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Biomedical subjects

B M Brenner

Publications and source records attributed to B M Brenner.

At least 253 records · Page 14Linked to original sources
PubMed1982

Glomerular charge alterations in human minimal change nephropathy.

A theoretical model of charge and size selectivity for the glomerulus has been applied to human data. Using previously published values for GFR, renal plasma flow, systemic oncotic pressure, and fractional clearances of neutral dextrans, albumin, salivary amylase, and transferrin, membrane parameters describing the glomerular barrier were determined for normal individuals under control conditions and during lysine infusion (which retards tubule protein reabsorption), and for patients with minimal change nephropathy (MCN). To permit the estimation of membrane charge from fractional clearances, molecular charge values for human transferrin (-9.4 Eq/mole) and human salivary amylase (-4.1) were determined by measuring electrophoretic mobilities of these proteins in polyacrylamide gels. Assuming no large changes in the transmural hydraulic pressure difference (delta P), the glomerular ultrafiltration coefficient (Kf, the product of hydraulic permeability and capillary surface area) was calculated to be reduced by greater than 50% in MCN. The effective pore radius (approximately 55 A) is virtually unaltered in MCN, suggesting that the decline in Kf is due to a reduced number of pores. The degree of albuminuria observed in MCN is attributable to an approximately 50% reduction in the concentration of fixed negative charges in the glomerular capillary wall. The concentrations of fixed charges calculated from albumin data in normal individuals (140 to 160 mEq/liter) and in patients with MCN (60 to 90 mEq/liter) are insensitive to the assumed values of delta P.

Albumins↗
PubMed1982

Mechanism of glomerulotubular balance in the setting of heterogeneous glomerular injury. Preservation of a close functional linkage between individual nephrons and surrounding microvasculature.

Autologous immune complex nephropathy (AICN), an experimental model for human membranous glomerulopathy, is characterized by marked heterogeneity in function from glomerulus to glomerulus. However, the fraction of the filtered load of fluid reabsorbed by the proximal tubule remains nearly constant from nephron to nephron, despite wide variation in single nephron glomerular filtration rate (SNGFR). To define the physiological mechanisms responsible for this marked variation in SNGFR values within a given kidney and for the remarkable preservation of glomerulotubular balance, the various determinants of fluid exchange across glomerular and peritubular capillary networks were evaluated in Munich-Wistar rats with AICN. For comparison, similar measurements were obtained in rats with the functionally more homogeneous lesion of heterologous immune complex nephropathy. In AICN rats studied approximately 5 mo after injection of renal tubule epithelial antigen (Fx1A), a high degree of glomerulus-proximal tubule balance was found, despite marked variations in SNGFR values within a single kidney. These changes were associated with marked heterogeneity in immunoglobulin and complement deposition within and among glomeruli. Although mean capillary hydraulic pressure and Bowman's space hydraulic pressure ranged widely from glomerulus to glomerulus, the mean glomerular transcapillary hydraulic pressure difference was remarkably uniform among these functionally diverse glomeruli and could not, therefore, be implicated as the cause of the dispersion in SNGFR values. The two remaining determinants of SNGFR, namely, glomerular plasma flow rate (Q(A)) and ultrafiltration coefficient (K(f)), varied markedly from glomerulus to glomerulus, but always in direct proportion to SNGFR, and proved to be responsible for the marked variation in SNGFR. The mean net peritubular capillary reabsorptive force ( P(r)) correlated closely with the absolute rate of fluid reabsorption in adjacent proximal tubules (APR) in AICN. Of the factors determining P(r), peritubular capillary hydraulic pressure was essentially constant in a given AICN kidney, whereas peritubular capillary plasma protein concentration and oncotic pressure varied directly with APR and largely accounted for the observed tight correlation between P(r) and APR. ON THE BASIS OF THESE OBSERVED CORRELATIONS, WE SUGGEST THAT THE CLOSE QUANTITATIVE COUPLING BETWEEN SNGFR AND APR IN INDIVIDUAL NEPHRONS IN AICN IS DUE TO THE FUNCTIONAL RESPONSE OF INDIVIDUAL GLOMERULI: those with the most pronounced declines in SNGFR are characterized by the most pronounced declines in Q(A) and K(f). The resultant low peritubular capillary oncotic pressure favors a decline in APR, thus favoring nearly perfect glomerulotubular balance. In glomeruli with higher SNGFR values, Q(A) and K(f) values are also higher. These changes in K(f) once again are capable of establishing the conditions in downstream peritubular capillaries, this time favoring augmented APR (i.e., high intracapillary oncotic pressure), again leading to nearly perfect glomerulotubular balance.

