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Biomedical subjects

R C Blantz

Publications and source records attributed to R C Blantz.

At least 19 recordsLinked to original sources
PubMed1996

Agmatine, a bioactive metabolite of arginine. Production, degradation, and functional effects in the kidney of the rat.

Until recently, conversion of arginine to agmatine by arginine decarboxylase (ADC) was considered important only in plants and bacteria. In the following, we demonstrate ADC activity in the membrane-enriched fraction of brain, liver, and kidney cortex and medulla by radiochemical assay. Diamine oxidase, an enzyme shown here to metabolize agmatine, was localized by immunohistochemistry in kidney glomeruli and other nonrenal cells. Production of labeled agmatine, citrulline, and ornithine from [3H]arginine was demonstrated and endogenous agmatine levels (10(-6)M) in plasma ultrafiltrate and kidney were measured by HPLC. Microperfusion of agmatine into renal interstitium and into the urinary space of surface glomeruli of Wistar-Frömter rats produced reversible increases in nephron filtration rate (SNGFR) and absolute proximal reabsorption (APR). Renal denervation did not alter SNGFR effects but prevented APR changes. Yohimbine (an alpha 2 antagonist) microperfusion into the urinary space produced opposite effects to that of agmatine. Microperfusion of urinary space with BU-224 (microM), a synthetic imidazoline2 (I2) agonist, duplicated agmatine effects on SNGFR but not APR whereas an I1 agonist had no effect. Agmatine effects on SNGFR and APR are not only dissociable but appear to be mediated by different mechanisms. The production and degradation of this biologically active substance derived from arginine constitutes a novel endogenous regulatory system in the kidney.

Agmatine↗
PubMed1996

Acetaminophen: acute and chronic effects on renal function.

Acetaminophen (APAP) is normally metabolized in the liver and kidney by P450 enzymes. No toxicity is observed with therapeutic doses of APAP. However, after ingestion of large quantities of APAP (>2,000 mg/kg), highly reactive quinones, metabolites of APAP, are generated; these react with glutathione and sulfhydryl groups on critical proteins, resulting in cellular dysfunction and hepatic and renal toxicity. The P450 metabolizing enzymes differ somewhat in character between the liver and kidney. Factors that enhance renal toxicity include chronic liver disease, possibly gender, concurrent renal insults, and conditions that alter the activity of P450-metabolizing enzyme systems. Acute renal toxicity is characterized by cellular injury primarily confined to the proximal tubule and significant reductions in glomerular filtration rate. However, there is little evidence that chronic administration of APAP contributes to chronic renal disease and analgesic nephropathy. The only report on this subject suggests that combination therapy with aspirin is required for medullary damage in rats. No evidence exists for the development of chronic analgesic nephropathy with APAP alone. Epidemiologic studies in healthy individuals have failed to demonstrate a significant correlation between APAP use and chronic renal disease and classic analgesic nephropathy. Therefore, large doses of APAP can produce both renal and hepatic failure, but little evidence exists for production of classic analgesic nephropathy with the use of APAP alone.

Acetaminophen↗
PubMed1996

Increased tubular flow induces resetting of tubuloglomerular feedback in euvolemic rats.

As single-nephron glomerular filtration rate (SNGFR) and late proximal flow (VLP) increase during growth or following volume expansion, the tubuloglomerular feedback (TGF) function (defined as the decrement in SNGFR due to the process of TGF) shifts rightward in the plane defined by VLP and SNGFR as required to maintain the homeostatic efficiency of TGF. It is not known whether this resetting of TGF requires changes in the systemic hormonal milieu or results from prolonged activation of TGF itself. We employed micropuncture and videometric flow velocitometry (an optical technique for measuring flow in unobstructed nephrons) to address this issue in Inactin-anesthetized euvolemic rats. The fractional compensation (C) of TGF for perturbations [late proximal flow perturbation (VH) = +/- 5 nl/min] in VLP was assessed repeatedly before and during a sustained increase in flow imposed by adding 20 nl/min to early proximal flow (VEP). Augmenting VEP initially saturated TGF, thus suppressing C. Over the next 30 min, C recovered to 70% of its original value, suggesting a rightward resetting of the TGF function to match the increase imposed on VLP. Resetting was confirmed by documenting an evolving asymmetry of C about VH = 0 by testing C vs. VH for -12 < or = VH < or = 12 in increments of 4 nl/min. Beyond 30 min of augmented VEP, C gradually declined due to desensitization of TGF. A sustained increase in VLP is sufficient to include TGF resetting, independent of any change in the systemic neurohumoral milieu.

