A new frontier in physiology?
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Physiology↗
Biomedical subjects
F G Knox
Publications and source records attributed to F G Knox.
Effect of phosphate infusion on proximal tubule phosphate reabsorption in phosphate-deprived and respiratory alkalotic rats.
Phosphate deprivation and acute respiratory alkalosis both stimulate phosphate conservation by the kidney. To evaluate the response of the superficial proximal tubule to increases in the filtered load of phosphate (Pi), micropuncture studies were performed in these two models of Pi conservation, rats fed a low-phosphate diet (0.07% Pi), and rats with acute respiratory alkalosis (RA). All animals were acutely thyroparathyroidectomized. After basal collections, the animals were infused with Pi at a rate of 4 microM/min and then the samples recollected 30 min after the initiation of the Pi infusion. Infusion of phosphate increased the filtered load of phosphate (FLPi) of single nephrons from 112 +/- 13 to 266 +/- 44 pmol/min in phosphate-derived rats and from 123 +/- 21 to 217 +/- 44 pmol/min in respiratory alkalotic rats. However, absolute reabsorption of phosphate (ARPi) increased only in phosphate deprivation (94 +/- 16 to 126 +/- 25 pmol/min). These results indicate that the superficial proximal convoluted tubule responds to phosphate infusion by increasing reabsorption in the phosphate-deprived model, but not in the respiratory alkalotic model, of phosphate conservation.
Absorption↗
Resistance to the phosphaturic effect of parathyroid hormone during phosphate conservation is due to enhanced phosphate reabsorption by the pars recta.
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Absorption↗
Effect of renal perfusion pressure on sodium reabsorption from proximal tubules of superficial and deep nephrons.
Previous studies in rats have demonstrated that superficial proximal tubule sodium reabsorption does not change in response to alterations in renal perfusion pressure (RPP). The first objective of the present study was to estimate sodium reabsorption in response to acute changes in RPP utilizing fractional lithium reabsorption (FRLi) as an index of fractional sodium reabsorption (FRNa) by the proximal tubule of the kidney as a whole. FRLi decreased in response to increases in RPP, suggesting that sodium reabsorption by the proximal tubule of some nephron population is decreased. Therefore, the second objective of the present study was to test the hypothesis that superficial and deep proximal tubules respond differently to changes in RPP by comparing proximal tubule sodium reabsorption from both nephron populations. In response to an acute change in RPP from 114 +/- 4 to 138 +/- 5 mmHg, FRNa by the proximal tubule and descending limb of Henle's loop in deep nephrons decreased from 71.3 +/- 2.3 to 55.8 +/- 5.6%, but FRNa by the superficial late proximal tubule was not changed: (44.3 +/- 4.8 to 45.1 +/- 3.9%). The urinary fractional reabsorption of sodium decreased from 96.7 +/- 0.6 to 94.5 +/- 0.5%. In summary, these studies demonstrate that increases in RPP have no effect on sodium reabsorption by the proximal tubule of superficial nephrons. In contrast, sodium delivery to the point of micropuncture in the descending limb of Henle's loop of deep nephrons was increased, suggesting inhibition of sodium reabsorption by proximal tubules of deep nephrons in response to increases in RPP.
Absorption↗
Effect of dexamethasone on segmental phosphate reabsorption in phosphate-deprived rats.
These experiments were designed to test the hypothesis that avid phosphate reabsorption by the pars recta accounts for the resistance to the phosphaturic effects of acute dexamethasone (DEX) and parathyroid hormone (PTH) infusions in rats fed a low-phosphate diet. Acute infusion of DEX [0.4 mg/(kg X h)] increased the fractional delivery of phosphate (FDPi) to the late proximal tubule from 7.1 +/- 2.1 to 14.4 +/- 3.5%, whereas FDPi to the early distal tubule and urine were not different. PTH alone [1 U/(kg X min)] increased FDPi to the late proximal tubule from 4.0 +/- 1.1 to 15.7 +/- 3.7%, whereas FDPi to the early distal tubule or urine was not different. The combination of DEX and PTH further increased FDPi to the late proximal tubule (32.7 +/- 6.4%) and resulted in an increase in fractional excretion of phosphate (FEPi), in spite of the fact that the FDPi to the early distal tubule was not significantly increased. The increased delivered load of phosphate to the pars recta following inhibition of phosphate transport in superficial proximal convoluted tubules resulted in a comparable increase in phosphate reabsorption in the pars recta, based on linear regression analysis, in rats fed low-phosphate diet but not in rats fed normal phosphate diet. These results demonstrate that acute infusion of DEX or PTH inhibits fractional phosphate reabsorption in the superficial proximal tubule but does not result in an increase in FEPi due at least in part to avid phosphate reabsorption in the superficial pars recta in rats fed low-phosphate diet.(ABSTRACT TRUNCATED AT 250 WORDS)
Absorption↗
Effects of long-term treatment with indomethacin on renal function.
