Bilateral Ureteral Ligation Research Articles

Effect of biological activity of PTH on its peripheral metabolism in the rat

Previous studies from our laboratory have characterized the peripheral metabolism of parathyroid hormone (PTH) in the dog using radioimmunoassay techniques following injection or infusion of biologically active, bovine PTH preparations. Other investigators have used biologically-inactive labelled PTH and interpreted their results as representative of the normal physiological processes. Since oxidized inactive PTH does not bind to PTH receptors and since we have found substantial differences between the tissue uptake of active and inactive PTH preparations, it is possible that results obtained with inactive PTH preparations may not totally represent the normal metabolism of PTH. Therefore, we performed studies in rats to compare the disappearance of immunoreactive PTH (i-PTH) from plasma following injection of active or inactive syn b-PTH 1-34. The maneuvers of bilateral ureteral ligation and bilateral nephrectomy were utilized to characterize the sites of tissue uptake of i-PTH. The results obtained indicate that inactive syn b-PTH 1-34 has a significantly slower disappearance from plasma than biologically active syn b-PTH 1-34. Reduction of glomerular filtration by acute bilateral ureteral ligation decreased the disappearance of oxidized PTH more than active PTH. Thus, the results indicate a major dependence on glomerular filtration for the removal of inactive syn b-PTH 1-34. The demonstration that the peripheral metabolism of active and inactive syn b-PTH 1-34 is not identical suggests that studies of the metabolism of inactive PTH preparations do not accurately reflect that of biologically active PTH.

Plasma and tissue radioactivity of 3H-digitoxin in dogs with experimental acute renal failure.

Twenty-two dogs were divided into 3 groups; a control (C) group of sham-operated dogs, a bilateral ureter ligation (L) group, and a bilateral nephrectomy (N) group. 3H-digitoxin was given to these dogs in a single intravenous administration, and the kidney involvement in the metabolism and excretion of digitoxin was investigated on the basis of radioactive indications in plasma and the tissue of the heart, liver and kidney. During the 24hr observation, the radioactivity from the plasma dichloromethane (CH2Cl2)-soluble fraction was significantly higher in both the L and N groups than in the C group. The plasma elimination half-life of the CH2Cl2-soluble fraction in the C group was about 9.3hr. The L and N groups had a significantly longer (about 2 times) plasma elimination half-life than the C gloup. The radioactivity in canine heart and liver were almost the same in each group 24hr after dosing. They were lowest in the C group, intermediate in the L group and highest in the N group. In the C and L groups, the radioactivity was higher in the kidney than in the heart or liver. The radioactivity in the kidney was higher in the C group than in the L group. There was a significant positive correlation between the tissue radioactivity and the plasma CH2Cl2-soluble fraction radioactivity. This indicates that the kidney may affect digitoxin metabolism and excretion in the dog. Also, patients should be evaluated regarding not only liver function but also renal function.

Effect of furosemide on fully established low pressure pulmonary edema

It has been shown that furosemide, via nondiuretic vascular effects, reduces pulmonary shunt and lung water during the development of oleic acid permeability edema. We studied this effect in a fully established stable model of oleic acid permeability edema. Sixteen anesthetized mongrel dogs, mechanically ventilated with a F IO 2 of 0.5, were studied 24 hr after induction of pulmonary capillary leak by intraveneous oleic acid (0.06 cc/kg). After stabilization of pulmonary capillary wedge pressure (PCWP) in the range of 0.5–3 mm Hg., bilateral ureteral ligation was performed. Furosemide (2 mg/kg) was then administered intravenously to eight dogs (treated group). An equivalent volume of saline was given to eight control dogs (control group). Pulmonary artery (PAP) and capillary wedge pressures (PCWP), thermodilution cardiac output ( Q t), thermal dye lung water (LW), venous admixture ( Q va/ Q t), arterial and mixed venous blood gases ( P a O 2, MVO 2) were then measured at hourly intervals for 4 hr. During this period of time, central hemodynamics (PCWP, PAP, Q t) remained stable in both groups. Indices of gas exchange and edema formation ( Q va/ Q t, LW, P a O 2) did not change significantly in either control or treated animals. We conclude that furosemide, previously shown to reduce pulmonary shunt and lung water in the early phase of oleic acid permeability edema, does not have any effect once the pulmonary injury is well-established.