Animals↗
PubMed1981

Effects of catecholamines on electrolyte transport in cortical collecting tubule.

We examined the direct effects of isoproterenol (ISO) and L-norepinephrine (NE) on electrolyte transport in isolated rabbit cortical collecting tubules (CCT) perfused in vitro. The addition of either ISO (10(-6) M) or NE (10(-6) M) to the bath decreased transepithelial potential difference (PD), on average by 51 and 25%, respectively. These effects of ISO and NE were abolished by prior addition of the beta-adrenergic blocker, L-propranolol. ISO (10(-5) M) had no effect from lumen. Also, osmotic water permeability was not influenced by ISO. Ouabain and ISO had additive effects on PD. Elimination of chloride from both perfusate and bath, or addition of acetazolamide, abolished the effect of ISO on PD. Although isotopic sodium flux for lumen to bath was not influenced by ISO, chemical net chloride absorption increased from 1.1 +/- 0.4 to 2.7 +/- 0.6 peq . cm-1 . sec-1 (n = 8, p less than 0.005). In conclusion, both ISO and NE and capable of decreasing PD in rabbit CCT perfused in vitro. This effect is mediated by beta-adrenergic receptors and is accompanied by the increase in net chloride absorption. Although the mechanism responsible for this decrease in PD with ISO in unclear, active chloride absorption, active hydrogen secretion, or membrane chloride permeability changes may account for the effects of ISO.

Acetazolamide↗
PubMed1981

Body fluid homeostasis in man. A contemporary overview.

In the steady state, urinary excretion of sodium is closely matched to dietary salt intake. Given rigorous defense of extracellular fluid osmolality, it is the quantity of sodium in the extracellular fluid that determines the volume of this compartment. Changes in extracellular fluid volume are detected by volume sensors located in the intrathoracic vascular bed, kidney and other organs. These mechanoreceptors gauge the adequacy of intravascular volume, relative to capacitance, at various sites within the circulation. The perception of a change in the normal relationship between intravascular volume and circulatory capacity evokes a host of renal effector mechanisms that lead ultimately to physiologically appropriate changes in urinary sodium excretion. These effector mechanisms involve physical adjustments in the glomerular filtration rate, renal microvascular hemodynamics and peritubular capillary Starling forces, tubule fluid composition, flow rate and transtubular ion gradients. Neural and humoral pathways are also involved and, among the latter, angiotensin II, aldosterone, prostaglandins and kinins have been studied extensively. The continuous interaction between these sensor and effector mechanisms serves to ensure near-constancy of the extracellular fluid volume, a condition essential for optimal circulatory performance.

Aldosterone↗
PubMed1981

Inhibition of Na Transport by prostacyclin (PGI2) in rabbit cortical collecting tubule.

The effects of prostacyclin (PGI2) on transepithelial potential difference (PD) and sodium transport were examined in rabbit cortical collecting tubules (CCT) perfused in vitro. Addition of PGI2 (10-6M) to the bathing medium, which was bubbled with 95% O2 - 5% CO2, caused a reversible decrease in PD averaging 49 +/- 9.4(SE)%. Maximal effect was evident between 5-10 min. after addition of PGI2 and PD returned spontaneously towards control values within 30 min., corresponding to the rapid degradation of PGI2. In a more alkaline bathing solution achieved by bubbling with 100% O2, in which the degradation of PGI2 is known to be delayed markedly, the decrease in PD by PGI2 was continuous and dose-dependent, with half-maximal and maximal effects achieved at 10-7M and 10-5M, respectively. Neither 10-8M PGI2 nor vehicle alone exerted significant effects on PD. 6-keto-PGF1 alpha (10-5M), believed to be the major metabolite of PGI2, had no effect on PD. Lumen-to-bath flux of Na decreased with PGI2 from 9.0 to 5.6 pEq/cm/sec (n=4, p less than 0.005), although bath-to-lumen flux did not change significantly. In summary, PGI2 caused a dose-dependent decrease in PD of rabbit CCT and inhibited Na absorption in this segment in vitro. These results suggest that PGI2 may play as important role in regulating Na transport in CCT.