The prolonged effects (42 days) of indomethacin treatment on the renin-angiotensin-aldosterone axis, renal hemodynamics, and renal excretory function in humans were studied. Indomethacin produced a 41% sustained depression in the 24-hour excretion of prostaglandin E2 and a mild (7%) decrease in inulin clearance but did not affect the clearance of p-aminohippurate, the 24-hour excretion of sodium and potassium, or the basal values of plasma aldosterone; however, it decreased the basal values of renin and prevented the stimulated (3 hours of walking) responses of plasma renin activity and plasma aldosterone. Indomethacin also produced a decrease in both the diuretic and saluretic response to furosemide and in the renal ability to concentrate urine. The indomethacin-induced hyporeninism and hypoaldosteronism were more pronounced when the subjects were receiving a sodium-restricted diet. This finding indicates that prolonged administration of anti-inflammatory drugs induces chronic hyporeninism and hypoaldosteronism. Prolonged treatment with indomethacin also produced some of the symptoms of a syndrome of hypoprostaglandinism, such as decreased plasma renin activity, plasma aldosterone, and urinary prostaglandin E2 in association with increases in plasma potassium levels and diastolic pressure.
Adult↗
Effect of allopurinol on the renovascular responses to adenosine.
It is known that renal ischemia enhances the production of adenosine, which is further metabolized by xanthine oxidase, and that the inhibition of this metabolizing enzyme by allopurinol ameliorates the consequences of renal ischemia. This study was undertaken to define the effect of allopurinol on the renal responses to adenosine. It was found that 5 minutes of intrarenal infusion of adenosine in control dogs produced a typical biphasic response characterized by an initial vasoconstriction, decreasing renal blood flow by 46.3% +/- 6.0%, followed by vasodilation, increasing renal blood flow by 8.5% +/- 3.6% above the control levels. Adenosine infusion was also accompanied by a significant reduction of plasma renin activity, from 8.4 +/- 0.6 ng/ml/hour to 3.8 +/- 0.4 ng/ml/hour. The administration of an intravenous infusion of 50 mg allopurinol did not alter the vasoconstrictor phase of adenosine--the average decrease was 41.1% +/- 3.3%; however, it prevented much of the vasodilation because renal blood flow over the 5 minutes remained 17.9% +/- 5.0% less than the levels recorded before adenosine infusion. Allopurinol also prevented the decrease of plasma renin activity, for which the average values recorded before and after adenosine were 9.6 +/- 0.6 ng/ml/hour and 8.2 +/- 0.6 ng/ml/hour, respectively. The results of this study indicate that allopurinol exerts specific effects on the vasodilatory component of adenosine and prevents the adenosine-suppressive effect on the renin-angiotensin system.
Adenosine↗
Renal cortical perfusion--preliminary experience with the dynamic spatial reconstructor (DSR).
The three-dimensional image data generated by the Dynamic Spatial Reconstructor (DSR) enables measurement of the three-dimensional distribution of blood supply in organs. We have applied this imaging technique to evaluate renal cortical blood flow distribution and compare it with distribution of radiolabeled microspheres. The DSR, a high temporal resolution volumetric roentgenographic computed tomographic scanner, was used to scan the volume containing a kidney in 0.13-0.26 s and repeating this scan 8-4 times per s for six s during a renal arteriogram. Five anesthetized dogs were studied in the prone position with the left kidney exteriorized through a flank incision. An electromagnetic flowmeter was placed around the renal artery and a needle placed retrograde into the artery for injection of a 2 cc bolus of contrast agent. During the scan the contrast agent was injected over a four s period during which radioactively labelled microspheres were injected into the left atrium. The tomographic images of approximately 10 parallel, 5 mm thick sagittal slices corresponding to the slices of the kidney used for counting microspheres in the cortical layers were displayed and analyzed. The time point chosen for analysis was the one in which peak brightness (i.e., concentration of contrast agent) was detected in the cortex. The spatial distribution of peak brightness values was compared to the number of microspheres at the same sampling locations. The microsphere-based value of regional cortical blood flow fell below the regression line for the juxtamedullary cortex and above for the outer cortex. This result is consistent with the preferential distribution of microspheres to the outer cortex whereas the contrast agent distributed more uniformly throughout the cortex.