Changes in blood urea nitrogen (BUN) concentration during pregnancy in the rat with or without obstructive uremia

Bilateral ureteral ligation changes the blood urea nitrogen (BUN) concentration in pregnant and non-pregnant rats. Marked increases of the BUN concentration occurred in both pregnant and non-pregnant specimens after ligation. The BUN concentration in sham-ligated rats did not change from day 16 through 19 of pregnancy, but increased on day 20 of pregnancy and thereafter. There was no significant difference in BUN between ligated pregnant rats on days 16 and 17 of pregnancy and ligated non-pregnant rats. As pregnancy progressed from day 18 onward, the BUN in ligated pregnant rats decreased when compared with that of ligated non-pregnant rats, but did not reach the level in sham-ligated pregnant rats. The BUN of mothers and fetuses both in the ligated and the sham-ligated groups were similar. Amniotic fluid urea nitrogen levels were higher than in blood on late fetal days. In ligated mothers, a significant relationship between maternal BUN and the number of fetuses was noted on day 22 of pregnancy. These results suggest that the fetal kidney becomes functional for excreting urea in late fetal life.

The effect of captopril on sodium appetite in adrenalectomized and deoxycorticosterone-treated rats.

Captopril caused a renin-dependent increase in water intake in rats with bilateral ureteric ligation. But despite the fluid retention and fall in osmolality caused by the increased water intake, rats with ureteric ligation did not drink the 2.7% NaCl also offered to them. In rats with a pre-existing increase in sodium appetite caused by adrenalectomy, low dosage of captopril augmented intake of both water and 2.7% NaCl whereas high dosage inhibited intake of both fluids after an initial increase in water intake. In contrast, rats with a pre-existing increase in sodium appetite caused by daily injections of deoxycorticosterone showed no changes in intake of water or 2.7% NaCl after either low or high dosage of captopril, though they drank both fluids after intracranial injection of angiotensin II. Increases in water and 2.7% NaCl intake caused by low dosage of captopril in adrenalectomized rats were not secondary to increased urinary fluid and electrolyte losses. Decreases in intake after high dosage were not explained by the rats being too weak to drink. Low and high dosage of captopril caused increases in plasma renin concentration in adrenalectomized rats, but in contrast renin remained undetectable in the plasma of deoxycorticosterone-treated rats after the highest dosage of captopril. Whether or not captopril affected a pre-existing sodium appetite depended on whether or not it increased plasma renin. Since it affected the pre-existing sodium appetite and plasma renin in the adrenalectomized rat but neither of these in the deoxycorticosterone-treated rat, it is likely that the appetite was renin-dependent in the former but not in the latter. Because captopril only affected thirst in the rat with ligated ureters whereas it affected both sodium appetite and thirst in the adrenalectomized rat, increases in renal renin secretion alone may not be enough to stimulate sodium appetite. The additional stimulus provided by adrenalectomy, or the absence of some inhibitory factor that may be present after ureteric ligation, is also needed.

Effect of imidazole and indomethacin on hemodynamics of the obstructed canine kidney

In the anesthetized dog renal blood flow (RBF) and its intrarenal distribution were investigated by the radioactive microsphere technique 24 hr after bilateral (BUL) and unilateral (UUL) ureteral ligation. In the control series indomethacin (IM) led to a decrease in RBF with outward shifting of zonal perfusions; imidazole (IA) did not cause significant changes in renal hemodynamics. In the BUL series there was a sharp drop in RBF with a proportional decrease in outer (OC) and inner (IC) cortical perfusion; IM treatment resulted in a further decrease in overall and zonal perfusions. IA, a selective inhibitor of thromboxane synthetase, relieved IC vasoconstriction. In the ligated kidney of the UUL preparations decrease in RBF was due to OC vasoconstriction, while IC perfusion equalled controls. IM led to an overall vasoconstriction in all cortical layers; IA did not influence either total RBF or its distribution. It was concluded that BUL "unmasked" TXA2 production in the IC layers, while IM treatment, by inhibiting the production of PGE2, PGI2, and TXA2, resulted in an overall vasoconstriction both in controls and the BUL and UUL preparations.