6-Ketoprostaglandin F1 alpha↗
PubMed1981

Mechanisms of action of various hormones and vasoactive substances on glomerular ultrafiltration in the rat.

Angiotensin II (AII) and arginine vasopressin are capable of triggering glomerular mesangial cell contraction in vitro. A similar mechanism acting in vivo to reduce glomerular capillary surface area could account for the decline in the ultrafiltration coefficient (Kf)( that occurs in single glomeruli in response to infusion of these substances. Less clear is the mechanism whereby similar declines in Kf are induced with infusions of dibutyryl cyclic AMP (DBcAMP), parathyroid hormone (PTH), and prostaglandins, because PTH and PGE2, at least, are incapable of eliciting mesangial cell contraction in vitro. To further explore the factors that regulate Kf in vivo, we performed micropuncture experiments in 47 euvolemic Munich-Wistar rats. Infusions of DBcAMP, PTH, prostaglandins I2 and E2 led to lower mean values for plasma flow rate (QA) and Kf in superficial glomeruli than were found in animals given vehicle alone (control group), whereas average values for glomerular transcapillary hydraulic pressure difference (delta P) and total renal arteriolar resistance (RTA) tended to be higher. These increases in delta P and RTA, and decreases in QA and Kf, with DBcAMP, PTH, PGI2, and PGE2 are typical of changes induced by AII. Indeed, when saralasin, a competitive AII antagonist, was infused together with these various vasoactive substances, the effects on delta P, QA, RTA, and Kf were largely abolished. Therefore, the actions of DBcAMP, PTH, PGI2, and PGE2 on the glomerular microcirculation appear to depend on an intermediate action of AII. By contrast, although pitressin (ADH) infusion also led to a significant decline in Kf, saralasin administration did not reverse this change, suggesting that the action of ADH on the glomerular microcirculation is independent of a pathway involving AII. Based on these studies, it seems reasonable to propose that AII and ADH are both potentially important regulators of mesangial cell contraction, and thereby, glomerular capillary filtering surface area and Kf.

Animals↗
PubMed1981

Pathophysiology of altered glomerular function in aminoglycoside-treated rats.

To evaluate the relative influences of gentamicin and tobramycin on glomerular function, we studied three groups of normal hydropenic rats. Group 1 had 8 rats that served as control. Group 2 had 9 rats that were given gentamicin (40 mg/kg of body wt per day for 10 days). Group 3 had 10 rats that received tobramycin instead of gentamicin. In addition, we attempted to suppress angiotensin II (AII) generation in two additional groups of rats and then study the glomerular response to gentamicin: in 6 rats, isotonic sodium chloride was substituted for tap water for drinking throughout the period of study (group 4), and in 7 other gentamicin-treated rats, captopril was given orally (group 5). A sixth group received captopril alone (group 6). Following gentamicin treatment in group 2, values for single nephron GFR (SNGFR) were markedly lower (21.7 +/- 2.1 nl/min) than they were in groups 1(35.7 +/- 1.4) or 3(34.1 +/- 2.9). Declines in whole kidney GFR in group 2 paralleled the fall in SNGFR. Reduction in SNGFR with gentamicin was due both to a marked decline in the glomerular capillary ultrafiltration coefficient, Kf, and in the initial glomerular plasma flow rate, QA. With saline administration (group 4), the decline in SNGFR was partially blunted, whereas with captopril (group 5) the effects of gentamicin on SNGFR, QA, and Kf were largely abolished. Morphologic studies revealed no discernible glomerular defects in any groups, whereas proximal tubule damage was evident with both aminoglycosides, irrespective of the state of the renin-angiotensin system. Thus, in the dosage used, gentamicin elicits greater impairment in glomerular function than does tobramycin, and by mechanism(s) that are at least partially responsive to suppression of AII generation.

