Effect of dietary protein and enalapril on proximal tubular delivery and absorption of albumin in nephrotic rats.

In passive Heymann nephritis (PHN), angiotensin-converting enzyme inhibition (ACEI) or a low dietary protein intake decreases albuminuria (UAlbV). Although this reduction in albuminuria appears to result from an improvement in glomerular permselectivity, the effect of these treatments on albumin permeation and absorption by the nephron has not been clarified. This study used micropuncture techniques to examine the effect of these two treatments on albumin permeation (by measuring the delivery of albumin to the proximal tubule) and the tubular absorption of albumin. PHN rats (12-18 days after injection of FX1A) were switched from 23% to either 40% protein diet (HP), 40% protein diet and concomitantly treated with enalapril (40 mg.kg-1.day-1) (HPE), or to 8% (LP) protein diet for 4-6 days. Although left kidney glomerular filtration rate (GFR) did not differ among the groups, UAlbV from the left kidney in LP and HPE was only 20-40% of that observed for the HP group. In protocol 1, the fractional recovery of albumin (FRAlb) in urine was calculated following injection of artificial tubular fluid containing [14C]inulin and 125I-labeled albumin into the earliest identifiable proximal loops. There were no differences in FRAlb among the three groups. In protocol 2, timed quantitative collections of tubular fluid were obtained from proximal tubular loops. The rate of albumin delivery to the earliest accessible loops of the proximal tubule was significantly lower for the LP and HPE groups compared with the HP group. For each group, albumin concentration corrected for water absorption was not altered along the proximal tubule. The data indicate that alterations of dietary protein intake or ACEI treatment results in large changes in the delivery of albumin at the proximal tubule that could singularly account for the changes in urinary albumin excretion.

The antiproteinuric action of angiotensin-converting enzyme is dependent on kinin.

Converting enzyme inhibitors (CEI) reduce proteinuria in nephrotic humans and animals, but the mediator(s) of this effect has not been identified definitively. To determine whether enhanced kinin activity contributes to the antiproteinuric action of CEI, rats with passive Heymann nephritis were treated with the B2 kinin receptor antagonist HOE 140, 300 micrograms/kg per day, for 3 days and then the CEI enalapril (ENAL), 35 mg/kg per day, was given for another 4 days while HOE 140 was continued (HOE/ENAL). Additional groups of nephrotic rats were untreated (CON), received HOE 140 only (HOE), or received ENAL only. ENAL alone produced a > 60% decrease in albuminuria after 4 days, whereas HOE 140 alone had no effect on albuminuria. In HOE/ENAL, pretreatment with HOE 140 prevented the decrease in albuminuria observed in ENAL. GFR increased significantly over time in all groups but was not different among the groups on any day. The clearance of albumin decreased significantly in ENAL (P < 0.001) and was significantly lower than in CON, HOE, or HOE/ENAL on Day 10. The fractional clearance of albumin decreased in all groups as a result of the increase in GFR but was significantly lower in ENAL compared with the other three groups at Day 10 and was not different between CON, HOE, and HOE/ENAL. Plasma renin activity and concentration were increased significantly in both ENAL and HOE/ENAL, indicating that converting enzyme was effectively inhibited in both groups. It was concluded that enhanced kinin activity contributes to the antiproteinuric action of CEI in this model of nephrotic syndrome.

Altered renal kallikrein and renin gene expression in nephrotic rats and modulation by converting enzyme inhibition.

Urinary kallikrein excretion (UKE) is decreased in rats with passive Heymann nephritis (PHN), but increases after converting enzyme inhibition (CEI). Although CEI potentiates bradykinin activity, neither the effect of CEI on kallikrein secretion nor the abnormal renal kallikrein metabolism in PHN has been examined previously. To determine the mechanism by which CEI increases UKE, normal rats and PHN received enalapril, 40 mg/kg per d orally for 4 d. UKE was 85% lower in PHN than in normals and increased in both groups after CEI, although UKE in PHN remained significantly less than in normals. Kallikrein mRNA was significantly lower in PHN compared to normals but not in PHN treated with CEI and did not change in normal rats. Renin mRNA was significantly lower in PHN, and was stimulated by CEI only in normals. Renal kallikrein and renin content were not different and were not altered by CEI. Both kallikrein and renin genes appear to be transcriptionally suppressed in rats with PHN and the depressed kallikrein mRNA levels can be reversed by CEI. The modest increase in UKE despite normalization of kallikrein mRNA after CEI suggests that there is also a posttranscriptional defect in synthesis and/or secretion of kallikrein.