Acute blood pressure and urinary responses to single dose combinations of captopril and diuretics in conscious spontaneously hypertensive rats.

The present studies involved oral administration of captopril alone or in combination with individual diuretics in conscious, freely-moving spontaneously hypertensive rats (SHR). Both blood pressure (BP) and urinary fluid and electrolyte excretion were concomitantly measured. Captopril, 10 mg kg-1, caused a decrease in BP (-18 +/- 3 mm Hg) which was not significantly different from control (-10 +/- 2 mm Hg). Diuretics alone also failed to alter BP. However the BP-lowering effect of captopril was readily potentiated by concomitant administration of a single oral dose of frusemide (10 and 30 mg kg-1) in proportion to the magnitude of urinary loss. Hydrochlorothiazide at 1 and 3 mg kg-1 oral and metolazone at 0.3 and 1 mg kg-1 oral induced fluid loss similar to frusemide at 10 mg kg-1 and all produced comparable BP reduction in combination with captopril (25-32 mm Hg). Triamterene did not increase fluid excretion and was ineffective. In SHR with bilateral ureteral ligation, the synergistic effect of frusemide was abolished while that of hydrochlorothiazide still occurred with a delayed onset. It is concluded that concomitant measurement of BP and urinary excretion in conscious, freely-moving SHR is a useful technique for studying new antihypertensive drugs. Using this preparation it was found that enhancement of the acute hypotensive response to captopril with concomitant diuretic therapy occurs within 10 min and is primarily related to the fluid and Na loss, regardless of the diuretic agent used.

Studies on the mechanism for renal elimination of N-acetylphenylalanine: its pathophysiologic significance in phenylketonuria.

To elucidate the mechanism and biologic significance of urinary occurrence of N-acetylphenylalanine in phenylketonuria, the metabolic fate of N-acetylphenylalanine was studied in rats. In vivo and in vitro analysis revealed that N-acetyl-14C(ul)-phenylalanine bound to plasma albumin with an association constant of 8.52 X 10(3) M-1 and that the number of binding sites was 0.98 per mole albumin. Intravenously administered N-acetylphenylalanine was rapidly extracted from the circulation predominantly by the kidney and excreted into urine. Plasma clearance of the injected ligand was markedly decreased by bilateral nephrectomy but not by bilateral ureter ligation. Probenecid, a potent inhibitor of the renal excretory system for organic anions, such as hippuric acid, sharply decreased the rate of disappearance from the circulation, renal accumulation, and urinary secretion of intravenously administered N-acetylphenylalanine. These results indicate that intravenously administered N-acetylphenylalanine undergoes renal peritubular transport via a probenecid-sensitive excretory system for organic anions. This renal transtubular excretory mechanism may possibly operate in elimination of N-acetylphenylalanine, a hazardous amphipathic metabolite of phenylalanine, from plasma into urine in phenylketonuric patients.

Mechanism of intestinal adaptation in rats with acute renal failure

Acute renal failure (ARF) was experimentally induced in rats and the specific activity of mucosal Na-K-ATPase activity in segments of the small intestine and colon was measured. Bilateral nephrectomy (BN) resulted in a significant evaluation of the enzyme activity in all segments examined. With an additional procedure of adrenalectomy (BN + Ax), the enzyme activity failed to show any increase in ARF rats produced by BN. However, a supplementation of a maintenance dose of dexamethasone to adrenalectomized ARF rats (BN + Ax + DM 10) resulted in a significant resumption of the activity in all intestinal segments, although its increase was insignificant in the duodenum. Addition of a high dose of DOCA (BN + Ax + DOCA 500) was effective in increasing the enzyme activity only in the colon but not in the small intestine. With a high dose of DM or a maintenance dose of DM plus a high dose of DOCA (BN + Ax + DM 30 or BN + Ax + DM 10 + DOCA 500), there was an increase in the enzyme activity of all intestinal segments. In ARF rats induced by bilateral lower ureteral ligation (BLUL), the enzyme activity did not show any increase at all. Addition of a high dose of DOCA to this animal model (BLUL + DOCA 500) brought about the increase of the enzyme activity in the intestinal segments but for the jejunum.(ABSTRACT TRUNCATED AT 250 WORDS)

Prolactin plasma levels and its size heterogeneity in acutely uremic rats.