Animals↗
PubMed1981

Glomerular hemodynamics in experimental diabetes mellitus.

Micropuncture studies were performed in three groups of euvolemic male Munich-Wistar rats: 8 control rats, 7 severely hyperglycemic rats made diabetic with streptozotocin (60 mg/kg, i.v.), and 6 moderately hyperglycemic rats made diabetic by the same method but given 2 U of NPH insulin daily. Glucose concentrations at the time of micropuncture study averaged 115 +/- (sem) 10, 565 +/- 12, and 375 +/- 23 mg/dl, respectively. Single nephron GFR (SNGFR) values were significantly lower (28.8 +/- 1.9nl/min) in severely hyperglycemic rats than they were in controls (48.9 +/- 3.8). This reduction in SNGFR was due mainly to a fall in glomerular plasma flow rate ((Q(A)). In contrast, moderately hyperglycemic rats exhibited glomerular hyperfiltration, with SNGFR values averaging 69.0 +/- 8.0 nl/min. This hyperfiltration, with resulted from elevations in values for Q(A) and glomerular transcapillary hydraulic pressure difference (delta P) to levels significantly above control. These alterations in SNGFR in severely hyperglycemic and moderately hyperglycemic rats, relative to controls, were paralleled by changes in whole kidney GFR and mimic the changes in GFR observed in diabetic patients with analogous degrees of hyperglycemia. Measurements of blood volumes in separate groups of control, severely, and moderately hyperglycemic rats revealed equivalent absolute blood volumes in all three conditions and increased blood volumes, relative to body weight, in both groups of hyperglycemic rats. Thus, SNGFR is increased in diabetic rats with moderate hyperglycemia but decreased in those with severe hyperglycemia, and these changes are not simply related to variations in circulating blood volume.

Animals↗
PubMed1981

Hyperfiltration in remnant nephrons: a potentially adverse response to renal ablation.

Micropuncture studies were performed in three groups of male Munich-Wistar rats 1 wk after surgery: group I, eight control rats that underwent laparotomy and were fed a normal diet; group II, nine rats that underwent right nephrectomy and segmental infarction of five-sixths of the left kidney and were fed a normal diet; and group III, seven rats that underwent the same renal ablative procedure and were fed a low protein diet. Single nephron glomerular filtration rate (SNGFR) was higher in the remnant kidney of group II rats compared with group I rats due to higher average values for mean glomerular transcapillary hydraulic pressure difference (delta P) and initial glomerular plasma flow rate (QA) in group II. Glomeruli in remnant kidneys of group II showed striking alterations in morphology, including epithelial cell protein reabsorption droplets, foot process fusion, and mesangial expansion. Group III rats demonstrated a mean SNGFR not statistically different from that of group I, but significantly less than that of group II rats. This lack of absolute hyperfiltration in remnant glomeruli of group III rats relative to group I obtained because QA and delta P did not increase above values found in group I. The glomerular structural lesions seen in group II were also largely attenuated in group III. These studies demonstrate that alterations in glomerular hemodynamics associated with renal ablation are accompanied by structural lesions and suggest that sustained single nephron hyperfiltration may have maladaptive consequences by damaging remnant glomeruli.

Animals↗
PubMed1981

Relative contributions of arginine vasopressin and angiotensin II to maintenance of systemic arterial pressure in the anesthetized water-deprived rat.

