion pressure and 41 ± 1 nliters/min at reduced perfusion pressure. Similarly, glomerular filtration rate was 4.6 ± 0.4 ml/min kg -1 body weight and 4.7 ± 0.3 ml/min kg -1 body weight at elevated and reduced perfusion pressures, respectively. Additional studies in seven dogs showed good correlation between autoregulation of single nephrons in the absence of flow to the macula densa and autoregulation of the micropunctured kidney. It is concluded that autoregulation of single nephron filtration rate is unaltered by interruption of tubule fluid flow to the macula densa.