The size distribution pattern of circulating rPRL was studied in intact control (C) rats and in three uremic models, namely urine autoinfusion (UA), bilateral ureteral ligation (BUL), and bilateral nephrectomy (BNx). Plasmas were chromatographed by gel filtration in Sephadex G-100. Rat PRL was measured by RIA. The rPRL levels as well as the size distribution pattern of UA were similar to that of C. BUL and BNx showed a similar degree of hyperprolactinemia which corresponded to an increase in little rPRL. The results suggest that acute uremic hyperprolactinemia seems to be the result of accumulation of little rPRL. Acute uremia by itself does not increase rPRL plasma levels nor does it seem to affect the size distribution pattern of circulating rPRL.

Central and peripheral nervous system effects of chronic renal failure

Although neurologic dysfunction is a major cause of disability in patients with chronic renal failure, there is little knowledge of the underlying metabolic defect(s). We used a canine model to study the effects of chronic renal failure (CRF: 4 months after 1-7/8 nephrectomy, GFR 11 +/- 2 ml/min) on the composition and function of the nervous system. We also studied the effect of acute renal failure (ARF: 3.5 days after bilateral ureteral ligation) on peripheral nerve composition and function. In dogs with CRF for 4 months intracellular pH of brain and cerebro-spinal fluid (CSF) pH remained normal, despite metabolic acidemia. Osmotic equilibrium of the brain with plasma and CSF (and thus a normal water content) was maintained by almost equivalent increases in brain of urea and idiogenic osmoles (25 mmoles/kg H2O and 23 to 26 mOsm/kg H2O, respectively). Electrolyte concentration in brain tissue water did not change significantly. Calcium content was increased in cortical gray matter and hypothalamus of dogs with CRF, but was normal in the six other regions measured. Functional changes measured by the electroencephalogram were just as severe as those previously seen in dogs with ARF. The motor nerve conduction velocity (MNCV) was normal in dogs with ARF and did not change after up to 6 months of CRF.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of acute changes in the PaCO2 on acid–base parameters in normal dogs and dogs with metabolic acidosis or alkalosis

There is a linear relationship between the PaCO2 and blood hydrogen ion concentration in normal dogs, but for theoretical reasons to be discussed, we questioned whether this relationship would apply in animals with metabolic acidosis or alkalosis. To study this in more detail, animals were divided into three groups: normal, metabolically acidotic, and metabolically alkalotic. Following anesthesia and bilateral ureteral ligation, dogs were intubated and ventilated to produce acute steady state PaCO2 values corresponding to the range observed during disease states. Changes in the volume and electrolyte composition of the gastrointestinal fluid and urine as well as the concentration and distribution of lactate were evaluated in all experiments. We observed the previously described linear relationship between the PaCO2 and blood hydrogen ion concentration in normal dogs, but the slope of the regression line differed significantly from those of dogs with metabolic acidosis and metabolic alkalosis. On the other hand, there was a consistent relationship between the ratio of the PaCO2 values, but not the absolute PaCO2, and the change in the plasma bicarbonate concentration over a wide range of PaCO2 values in all groups of dogs. The chemical basis for these observations will be discussed.

Diazepam-induced NaCl solution intake: Independence from renal factors

Rehydrating rats injected with diazepam (8 mg/kg, SC) increased their intake of 2.0% NaCl solution. Neither bilateral nephrectomy nor bilateral ureter ligation interfered with the increased NaCl solution ingestion produced by diazepam. It is concluded that the increased intake of the NaCl solution is not secondary to renal water-electrolyte losses nor dependent upon intact renal benzodiazepine receptors.