Effect of ANG II receptor antagonist on albuminuria and renal function in passive Heymann nephritis.

Angiotensin-converting enzyme inhibitors reduce albuminuria in nephrotic subjects, but the hormonal mechanism of this effect is not known. To determine whether specific inhibition of angiotensin (ANG) II activity would decrease albuminuria as occurs after converting enzyme inhibition, rats with passive Heymann nephritis received enalapril or the ANG II receptor antagonist losartan (6 mg.kg-1.day-1) for 4 days. Enalapril reduced both albuminuria (from 583 +/- 53 to 286 +/- 55 mg/day, P less than 0.001) and the fractional clearance of albumin (FCAlb) each day after starting treatment but did not affect glomerular filtration rate (GFR). Losartan reduced albuminuria significantly only after 4 days of treatment, but this value was not different from controls. GFR significantly increased with losartan (from 1.24 +/- 0.09 to 1.73 +/- 0.21 ml/min, P less than 0.05) so that FCAlb was reduced (from 0.0134 +/- 0.0027 to 0.0080 +/- 0.0018, P less than 0.05). Blood pressure decreased only in the enalapril group. Although plasma renin activity increased and the pressor response to ANG I was inhibited by both enalapril and losartan, suggesting effective peripheral blockade of ANG II activity, a third group of nephrotic rats was treated with losartan (18 mg.kg-1.day-1) to ensure that adequate ANG II blockade was achieved. Blood pressure decreased 10 mmHg, GFR increased from 1.35 +/- 0.14 to 1.79 +/- 0.12 ml/min (P less than 0.01), but albuminuria and FCAlb did not change. Urinary total kallikrein excretion was increased only in nephrotic rats treated with enalapril. Although both enalapril and losartan reduce ANG II activity, only the converting enzyme inhibitor reduces albuminuria.(ABSTRACT TRUNCATED AT 250 WORDS)

Developmental changes in the tubular capacity for phosphate reabsorption in the rat.

The need for young, immature animals to maintain positive phosphate balance for growth is well known. However, whether this process involves changes in the intrinsic capacity of the kidney to reabsorb phosphate is not clear. In the present study, the maximum capacity of phosphate reabsorption [Max RPi/glomerular filtration rate (GFR)] was measured in four groups of rats at different stages of development, from weanling to adulthood (3-4, 5-6, 10-14, and 52 wk of age). Clearance experiments were performed in acutely thyroparathyroidectomized (TPTX) rats in the presence and absence of fixed levels of parathyroid hormone (synthetic PTH-(1-34), 1 U.kg-1.min-1). Max RPi/GFR was determined with progressive infusions of phosphate (0-6 mumol Pi/min) that raised the filtered load of phosphate. Max RPi/GFR in TPTX 3- to 4- and 5- to 6-wk-old rats (5.55 +/- 0.36 and 4.28 +/- 0.18 mumol/ml, respectively) was significantly greater than in the corresponding 52-wk-old rats (3.51 +/- 0.13 mumol/ml, P less than 0.05). PTH decreased the Max RPi/GFR in all age groups. However, the developmental pattern was maintained, with the highest levels present in the youngest rats (2.79 +/- 0.25 mumol/ml, P less than 0.05) compared with the other age groups (1.92 +/- 0.23, 1.35 +/- 0.11, and 1.15 +/- 0.13 mumol/ml for 5- to 6-, 10- to 14-, and 52-wk-old rats, respectively). These results demonstrate that the tubular capacity for phosphate reabsorption per milliliter GFR is enhanced in immature rats and progressively decreases with age. This PTH-independent adaptation in young rats may contribute to the renal retention of phosphate during growth.

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)

Phosphonocarboxylic acids as specific inhibitors of Na+-dependent transport of phosphate across renal brush border membrane.