Animals↗
Synthetic atrial natriuretic factor decreases renal tubular phosphate reabsorption in rats.
Atrial natriuretic factor (ANF), a family of peptides isolated from cardiac atria, has marked effects on sodium excretion. A synthetic 26 amino acid sequence of ANF peptide has also been shown to be phosphaturic. However, it is difficult to assess whether the phosphaturia is due to changes in tubular reabsorption of phosphate without control of filtered load of phosphate. In the present study, the hypothesis that ANF peptide decreases tubular phosphate reabsorption was tested by using graded phosphate infusions of 0, 1, 2, and 3 mumol/min in thyroparathyroidectomized rats. Further, reabsorbed phosphate was similarly assessed in rats infused with parathyroid hormone (PTH) to allow comparison with a known phosphaturic hormone. ANF peptide decreased reabsorbed phosphate compared with saline controls (2.72 +/- 0.28 mumol/ml GFR compared with 3.35 +/- 0.35, P less than 0.05) but not as much as a maximally phosphaturic dose of PTH (2.04 +/- 0.13 mumol/ml GFR). We conclude that synthetic ANF peptide decreases tubular phosphate reabsorption in vivo.
Absorption↗
Effect of intrarenal angiotensin II infusion on the renal escape from mineralocorticoid.
This study examined the hypothesis that suppression of the antinatriuretic action of angiotensin II (ANG II) is an important determinant of the escape from the sodium-retaining effects of mineralocorticoid. In five uninephrectomized dogs aldosterone (ALDO) infusion (10 ng X kg-1 X min-1) produced a fall in sodium excretion (UNaV) on the first day that returned to control on the fourth day of ALDO infusion. Mean arterial pressure (MAP) increased from 89 +/- 1 to 100 +/- 1 mmHg, and glomerular filtration rate (GFR) increased from 38 +/- 3 to 45 +/- 3 ml/min during ALDO infusion. After recovery, intrarenal infusion of ANG II (1.5 ng X kg-1 X min-1) was initiated to maintain a constant level of ANG II during the subsequent aldosterone administration. The intrarenal ANG II infusion produced a sustained increase in MAP (12 +/- 4 mmHg) and a sustained decrease in GFR (11 +/- 5 ml/min) and effective renal plasma flow (42 +/- 17 ml/min). With intrarenal ANG II levels fixed, ALDO infusion again produced a marked decrease in UNaV on the first day followed by a return to control levels on the third day. Again, MAP and GFR increased significantly during ALDO infusion (from 101 +/- 2 to 119 +/- 2 mmHg and from 27 +/- 6 to 35 +/- 4 ml/min, respectively). The absolute increase in MAP was significantly greater during ALDO infusion with intrarenal ANG II infusion as compared with ALDO infusion with intrarenal vehicle infusion alone.(ABSTRACT TRUNCATED AT 250 WORDS)
Aldosterone↗
Nephron site of resistance to phosphaturic effect of PTH during respiratory alkalosis.
This study was performed to evaluate the nephron site(s) responsible for the blunted phosphaturic effect of parathyroid hormone during respiratory alkalosis. In normocapnic thyroparathyroidectomized rats, parathyroid hormone administration markedly increased the fractional excretion of phosphate (FEp) from 2.1 +/- 0.5 to 36.6 +/- 5.0%. However, in the respiratory alkalotic rats, parathyroid hormone administration did not significantly increase the FEp (1.4 +/- 0.9 to 5.9 +/- 2.2%). This blunted phosphaturic response to parathyroid hormone was not due to a blunted inhibition of phosphate reabsorption by the superficial proximal tubule, since parathyroid hormone administration significantly increased the fractional delivery of phosphate (FDp) at the superficial late proximal tubule in both normal (25.3 +/- 3.0 to 36.2 +/- 3.8%, delta 10.9 +/- 3.2%) and respiratory alkalotic rats (12.2 +/- 3.1 to 30.3 +/- 4.9%, delta 18.0 +/- 4.7%). Parathyroid hormone administration significantly increased the FDp at the superficial early distal tubule from 9.3 +/- 3.9 to 38.7 +/- 7.4% (delta 29.4 +/- 5.1%) in normal rats and from 4.5 +/- 1.7 to 12.9 +/- 3.4% (delta 8.5 +/- 3.2%) in the respiratory alkalotic rats. We conclude that the blunted phosphaturic response to parathyroid hormone in respiratory alkalotic rats is not due to a blunted inhibition of phosphate reabsorption by the proximal convoluted tubule but is primarily due to enhanced reabsorption by the pars recta segment of the proximal tubule.
