Martin G. Cogan

Angiotensin II: a powerful controller of sodium transport in the early proximal tubule.

Angiotensin II has recently been shown to exert potent control over sodium and water absorption in the proximal convoluted tubule. This transport stimulation is effected by receptors on both the luminal and basolateral membranes of cells located predominantly in the early, S1 proximal tubule. Angiotensin II increases transport primarily by a Gi protein-mediated reduction in intracellular cyclic adenosine monophosphate, which enhances the affinity of the Na(+)-H+ antiporter. Change in early proximal acidification ultimately causes alteration in the amount of sodium chloride leaving the proximal tubule and entering the urine. These direct tubular transport actions by angiotensin II may participate importantly in various physiological actions of the kidney, including the renal response to change in dietary sodium intake and in extracellular volume, as well as in pathophysiological processes such as hypertension.

Renal mechanism of action of rat atrial natriuretic factor.

There has been conflict as to whether crude extracts of atrial natriuretic factor increase renal solute excretion by a hemodynamic mechanism or by direct inhibition of tubular transport. To investigate this issue, seven rats were studied during a euvolemic control period and following continuous administration of pure, synthetic 24 amino acid atrial natriuretic factor. A 10-25-fold increase in urinary sodium and chloride excretion occurred with a brisk kaliuresis but little bicarbonaturia. Atrial natriuretic factor caused whole kidney glomerular filtration rate to increase from 1.17 +/- 0.04 to 1.52 +/- 0.07 ml/min (P less than 0.005). A parallel increase in single nephron glomerular filtration rate, from 34 +/- 1 to 44 +/- 2 nl/min (P less than 0.001), and from 26 +/- 1 to 37 +/- 2 nl/min (P less than 0.005) was measured at the end-proximal and early distal nephron sites, respectively. Appropriate for the higher flows were an increase in absolute proximal and loop reabsorptive rates for bicarbonate, chloride, and water, with a slight decrease in fractional solute and volume reabsorption in proximal and loop segments. To exclude the possibility that atrial natriuretic factor increased filtration rate only in anesthetized animals, eight unanesthetized rats were studied. Glomerular filtration rate increased by 45%, from 2.04 +/- 0.17 to 2.97 +/- 0.27 ml/min (P less than 0.005) without significant change in renal plasma flow, as reflected by 14C-para-aminohippurate clearance (5.4 +/- 0.5-5.6 +/- 0.9 ml/min). The clearance and micropuncture data did not preclude changes in relative blood flow distribution to or in transport by deep nephron segments. In conclusion, atrial natriuretic factor appears to increase renal solute excretion predominantly by a hemodynamic mechanism without directly inhibiting superficial tubular transport.

Angiotensin II stimulates early proximal bicarbonate absorption in the rat by decreasing cyclic adenosine monophosphate.

These studies explored the hypothesis that angiotensin II increases bicarbonate absorption in the proximal convoluted tubule (PCT) by decreasing intracellular cAMP. In vivo microperfusion was performed in rat PCT with measurements of bicarbonate absorption and of tubular fluid cAMP delivery, as a reflection of intracellular cAMP. Intravenous angiotensin II potently increased S1 PCT bicarbonate absorption (348 +/- 11 to 588 +/- 8 peq/min.min, P less than 0.001) and decreased tubular fluid cAMP (18 +/- 2 to 12 +/- 2 fmol/mm.min, P less than 0.05). Parathyroid hormone had the expected opposite effects, which were additive to those of angiotensin II. Over a wide range of hormonal activities, there was an excellent inverse relationship between hormonally modulated bicarbonate absorption and cAMP delivery. Pertussis toxin pretreatment significantly attenuated (by 35-45%) the angiotensin-induced increase in bicarbonate absorption and decrease in cAMP delivery, indicating Gi-protein intermediation. Luminal dibutyryl cAMP abolished the transport response to angiotensin II. In conclusion, these in vivo results suggest angiotensin II stimulates bicarbonate absorption in the S1 PCT by a G1-mediated depression in intracellular cAMP.

Angiotensin II: a potent regulator of acidification in the rat early proximal convoluted tubule.