We investigated interactions of phosphonoformic acid (PFA), phosphonoacetic acid (PAA), and other phosphonyl derivatives with the Na+ gradient [Na+ extravesicular greater than Na+ intravesicular; Nao+ greater than Na+i]-dependent transport system for phosphate (Pi) in renal cortical brush border membrane vesicles (BBMV). PFA and PAA inhibited in a dose-dependent manner the Na+ gradient [Na+o greater than Na+i]-dependent uptake of Pi by rat kidney BBMV. PFA was a more potent inhibitor than PAA while phosphonopropionic acid, hydroxymethylphosphonic acid, and phenylphosphonic acid had no effect on Pi transport. The inhibitory effect of PFA was competitive (Ki approximately equal to 4.6 X 10(-4) M) and reversible upon dilution. The uptake of Pi by BBMV in the absence of Na+ gradient [Nao+ = Na+i] was also inhibited by PFA. The PFA had no effect on uptake of L-[3H]proline, D-[3H]glucose, or 22Na+ by BBMV nor did it alter intravesicular volume of BBMV. The relative (%) extent of inhibition by PFA was not altered by changes in the extravesicular pH or changes in the steepness of the Na+ gradient [Nao+ greater than Na+i]. The inhibition of PFA was analogous in renal BBMV from rats, mice, rabbits, or dogs. Unlike other known inhibitors of brush border membrane (BBM) transport of Pi, e.g. arsenate, NAD, and ethane-1-hydroxy-1,1-diphosphonate, PFA and PAA had no inhibitory effect on BBM-bound or solubilized alkaline phosphatase. Also, PFA did not interfere with the activity of renal cortical (Na-K)ATPase. Administration of PFA (0.5 g/kg/day, intraperitoneally) to thyroparathyroidectomized rats fed a low Pi diet elicited an increase in urinary excretion of Pi, but did not change the excretion of Na+, K, and Ca2+. The results show that the PFA, and to a lesser degree PAA, are specific competitive inhibitors of the Na+-Pi cotransport in renal cortical BBM and are suitable probes for studies of this transport system.

Developmental changes in the phosphaturic response to parathyroid hormone in the rat.

The need for young, immature rats to maintain positive phosphate balance for growth is well recognized. However, whether this process is associated with a resistance to the phosphaturic effect of parathyroid hormone (PTH) is not clear. In these experiments we examined the effect of PTH on urinary phosphate and cAMP excretion in rats at 3, 6, 12, and 20 wk of age. Clearance experiments were performed in acutely thyroparathyroidectomized (TPTX) rats fed a normal phosphate diet (0.86%). Basal fractional excretion of phosphate (FEPi) was low in all TPTX rats (less than 1%). The phosphaturic response to a high dose of PTH (1 U X kg-1 X min-1) increased with development (from 4 to 29%). The responses to increasing doses of PTH demonstrated a decrease in sensitivity to PTH in 6- compared with 20-wk-old rats. Urinary cAMP excretion (either per milliliter glomerular filtrate or per gram kidney weight) following PTH was not different among 6-, 12-, and 20-wk-old rats, thus demonstrating a dissociation between the increase in phosphate excretion and cAMP excretion. These results indicate that the phosphaturic response to PTH is blunted in immature, acutely TPTX rats and that the phosphaturia increases progressively with development.

Urea reabsorption along the papillary collecting duct in potassium-deficient rats.

These experiments were designed to evaluate the hypothesis that K+ deficiency may be associated with decreased delivery of urea to the renal papillary collecting duct and/or decreased reabsorption of urea from the papillary collecting duct. Either of these factors would result in diminished capacity for urea recycling and might explain the mechanism of the urinary concentrating defect that is observed in K+ depletion. Munich-Wistar rats were fed 25 ml of water and 12 g of normal (CON) or K+-deficient (KD) diet each day for 21 days. Papillary collecting duct samples were obtained by micropuncture through the intact ureter. Fractional delivery of H2O to the base and tip of the papillary collecting duct was increased in KD as compared to CON rats (1.50 +/- 0.30% in KD vs 0.72 +/- 0.09% in CON at the base, P less than 0.01; and 0.55 +/- 0.08% in KD vs 0.30 +/- 0.05% in CON at the tip, P less than 0.01). However, fractional delivery of urea to the base and tip of the papillary collecting duct was not different between KD and CON rats (26.9 +/- 5.6% in KD vs 21.4 +/- 3.3% in CON at the base, P greater than 0.05; and 12.4 +/- 1.5% in KD vs 10.4 +/- 1.4% in CON at the tip, P greater than 0.05). Furthermore, reabsorption of water or urea between the base and tip of the papillary collecting duct was not decreased in KD as compared to CON rats (water reabsorption was 57.8 +/- 4.4% in KD and 55.9 +/- 5.11% in CON and urea reabsorption was 45.0 +/- 6.5% in KD and 45.9 +/- 5.4% in CON, P greater than 0.05). These results demonstrate that water reabsorption, but not urea reabsorption, is impaired in renal tubules proximal to the accessible papillary collecting duct in hydropenic rats.

Vaginal organic acids and hormonal changes in the menstrual cycle.