Kidney Pressures after the Release of 24 Hours of Bilateral Ureteral Ligation in the Rat

Kidney function was studied in rats after the release of 24 hours of bilateral ureteral ligation (BUL). After deligation, natriuresis was observed for 1 day while diuresis persisted up to 4 days. The possible defective collecting tubule to reabsorb sodium may improve within 1 day, since the urinary sodium concentration was well below the sham value. During the early phase of deligation, the glomerular filtration rate (GFR) averaged only 15 per cent of the sham value. Heterogeneity of the surface nephrons was apparent. About 17 per cent of the observed surface nephrons had no tubular fluid flow, suggesting possibly that these nephrons may not contribute to the kidney GFR. In the other 83 per cent of the nephrons, the stop-flow pressure, 29.0mm. Hg, was lower than the sham value, 33.6mm. Hg, whereas the proximal tubular pressure of 15.1mm. Hg was significantly above the sham value of 13.2mm. Hg. Both these factors may have induced a reduction in the effective filtration pressure, from 20.1 to 13.9mm. Hg, and may have contributed to the reduction in GFR in those functioning nephrons. Four days later, a similar proportion of the surface nephrons still showed a marked reduction in function, whereas others had improved significantly. The proximal tubular pressure, the stop-flow and the effective filtration pressures approached the sham values. These improvements may be associated with an increase in GFR to 42 per cent of the sham value. It is suggested that the prolong suppression of the kidney GFR may not be due to the drastic change in the glomerular capillary pressure of the surface nephrons, at this latter period.

Renal function and Na-K-ATPase in rats after suprarenal ligation of inferior vena cava.

To assess the effects of altered renal function on Na-K-ATPase, the following groups of rats were studied: 1. rats with suprarenal vena cava ligation (SVCL), la. DOCA-treated rats with SVCL, 2. rats with infrarenal vena cava ligation (IVCL), 3. rats with glycerol-induced acute renal failure, 4. rats with bilateral ureteric ligation, and 5. K-exalate-treated rats with SVCL. In group 1, acute renal failure with hyperkalemia developed and medullary Na-K-ATPase increased from 95 +/- 5 in control to 155 +/- 7 mumol Pi/mg prot/h, P less than 0.001, DOCA did not prevent the increase of Na-K-ATPase. In group 2, medullary Na-K-ATPase decreased from 130 +/- 10 in control to 88 +/- 7, P less than 0.01, in rats with IVCL. In group 3, cortical Na-K-ATPase decreased from 55 +/- 5 to 27 +/- 6, P less than 0.02. In group 4, Na-K-ATPase was unchanged. In group 5, maintenance of normokalemia prevented the rise in Na-K-ATPase. These experiments demonstrated a K-dependent activation of medullary Na-K-ATPase after SVCL but not in other forms of renal failure. Because SVCL diminishes drastically GFR per nephron, the present findings imply that increased loads of Na and K per nephron are not a prerequisite for an increase in medullary Na-K-ATPase. Hyperkalemia in presence of increased renal venous pressure seems to be causally related to the rise in medullary Na-K-ATPase activity.

The effect of acute renal failure on the pharmacokinetics of indocyanine green in the rat

The pharmacokinetics of indocyanine green (ICG) have been studied in control rats and rats with acute renal failure (ARF). Three models of ARF were investigated, and these were produced in the following ways: by bilateral ureteral ligation (surgical model), or by parenteral injection of either uranyl nitrate or glycerol. In both control and uraemic rats, from all three models of ARF, the plasma disappearance of ICG was biexponential and from the plasma disappearance curves the rate constants for transfer from plasma to liver ( k 12), liver to plasma ( k 21); and liver to bile ( k 23) were calculated. The initial removal of ICG from plasma was significantly slowed and k 12 significantly decreased in male rats with surgically or uranyl nitrate-induced ARF. The plasma clearance of ICG was not affected by surgically-induced ARF but clearance was reduced in the uranyl nitrate model. More complex changes occurred in male rats with glycerol-induced ARF as k 12, k 21, k 23 and plasma clearance of ICG were all significantly decreased. Female rats with glycerol-induced ARF showed significant decreases in k 12, and plasma clearance, but these changes were much smaller than in uraemic males. Of the three models of ARF studied the glycerol model was preferred because surgery alone had a pronounced effect upon the kinetics of ICG and wet liver weight was significantly decreased in the uranyl nitrate model. These changes complicated interpretation of the results from the surgical and uranyl nitrate models. The results from the glycerol model suggest that the hepatic uptake of ICG, and possibly its biliary excretion, were reduced in rats with ARF. In addition, liver function in female rats appears to be more resistant than that in males to the effects of glycerol-induced ARF.

