Robert W. Berliner

The relationship between peritubular capillary protein concentration and fluid reabsorption by the renal proximal tubule

The relationship between peritubular capillary protein concentration and rate of sodium reabsorption by the rat proximal tubule was examined using free-flow recollection micropuncture techniques. Tubule fluid-to-plasma inulin ratios were measured before, during, and at successive intervals after brief (15-25 sec) intra-aortic injections (at the level of the renal artery) of colloid-free, isoncotic, and hyperoncotic solutions. Arterial hematocrit and protein concentrations were measured simultaneously in these rats. In other rats, total protein concentration of peritubular capillary blood plasma was determined before, during, and after these same infusions with a newly described submicroliter fiber-optic colorimeter. In the 15-25 sec interval necessary to infuse 2 ml of these test solutions, fractional and absolute sodium reabsorption varied directly with peritubular capillary colloid osmotic pressure, declining during infusion of colloid-free solutions, increasing during hyperoncotic infusions, and remaining unchanged during isoncotic infusions. In the subsequent 20-min interval after intra-aortic injection of these test solutions, capillary protein concentration remained at (isoncotic infusions) or returned to (colloid-free and hyperoncotic fluids) control values. Whereas reabsorption after colloid-free solutions returned to base line levels in parallel with the return in capillary protein concentration, after colloid infusions (which resulted in continued expansion of extracellular fluid volume), a progressive decline in reabsorption was observed. These results afford strong evidence that peritubular capillary colloid osmotic pressure is one important determinant of proximal sodium reabsorption. Nevertheless it is apparent that mechanisms other than or in addition to this must be invoked to explain the delayed inhibition of reabsorption that accompanies expansion of extracellular fluid volume by colloid solutions.

Micropuncture study of nephron function in the rhesus monkey

The function of the proximal and distal tubule was studied in the rhesus monkey during antidiuresis and during the diuresis after furosemide administration (during which extracellular fluid volume was maintained).In the proximal tubule, fluid to plasma ratios for sodium, potassium, and osmolality approximated unity. During antidiuresis, about 30% of the filtered water remained at the end of the accessible portion of this segment (92% of length). Fluid was hypotonic to plasma throughout the distal tubule. 25% of the filtered water was present in the early distal tubule. Small but significant water reabsorption (about 8% of filtered) occurred in remainder of this segment. Tubule fluid to plasma potassium concentration ratios tended to increase along the distal tubule, and the amount of potassium, relative to the amount filtered, increased from 13% in the early portion of this segment to 26% in the late portion.After furosemide was administered animals excreted about one-third of the filtered sodium and water. Despite this diuresis, electrolyte and water reabsorption along the proximal tubule did not differ from values obtained in control animals. Osmolality and sodium concentration of fluid from the distal tubule approached those of plasma. 22% of the filtered sodium (twice the control values) reached the distal tubule, whereas the fraction of filtered water remaining was only slightly increased. These findings indicate that, after the administration of this drug, inhibition of sodium reabsorption occurred in the water-impermeable segment of the nephron, rather than in the proximal tubule. After furosemide administration, all tubule fluid to plasma potassium concentration ratios in the distal tubule were equal to or greater than one, suggesting inhibition of active potassium reabsorption at or prior to this site.Fluid to plasma bicarbonate concentration ratios from the midportion of the proximal tubule were consistently less than one in normal monkeys. After acetazolamide was administered, the bicarbonate concentration of samples of tubule fluid recollected from these same sites was the same as, or higher than in plasma. This fact demonstrates the inhibition of bicarbonate reabsorption in this portion of the tubule.

The relationship between glomerular filtration rate and sodium reabsorption by the proximal tubule of the rat nephron

We have tested two of the hypotheses proposed to explain the adjustment in sodium reabsorption in the proximal tubule that follows a change in the rate of glomerular filtration (glomerulotubular balance). Using the recollection micropuncture technique, we were able to measure the immediate and late changes in reabsorptive rate after an acute alteration in filtration rate produced by aortic constriction and release of constriction. It was found that fractional reabsorption, as measured by the inulin tubule fluid to plasma (TF/P) ratio, increased after aortic constriction and decreased after release, but that in most instances, absolute reabsorptive rate changed in parallel to glomerular filtration rate. The change was similar whether the collections were made less than 1 or more than 5 min after the change in blood pressure. The rapid time course of this adjustment in reabsorptive rate is viewed as evidence against an intrarenal humoral feedback mechanism. In the same experiments we measured the (TF/P)(In), transit time, and flow rate of fluid in single nephrons before and during aortic constriction or release of aortic constriction. The change in reabsorptive rate and the simultaneous change in calculated cross-sectional area of the tubule lumen were rarely proportional, i.e., C/pir(2) was not constant. In other experiments, these same measurements were made before and during periods of increased ureteral pressure. Despite large increments in calculated cross-sectional area, the absolute rate of reabsorption either remained relatively unchanged or fell in proportion to the change in filtration rate. It is concluded that under these conditions, reabsorptive rate is governed by some factor other than tubule geometry.

An inhibitory effect of furosemide on sodium reabsorption by the proximal tubule of the rat nephron

The evidence from previous micropuncture studies for an inhibitory effect of furosemide on proximal sodium reabsorption in the rat has been conflicting. Intrinsic reabsorptive capacity, estimated in free flow and shrinking drop experiments, has been reported to be depressed, whereas fractional reabsorption usually remains unchanged. We have recently reported that, during conditions of elevated intraluminal hydrostatic pressure, unless care is taken to prevent retrograde flow of tubule fluid from more distal sites, the concentration of inulin in late proximal fluid is often factitiously elevated. Since furosemide raises intraluminal pressures, often markedly, the failure to detect a depression of fractional reabsorption might be the consequence of retrograde contamination during fluid collection. Experiments were designed to compare the effect of furosemide on fractional sodium reabsorption by the proximal tubule when collections were obtained with distal oil blocks of conventional length as well as with unusually long blocks of oil of low and high viscosities. When reflux is prevented, fractional sodium reabsorption is usually depressed by furosemide, whereas when conventional distal blocks are used, the calculated values for fractional reabsorption either remain unchanged or increase. Simultaneous measurements of nephron glomerular filtration rate indicate that the latter is the consequence of retrograde contamination.

STUDIES ON THE CHEMOTHERAPY OF THE HUMAN MALARIAS. VII. THE ANTIMALARIAL ACTIVITY OF PAMAQUINE

Pamaquine, synthesized in 1926, was introduced in the treatment of malaria as a schizonticide. It was soon found, however, that the great schizonticidal activity which it possessed in cathemerium malaria of canaries did not obtain in the human malarias. It was shown to be relatively ineffective in acute attacks of vivax malaria and to have only minimal activity against the asexual forms of P. falciparum, although it did eradicate the gametocytes in this infection. In addition, the general usefulness of pamaquine was limited by the frequent occurrence of toxic effects with doses in the therapeutic range. Nonetheless, evidence was advanced favoring both a prophylactic (1, 2, 3) and curative action (4) in vivax malaria. The toxicity of the drug and an incomplete understanding of the biology of vivax malaria led the commission on malaria of the Health Organization of the League of Nations (5) to state that its prophylactic action was not practical and to discount the work of Sinton on its curative action (4). The commission recommended that pama-