Twenty-seven women not using oral contraceptives (OCs) and 22 women using OCs were studied during one complete menstrual cycle. Twenty-four-hour vaginal secretions, collected on alternate days by a tampon method, were analyzed for acetic and other short-chain aliphatic acids and for lactic acid. Daily blood samples were analyzed for estrogens, progesterone (P), and luteinizing hormone (LH). No difference was found between OC users and nonusers in either amount or variability of vaginal aliphatic acids throughout the menstrual cycle. Aliphatic acids did not correlate with estrogen of P levels. A significant positive correlation was found between vaginal lactic acid and blood estrogens in those subjects not using OCs.

Effect of fasting on tubular phosphorus reabsorption.

In the thyroparathyroidectomized (TPTX) rat, fasting increased urinary phosphorus excretion by decreasing the tubular reabsorption of P1 (TRP) and resulted in hypophosphatemia. The administration of either sucrose or NaHCO3 prevented the metabolic acidosis associated with fasting and decreased the phosphaturia, indicating that the phosphaturia in fasting is in part due to metabolic acidosis. In rats on partial reduction of P1 intake selectively, the phosphaturic response to parathyroid hormone (PTH) was completely suppressed. On the other hand, the fasting rat partially retained the phosphaturic response to PTH, although dietary P1 intake was totally absent. These findings suggest that the renal P1 wasting in fasting may take place by dual mechanisms: a) the PTH-independent decrease in TRP, and b) an inability to totally suppress the response to PTH. Cyclic AMP generation in response to PTH, determined both in vivo and in vitro, was not measurably altered in fasting. However, the phosphaturic response to cyclic AMP was decreased in fasting, suggesting that the mechanism of partial resistance to PTH is probably not at but after cyclic AMP generation.

The Menstrual Symptom Questionnaire and spasmodic/congestive dysmenorrhea: measurement of an invalid construct.

Chesney and Tasto's (1975a) Menstrual Symptom Questionnaire (MSQ) was developed on the basis of Dalton's theory of spasmodic and congestive dysmenorrhea, which states that the two types are caused by opposite hormonal imbalances and therefore should not be found in the same woman. Evidence is offered which suggests that the theory is incorrect. A multiple-group factor analysis failed to adequately support the two-component model. Subsequently, a factor analysis of 275 MSQs revealed seven factors rather than the two predicted by the theory. In addition, the incidence of both high premenstrual and menstrual symptoms in the same women was demonstrated. Finally, symptoms reported by women using oral contraceptives differed little from those reported by women not using oral contraceptives. It is concluded that scoring for the MSQ should be modified to include two subscales for premenstrual and menstrual symptoms, and that the labels "spasmodic" and "congestive" be discontinued until some evidence is found for their support.

Impaired urinary concentrating ability and cyclic AMP in K+-depleted rat kidney.

The possibility that an alteration of the vasopressin-dependent cyclic AMP system plays a pathogenic role in the urinary concentrating defect in K+ depletion was investigated in the rat. The antidiuretic response to vasopressin was significantly less in K+-depleted rats. In these K+-depleted rats, the increase in urinary cyclic AMP excretion in response to vasopressin was also significantly less. However, repletion of K+ for 1 wk by feeding high-K+ diets restored the ability to increase urinary cyclic AMP excretion in response to vasopressin. In the in vitro incubation of renal medullary slices, the increase in cyclic AMP concentration in response to vasopressin was also significantly less in the slices obtained from K+-depleted rats than in those obtained from control rats. These findings suggest that, in K+ depletion, there is a reversible impairment of the vasopressin-dependent cyclic AMP system in the renal medulla; this impairment may play a pathogenic role in the urinary concentrating defect in K+ depletion.

Effects of acute metabolic acidosis on parathyroid hormone action and calcium mobilization.

Mechanisms through which metabolic acidosis increases calcium mobilization have been investigated in thyroparathyroidectomized rats with induction of acute metabolic acidosis by infusing NH4C1 intravenously. Acute metabolic acidosis directly raised serum calcium concentration and augmented the effect of parathyroid hormone (PTH) to raise serum calcium concentration. The same effects of metabolic acidosis were observed in rats with surgically removed intestines and bilateral nephrectomy, suggesting that acute metabolic acidosis directly increases calcium mobilization from bone and augments the effect of PTH to mobilize calcium from bone. In the kidney, acidosis directly inhibited the tubular reabsorption of calcium, but augmented the effect of PTH to increase tubular reabsorption of calcium. Acidosis had no measurable effect on calcitonin action.