Excess in vitro secretion of the free alpha-subunit of the glycoprotein hormones by pituitary cells from chronically uremic rats.

In an attempt to develop an animal model of uremic hypogonadism, various parameters of in vivo and in vitro pituitary-Leydig cell function were examined in control, chronically uremic (4 weeks after 5/6th nephrectomy), and acutely uremic (2 days after bilateral ureteral ligation) adult male Sprague-Dawley rats. Levels of serum urea nitrogen (SUN) were 12.6 ± 0.4, 46.3 ± 2.9, and 233.4± 9.9 mg/dl (mean ± SEM) in control, chronically uremic, and acutely uremic rats, respectively, while the corresponding serum testosterone (T) values were 446.6± 85.2, 177.3 ± 52.0, and 45.8 ± 4.0 ng/dl. There was a significant inverse correlation between levels of SUN and those of T (r = -0.508; P < 0.05). Despite the decreased levels of serum T in uremic rats, there were significant reductions in serum levels of LH (P < 0.01) and FSH (P < 0.05) in both chronically uremic and acutely uremic rats. However, there were significant elevatios (P < 0.01) of PRL and a positive correlation between PRL and SUN values (r= 0.366; P < 0.05) in the sera of uremic rats. The release of LH, FSH, and the free α-subunit of the glycoprotein hormones was measured in primary cultures of dispersed anterior pituitary cells from the three groups of rats. During 48 h of incubation, the basal secretion rates (nanograms per 106 cells/h) of the glycoproteins from cells of control, chronically uremic, and acutely uremic rats were, respectively, 0.03, 0.12, and 0.03 for LH, 0.13, 0.43, and 0.13 for FSH, and 0.53, 4.82, and 0.39 for a. After LHRH (10-8 M) stimulation, the absolute increment in the secretion of each of the glycoproteins was greater from cells of chronically uremic rats than from cells of control or acutely uremic rats. Under baseline conditions, the molar ratio of α to LH plus FSH secreted by cells from chronically uremic rats was 2.7-fold greater than that by cells from control rats and 3.9-fold greater than that by cells from acutely uremic rats. Excess glycoprotein secretion by cells from chronically uremic rats was also evident after stimulaion with variable doses of LHRH (10-1010-7 M); molar ratios of a to LH plus FSH released by cells from chronically uremic rats varied from 5.4-8.6, while the corresponding ratios released by cells from control rats ranged from 1.2-2.2. In contrast to the in vitro findings, the molar ratios of a to LH plus FSH were similar in pituitary extracts from control (0.21), chronically uremic (0.23), and acutely uremic (0.25) rats. The immunochemical properties of α-subunit in media and pituitary extracts from control and uremic rats were similar to those of purified rat pituitary α However, by Sephadex G-100 chromatography, media a from cells of chronically uremic rats eluted as species of slightly larger apparent molecular size than purified rat pituitary α, but of a size similar to that of other eutopic and ectopic secreted forms of α These data suggest that hyperprolactinemia and hypogonadotropic hypogonadism are concomitants of both moderate and severe renal dysfunction in the male rat. Moreover, the finding of a disproportionate excess in the in vitro secretion of free a-subunits, ompared with LH and FSH, by pituitary cells from chronically uremic rats together with previously reported data indicating discordant elevation of serum a levels in uremic humans suggest that uremia is associated with major derangements in normally coordinated α- and β-subunit synthesis and/or secretion.