The early proximal convoluted tubule (PCT) is the site of 50% of bicarbonate reabsorption in the nephron, but its control by angiotensin II has not been previously studied. In vivo microperfusion was used in both the early and late PCT in Munich-Wistar rats. Systemic angiotensin II administration (20 ng/kg X min) or inhibition of endogenous angiotensin II activity with saralasin (1 microgram/kg X min) caused profound changes in bicarbonate absorption in the early PCT (169 +/- 25 and -187 +/- 15 peq/mm X min, respectively). Because the bicarbonate absorptive capacity of the early PCT under free-flow conditions is 500 peq/mm X min, angiotensin II administration or inhibition affected greater than 60% of proton secretion in this segment. Both agents less markedly affected bicarbonate absorption in the late PCT (+/- 28 peq/mm X min) or chloride absorption (+/- 68-99 peq/mm X min) in both the early and late PCT. Because of its potential for controlling the majority of bicarbonate absorption in the early PCT (hence greater than or equal to 30% of bicarbonate absorption in the entire nephron), angiotensin II may be a powerful physiologic regulator of renal acidification.

Dynamics of Glomerular Ultrafiltration in Euvolemic Munich-Wistar Rats

After restoring plasma volume to conscious levels, glomerular pressures and flows governing single nephron glomerular filtration rate (SNGFR) were measured in Munich-Wistar rats possessing surface glomeruli accessible to micropuncture. Although the mean glomerular transcapillary hydraulic pressure difference in these euvolemic rats was similar to that observed in hydropenic animals, initial glomerular plasma flow rate and SNGFR were at least 50% higher than in hydropenic rats. Nevertheless, filtration pressure equilibrium was generally achieved in euvolemic rats, as in hydropenic rats. Afferent and efferent arteriolar resistances were found to be lower in euvolemic than hydropenic rats, suggesting more potent vasoconstrictor forces in the latter group.

Control of Proximal Bicarbonate Reabsorption in Normal and Acidotic Rats

This free-flow micropuncture study examined the dependence of bicarbonate reabsorption in the rat superficial proximal convoluted tubule to changes in filtered bicarbonate load, and thereby the contribution of the proximal tubule to the whole kidneys response to such changes. The independent effects of extracellular fluid (ECF) volume expansion and of acidosis on proximal bicarbonate reabsorption were also examined. When the plasma volume contraction incurred by the micropuncture preparatory surgery was corrected by isoncotic plasma infusion ( congruent with1.3% body wt), single nephron glomerular filtration rate (SNGFR), and the filtered total CO(2) load increased by 50%. Absolute proximal reabsorption of total CO(2) (measured by microcalorimetry) increased by 30%, from 808+/-47 during volume contraction to 1,081+/-57 pmol/min.g kidney wt after plasma repletion, as fractional total CO(2) reabsorption decreased from 0.90 to 0.77. Aortic constriction in these plasma-repleted rats returned the filtered load and reabsorption of total CO(2) to the previous volume contracted levels. In other animals isohydric ECF expansion with plasma (5% body wt) or Ringers solution (10% body wt), or both, produced no further diminution in fractional proximal total CO(2) reabsorption (0.76-0.81). Metabolic acidosis was associated with very high fractional proximal total CO(2) reabsorptive rates of 0.82 to 0.91 over a wide range of SNGFR and ECF volumes. At a single level of SNGFR, end-proximal total CO(2) concentration progressively decreased from 5.6+/-0.5 to 1.6 +/-0.2 mM as arterial pH fell from 7.4 to 7.1. Expansion of ECF volume in the acidotic rats did not inhibit the ability of the proximal tubule to lower end-proximal total CO(2) concentrations to minimal levels. In conclusion, bicarbonate reabsorption in the superficial proximal convoluted tubule is highly load-dependent (75-90%) in normal and acidotic rats. No inhibitory effect of ECF volume per se on proximal bicarbonate reabsorption, independent of altering the filtered bicarbonate load, could be discerned. Acidosis enabled the end-proximal luminal bicarbonate concentration to fall below normal values and reduced distal bicarbonate delivery.

Cine-CT measurement of cortical renal blood flow

A modified indicator-dilution technique using radiographic contrast material and a cine-CT scanner was used to measure blood flow in the renal cortex of dogs. To validate this technique. CT measurements were correlated with simultaneous measurements of flow determined by radioactive micro-spheres. Measurements were taken during euvolemic conditions and after hemorrhage. Thirty-nine measurements were compared, covering a flow range from 1 to 7 ml min−1 g−1, and a good correlation was found between the cine-CT and microsphere results (r = 0.93; p < 0.001). Additionally, cine-CT measurements were made of the mean transit time (MTT) of contrast material through the renal cortex, and the reciprocal of these MTT values was also well correlated to microsphere determined flow (r = 0.94; p < 0.001). Thus, cine-CT appears to be a promising new technique for measuring renal blood flow.

Chronic hypercapnia stimulates proximal bicarbonate reabsorption in the rat.