Absorption↗
Administration of atrial natriuretic factor inhibits sodium-coupled transport in proximal tubules.
The newly discovered peptides extracted from cardiac atria, atrial natriuretic factors (ANFs), when administered parenterally cause renal hemodynamic changes and natriuresis. The nephron sites and cellular mechanism accounting for profound increase in Na+ excretion in response to ANFs are not yet clarified. In the present study we investigated whether synthetic ANF peptide alters the reabsorption of Na+ and reabsorption of solutes cotransported with Na+ in the proximal tubules of rats. Synthetic ANF peptide consisting of 26 amino acids, 4 micrograms/kg body wt/h, or vehicle in controls, was infused to surgically thyroparathyroidectomized anesthetized rats. After determination of the fractional excretion (FE) of electrolytes (Na+, K+, Pi, Ca2+, Mg2+, HCO3), the kidneys were removed and luminal brush border membrane vesicles (BBMVs) were prepared from renal cortex. Solute transport was measured in BBMVs by rapid filtration techniques. Infusion of ANF peptide increased FENa, FEPi, and FEHCO3; but FECa, FEK, and FEMg were not changed. The increase in FENa was significantly correlated, on the one hand, with increase of FEPi (r = 0.9, n = 7; P less than 0.01) and with increase of FEHCO3 (r = 0.89, n = 7; P less than 0.01). On the other hand, FENa did not correlate with FEK, FECa, or with FEMg. The Na+ gradient-dependent uptake of Pi by BBMVs prepared from renal cortex of rats receiving ANF infusion was significantly (P less than 0.05) decreased (-25%), whereas the Na+ gradient-dependent uptake of L-[3H]proline and of D-[3H]glucose or the diffusional uptake of 22Na+ were not changed. ANF-elicited change in FEPi showed a close inverse correlation with decrease of Na+-dependent Pi uptake by BBMVs isolated from infused rats (r = 0.99, n = 7; P less than 0.001). Direct addition of ANF to BBMVs in vitro did not change the Na+ gradient-dependent Pi uptake. In rats infused with ANF, the rate of amiloride-sensitive Na+-H+ exchange across the brush border membrane (BBM) was significantly (P less than 0.05) decreased (-40%), whereas the diffusional 22Na+ uptake (0.5 min) and the equilibrium (120 min) uptake of 22Na+ were not changed. The inhibition of Na+-H+ exchange after ANF was likely due to alteration of the BBM antiporter itself, in that the H+ conductance of BBMVs was not increased. We conclude that synthetic ANF (a) decreases tubular Na+ reabsorption linked to reabsorption of HCO3 in proximal tubules, and (b) inhibits proximal tubular reabsorption of Pi coupled to Na+ reabsorption, independent of secretion and/or action of parathyroid hormone or calcitonin. These ANF effects are associated with inhibition of Na+-Pi synport and of Na+-H+ antiport in luminal BBMs. Our findings document that inhibition of Na+-coupled transport processes in proximal tubules is an integral part of the renal response to ANF.
Animals↗
Contribution of sympathetic neural reflexes to mineralocorticoid escape.
The administration of aldosterone to normal subjects induces sodium retention, which is only transient inasmuch as sodium balance is restored shortly after extracellular fluid volume is expanded. This escape from sodium-retaining effects of mineralocorticoids, which is normally attended by sympathetic withdrawal, is not seen in some forms of secondary hyperaldosteronism that evolve with edema and increased sympathetic activity. The precise significance of the reflexly mediated changes in sympathetic activity on renal function has been difficult to assess. In fact, changes in cardiovascular volumes are known to be accompanied by alterations in other parameters that play a crucial role on salt and water equilibrium, such as renal perfusion pressure and renal renin. In this short paper we have analyzed the most probable integrated sequence of responses in neural activity, systemic pressure, and renal renin that lead to escape from high circulating levels of aldosterone. A major role is ascribed to volume expansion and to arterial pressure-induced natriuresis in the restoration of sodium balance. However, such responses are greatly facilitated by a selective inhibition of renal sympathetic activity mediated by cardiopulmonary receptors, and by a fall in postglomerular vascular resistance specifically mediated by a decrease in intrarenal angiotensin. These two modulatory factors are thought to assume a greater influence on sodium excretion during instances of secondary hyperaldosteronism.