Studies on the Mechanism of the Synergistic Antihypertensive Activity of Captopril and Hydrochlorothiazide Following Acute Administration in Spontaneously Hypertensive Rats

In spontaneously hypertensive rats (SHR), captopril at 30 and hydrochlorothiazide (HCTZ) at 100 mg/kg/day p.o. for 2 days lowered mean arterial blood pressure (MABP) 16 and 10 mm Hg, respectively. Treatment with the combination of captopril plus HCTZ for one day lowered MABP to the same extent as captopril alone, but produced a synergistic 44 mm Hg MABP lowering after the second day combination treatment. Bilateral ureteral ligation did not prevent the synergistic antihypertensive effect demonstrating that removal of electrolytes was not the cause of this effect. Cardiovascular responses to angiotensin-I and -II, norepinephrine or bradykinin did not differ in rats given the combination or captopril alone. After the combination treatment for one day, captopril but not HCTZ alone on the second day lowered MABP in rats to the same degree as in those receiving the combination treatment for 2 days, suggesting that the diuretic action per se is unimportant. Captopril and HCTZ increased plasma renin activity (PRA) but only the combination of captopril and HCTZ produced a greater and longer lasting increase of PRA. It is concluded that the mechanism for the synergism is the renin dependency, created by the combination of HCTZ and captopril, resulting in a greater role of the renin system in blood pressure control and increased responsiveness to angiotensin converting enzyme inhibition by captopril.

Ammonia partitioning between glutamine and urea: Interorgan participation in metabolic acidosis

The distribution of precursor nitrogen between urea and glutamine was studied in control and acidotic rats. Acidosis, either acutely induced with hydrochloric acid or chronically induced with ammonium chloride, resulted in a rise in ammonia and a fall in urinary urea excretion; the percent of urinary nitrogen excreted as ammonia rose from 3.5 +/- 0.4 and 4.9 +/- 0.5 in fed and pair-fed controls to 25.9 +/- 3.9 and 37 +/- 5 in acidosis induced by hydrochloric acid and ammonium chloride. Hepatoportal vein urea concentration differences were significantly reduced, whereas glutamine concentration differences were significantly elevated, consistent with a shift of nitrogen from ureagenesis to glutamine; alanine and ammonia concentration differences were significantly decreased and increased respectively in the acidotic animals, suggesting that former supported urea synthesis whereas ammonia may preferentially support glutamine synthesis. Evidence of a feed-forward involvement of the gut in influencing hepatic nitrogen distribution was suggested by an increased ammonia and decreased alanine release in acidotic rats. Bilateral ureteral ligation was performed on control and acidotic rats to determine the fate of the redirected urinary ammonia. Ammonia did not accumulate in the blood, rather it was initially incorporated into glutamine, elevating the plasma level, and then it was subsequently deposited into urea. The shift of nitrogen back into urea in acidotic animals was confirmed by the greater postligation urea production rates supported by hepatic uptake of both alanine and glutamine. These results are discussed in terms of interorgan participation involving the liver, gut, and muscle in the partitioning of nitrogen between glutamine and urea.

Rapid computer prediction of total body water in fluid overload.

Using computer analysis of the early plasma arterial disappearance curve of tritiated water (HTO), we sought the fewest points and earliest times needed to predict the final volume of dilution, total body water (TBW). In ten anesthetized adult female dogs weighing 19.1 +/- 0.5 kg, with bilateral ureteral ligation, 500 muC HTO were given IV. Arterial blood samples were taken until equilibrium (3 hours), when the approximate equivalent of extracellular fluid (ECF), 4,000 ml of lactated Ringer's solution, was given IV within 1 hour. The next day, in the second phase of the study, 1,000 muC of HTO were given IV and arterial blood samples were taken at intervals up to equilibrium (5 hours). TBW at 3 hours after the first HTO infusion was 63.3 +/- 1.2% body weight. Using a curve-fitting Fortran program (CFIT), the arterial plasma HTO concentrations were fitted to one or two exponentials. Although initial TBW could be predicted from arterial plasma concentrations of HTO during 20 minutes after injection in normally hydrated dogs, values during 60 minutes were required for accurate prediction of TBW after infusion of 4 L of fluid. TBW in normal and fluid-loaded animals was predicted within 2.3 +/- 0.6% of the final HTO equilibrium (r = 0.987).