The hyperbicarbonatemia of chronic respiratory acidosis might be maintained by a reduction in filtration rate or an enhancement of tubular bicarbonate reabsorption. To investigate this question, 12 Munich-Wistar rats were exposed to a 10% CO2 atmosphere for 6-8 d. Chronic respiratory acidosis developed, with arterial pH 7.30 +/- 0.01, partial pressure of CO2 (pCO2) 80 +/- 2 mmHg, and total CO2 concentration 45 +/- 1 mM. Single nephron glomerular filtration rate was normal (42 +/- 1 nl/min). Chronic hypercapnia caused absolute proximal reabsorption to be significantly stimulated (1,449 +/- 26 pmol/min) as compared with reabsorption previously observed in normal animals (1,075 +/- 74 pmol/min) or in animals subjected to acute hypercapnia (1,200 +/- 59 pmol/min). This is the first demonstration that proximal bicarbonate reabsorption can be stimulated above normal euvolemic values. When eight animals were subsequently allowed to return toward a normocapnic state (arterial pCO2 46 +/- 1 mmHg) over the course of 1-1.5 h, bicarbonate reabsorption was still significantly higher (1,211 +/- 34 pmol/min) than in similarly alkalotic, normocapnic control groups (994 +/- 45 pmol/min). In conclusion, chronic, but not acute, hypercapnia stimulates absolute proximal bicarbonate reabsorption to exceed the level found in normal euvolemic rats.

HIGH-GRADE NON-HODGKIN'S LYMPHOMA IN PATIENTS WITH AIDSa

An apparent excess of high grade non-Hodgkins lymphoma has been reported among those at risk for acquired immunodeficiency syndrome (AIDS), especially homosexual men. Common to these cases are pre-existing lymphadenopathy, concomitant opportunistic infections or Kaposis sarcoma, and an extremely poor prognosis. The Cancer Registry for the San Francisco Bay Area was reviewed to obtain data on the incidence of undifferentiated non-Hodgkins lymphoma among single men ages 20-50 years in 2 periods: 1975-78 and 1979-82. The Registry recoreded no such cases in the earlier period and 9 cases (6 Burkitts and 3 non-Burkitts) in 1979-82. In addition, descriptive data were obtained from area oncologists on non-Hodgkins lymphomas that developed in 18 single men 20-60 years of age in 1979-83. 17 of these men were homosexual, and the median age was 36 years. Prodromal manifestations associated with AIDS were present in various combinations in all homosexual patients. All 10 patients treated with chemotherapy had complete responses, but relapse occurred quickly in all but 2 patients (including the 1 heterosexual). Only 3 men in this series remain alive, but have other diagnostic criteria for AIDS. The 1-year survival rate for the Bay Area cases was 13%, compared with 48% in heterosexual controls with undifferentiated lymphomas treated at the National Cancer Institute. 3 major differences were noted between the California cases and NCI controls: 1) all homosexual men had prodromal manifestations of either generalized lymphadenopathy or Kaposis sarcoma or opportunistic infections compared to none of the controls: 2) Most Bay Area men had stage D (widespread or central nervous system) lymphoma on presentation; 3) the response to chemotherapy was poorer among cases than controls. Because of these differences, it is argued that malignant lymphomas that occur in members of AIDS risk groups should be a diagnostic criterion for AIDS.

Evidence for coupled sodium/hydrogen exchange in the rat superficial proximal convoluted tubule

Recent in vitro studies from the rat and rabbit have suggested a tightly coupled sodium/hydrogen ion exchanger on the luminal membrane of proximal tubules. The steep sodium gradient from the lumen to cell supplies indirect energy for hydrogen ions to be pumped from the cell to the lumen. However, a proton translocating pump has been demonstrated in other epithelia, which is independent of sodium transport and directly driven by ATP. To examine the role that sodium might play in the process of acidification, rat proximal convoluted tubules and their surrounding peritubular capillaries were perfused in vivo with artificial ultrafiltrate-like perfusion solutions. Total CO2 absorption was measured by microcalorimetry during alterations in sodium transport by replacement of the sodium with an impermeant cation, choline, or by inhibition of the (Na++K+)-ATPase by removing potassium from both perfusion solutions. Under control conditions the absolute rate of total CO2 absorption was 140 pmol/mm·min. In the choline substitution and potassium removal experiments, absolute total CO2 absorption fell to 23 and 28 pmol/mm·min, respectively. The data suggest that: 1) in the rat superficial proximal convoluted tubule approximately 80% of the bicarbonate absorption is tightly coupled to sodium transport; 2) this process is driven indirectly by the (Na++K+)-ATPase system; and 3) the residual 20% of acidification appears to be mediated by another mechanism or may be a consequence of technical liminations.