We used a structural analogue of arginine vasopressin (AVP) and investigated the role of AVP in the maintenance of mean arterial pressure (AP) in anesthetized, water-deprived rats. The administration of [1(beta-mercapto-beta,beta-cyclopentamethylene propionic acid) 4-valine-8-D-arginine] vasopressin, d(CH2)5VDAVP, completely inhibited to 30-40 mma Hg rise in AP which normally accompanied the administration of 50 mU exogenous AVP (group 1). Thus, d(CH2)5VDAVP is a specific antagonist of the vascular effects of AVP. d(CH2)5VDAVP failed to significantly alter AP in water diuretic rats (group 3) and was without effect on urine osmolality during water diuresis or antidiuresis. However, bolus injection of d(CH2)5VDAVP into water deprived rats (group 2) prompted an abrupt fall in AP from 112 +/- 4 to 94 +/- 4 mm Hg (P less than 0.001). This fall in AP was transient, with return of AP to 110 +/- 4 mm Hg within 15 minutes. Administration of saralasin, an angiotensin II antagonist, not only prevented the compensation in AP, but also significantly magnified the maximal hypotensive response seen following d(CH2)5VDAVP (group 4). Discontinuing the saralasin allowed AP to return to baseline. Bilateral nephrectomy (group 5) also prevented the return of AP, further implicating endogenous angiotensin II as the specific mediator of the compensation in AP following d(CH2)5VDAVP administration. These studies clearly demonstrate that circulating AVP contributes to the maintenance of AP during water deprivation in the anesthetized rat. When this vascular action of AVP is blocked, angiotensin II assumes major responsibility for blood pressure regulation in the antidiuretic state.

Angiotensin II↗
PubMed1980

Glomerular adaptations to chronic dietary salt restriction or excess.

Micropuncture studies were performed in 33 Munich-Wistar rats maintained chronically either on dietary NaCl restriction (group 1) or excess (group 2). Values for single nephron (SN) and total kidney glomerular filtration rate (GFR) were identical in both groups. Nevertheless, because of preferential efferent vasoconstriction, glomerular capillary hydraulic pressure (PGC) was higher in group 1, offsetting the lower initial glomerular plasma flow rate (QA) also found in group 1. The pressor response to infusion of exogenous angiotensin II (AII) was less in group 1 than in group 2, suggesting that vascular receptors for AII may have been occupied by endogenous hormone, the latter leading to the efferent arteriolar vasoconstriction. In addition to AII, prostaglandins also appear to be involved in the adaptations of the glomerular microcirculation to chronic variations in salt intake. In group 1, indomethacin or meclofenamate infusion mimicked exogenous AII, causing declines in QA and SNGFR. These changes were lacking in group 2. Because of relative contraction of plasma volume, the vasodilatory effects of prostaglandins appear to be needed in low salt animals to sustain SNGFR and QA. In the high salt group, however, since plasma volume is not contracted, maintenance of SNGFR and QA appears to be less critically dependent on endogenous prostaglandins.

Angiotensin II↗
PubMed1980

Interaction between antidiuretic and parathyroid hormones on urine concentration.

Experiments were performed on 26 acutely thyroparathyroidectomized (TPTX) Sprague-Dawley rats undergoing maximum water diuresis to determine whether the rise in urinary osmolality (Uosmol) in response to a submaximal dose of antidiuretic hormone (ADH) is modified by exogenous administration of parathyroid hormone (PTH). During administration of a submaximal dose of PTH to 11 TPTX rats, the ADH-induced increase in Uosmol averaged 267 +/- 15 mosmol, or twice the average increment of 131 +/- 18 mosmol observed when the same dose of ADH was given prior to PTH infusion (P < 0.001). This difference could not be attributed to changes in endogenous ADH release, renal hemodynamics, or solute excretion, and was not observed in a second group of eight other water-diuretic TPTX rats given sham PTH infusion. A third group of seven water-diuretic TPTX rats were studied with verapamil, a compound known to antagonize calcium ion entry into cells. Pretreatment of these rats with intravenous verapamil abolished the PTH potentiation of the Uosmol response to ADH described above. We conclude, therefore, that PTH enhances the Uosmol response to ADH, perhaps via a mechanism requiring a PTH-mediated change in the cellular calcium concentration or content of cells important in the urinary concentrating process.

Animals↗