Aldosterone↗
Intrarenal distribution of blood flow: evolution of a new approach to measurement.
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Animals↗
Nephron sites of action of nicotinamide on phosphate reabsorption.
The administration of nicotinamide results in urinary phosphate excretions similar to those obtained with pharmacologic doses of parathyroid hormone (PTH). Free-flow micropuncture was performed to localize the nephron site(s) of inhibition of phosphate reabsorption by nicotinamide or PTH in thyroparathyroidectomized (TPTX) rats stabilized on a normal or low phosphate diet. In rats fed a normal phosphate diet phosphaturia was observed following either nicotinamide or PTH treatment. Nicotinamide inhibited phosphate reabsorption in the loop of Henle (pars recta) but not in the accessible proximal tubule. PTH inhibited phosphate reabsorption in both the accessible proximal tubule and the pars recta. In phosphate deprivation, the phosphaturic response to either nicotinamide or PTH was blunted. Although phosphate reabsorption was markedly inhibited in the accessible proximal tubule with both nicotinamide and PTH, subsequent reabsorption in the loop of Henle and distal tubule blunted the phosphaturia. We conclude that nicotinamide primarily inhibits phosphate reabsorption by the pars recta in rats fed a normal phosphate diet, whereas it inhibits phosphate reabsorption by the proximal convoluted tubule in rats fed a low phosphate diet. Furthermore, avid reabsorption of phosphate in the pars recta accounts for the resistance to the phosphaturic effect of nicotinamide or PTH seen in rats fed a low phosphate diet.
Absorption↗
Nephron heterogeneity of phosphate reabsorption: effect of parathyroid hormone.
We evaluated the response of superficial and deep nephron proximal tubules to PTH in thyroparathyroidectomized (TPTX) rats fed a normal phosphate diet (0.7%). As phosphate reabsorption is not detectable in the ascending limb of the loop of Henle, fractional phosphate delivery (FDPi%) to the superficial early distal tubule and papillary loop of Henle reflects delivery from superficial and deep nephron proximal tubules, respectively. Re-collection micropuncture experiments were performed in nine acutely TPTX rats before and after the infusion of PTH (33 U/kg bolus; 1 U X kg-1 X min-1). In response to PTH, fractional phosphate excretion increased from 3.3 to 26.2% (P less than 0.05). FDPi% was less from the deep than from the superficial proximal tubule (5.7 vs. 15.7%, P less than 0.05) prior to PTH, indicating enhanced phosphate reabsorption by deep compared with superficial proximal tubules. During PTH infusion, FDPi% was increased in both nephron groups compared with control (P less than 0.05), but there were no differences in phosphate delivery between deep (28.0%) and superficial (29.7%) proximal tubules. We conclude that in acutely volume-expanded TPTX rats, infusion of a pharmacologic dose of PTH decreases phosphate reabsorption in both superficial and deep nephrons. Furthermore, the heterogeneity of FDPi% from deep compared with superficial proximal tubules seen in TPTX rats is absent during PTH infusion.
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Proximal tubule site of inhibition of phosphate reabsorption by calcitonin.
The present study was performed to evaluate the nephron site of inhibition by calcitonin of phosphate reabsorption in the thyroparathyroidectomized rat. Pharmacologic doses of salmon calcitonin markedly inhibited fluid and phosphate reabsorption by the superficial proximal tubule. However, continued phosphate reabsorption between the superficial late proximal and early distal tubule, as well as along the distal tubule, blunted the phosphaturic effect of calcitonin. We conclude that the phosphaturic effect of a pharmacologic dose of salmon calcitonin is primarily due to an inhibition of fluid and phosphate reabsorption by the proximal convoluted tubule.
Absorption↗
Effects of bradykinin on renal interstitial pressures and proximal tubule reabsorption.
Renal interstitial Starling forces have been postulated as the link between the peritubular microcirculation and fluid reabsorption by the proximal tubule. The renal vasodilator bradykinin was used as a tool to test this relationship in micropuncture studies in the rat. Bradykinin increased peritubular capillary and interstitial hydrostatic pressures and decreased peritubular and interstitial oncotic pressures. The balance of Starling forces in the interstitium (interstitial oncotic pressure minus interstitial hydrostatic pressure) was significantly decreased from 6.5 +/- 2.3 to -4.0 +/- 1.3 mmHg without a change in fluid reabsorption by the proximal tubule. We conclude that renal interstitial Starling forces do not regulate reabsorption by the superficial proximal tubule in the rat in response to bradykinin.
Animals↗