Animals↗
PubMed1996

Asymmetry of tubuloglomerular feedback effector mechanism with respect to ambient tubular flow.

The contribution of preglomerular resistance changes to the tubuloglomerular feedback (TGF) effector response was evaluated by micropuncture in hydropenic rats. Studies were performed in free-flowing nephrons to compare the fractional compensation (C) for perturbations in late proximal flow (VLP) with associated changes in glomerular capillary hydrostatic pressure (PGC). VLP was monitored by a noninvasive optical technique, and PGC was monitored by direct capillary micropuncture. Data were employed in conjunction with a model of glomerular filtration to analyze the TGF effector mechanism. C varied with the applied perturbation (VH), showing a single peak near the natural operating point. In contrast, the effect of TGF on PGC was asymmetric about the operating point, such that PGC was sensitive only to large positive perturbations. The model predicts that changes in preglomerular resistance account for only a small fraction of the integrated TGF response to small disturbances in the ambient state of the nephron but account for a greater share of the response to larger increments in flow. The TGF response in hydropenic rats is mediated by both pre- and postglomerular vascular elements.

Animals↗
PubMed1996

Renal response to blood pressure elevation in normal and glomerulonephritic rats.

Concurrent renal disease appears to augment greatly the adverse effects of systemic hypertension on renal function and the development of glomerulosclerosis. This study examined the effects of systemic hypertension and treatment of hypertension in groups of normal non-nephritic rats and rats submitted to 16 wk of glomerulonephritis induced by the administration of anti-glomerular basement membrane antibody. Hypertension was produced by application of a clip to the right renal artery and blood pressure was treated with an angiotensin-converting enzyme (ACE) inhibitor, quinapril. Glomerulosclerosis of two types developed: a diffuse type that is characteristic of anti-glomerular basement membrane glomerulonephritis, and a focal segmental glomerulosclerosis that is characteristic of systemic hypertension. Glomerulonephritis significantly reduced the capacity of ACE inhibitors to decrease systolic blood pressure in awake animals. In addition, glomerulonephritis produced significant effects on plasma angiotensin II concentrations, whereby ACE inhibition no longer lowered plasma angiotensin II levels and in fact produced an increase. Glomerular capillary hydrostatic pressure and hydrostatic pressure gradient correlated with systolic blood pressure and with the incidence of focal glomerulosclerosis in non-nephritic rats. However, in glomerulonephritis, systolic blood pressure no longer correlated with glomerular capillary pressure, and glomerular capillary pressure no longer correlated with the development of glomerulosclerosis, although systolic blood pressure did correlate with the degree of focal segmental glomerulosclerosis. Concurrent glomerulonephritis strongly conditions the effects of superimposed hypertension by altering the relationship between systemic blood pressure and glomerular capillary hydrostatic pressure and by decreasing the response of hypertension to therapy.

Angiotensin II↗
PubMed1996

Activities of nitric oxide in normal physiology and uremia.

Nitric oxide (NO) generated from arginine exerts a variety of renal and extrarenal physiological and pathophysiological effects. NO is generated by two types of nitric oxide synthases: acutely responsive, constitutive NOS and slower, more persistent inducible NOS (iNOS). The latter is transcriptionally dependent, often stimulated by cytokines. NO regulates glomerular ultrafiltration, tubular reabsorption, and intrarenal renin secretion; many of these renal effects are mediated by interactions with angiotensin II and adrenergic (alpha 2) activity. Decreased NO activity also enhances tubuloglomerular feedback activity, which could contribute to renal vasoconstriction, NaCl retention, and elevated blood pressure. Loss of renal function could influence NO activity via: (1) endothelial dysfunction; (2) decreased arginine synthesis by kidney; (3) responses to arginine analogs that act as NOS inhibitors; (4) increased cytokine activity; and (5) altered oxidation:reduction status of cells, etc. For example, platelet dysfunction in uremia may be caused by cytokine-induced iNOS activation. Moreover, acutely responsive, constitutive NOS activity may be depressed in progressive loss of renal function. Decreased NO activity might contribute to baroreceptor dysfunction observed in hypertension and progressive renal disease. Studies of the impact of uremia suggest that iNOS may be chronically stimulated by cytokines, whereas acutely responsive, constitutive NOS activity may be concurrently depressed.

Animals↗
PubMed1995

Interactive control of renal function by alpha 2-adrenergic system and nitric oxide: role of angiotensin II.

We studied the role of angiotensin II (AII) in the interactive control of renal function by the alpha 2-adrenergic system and nitric oxide (NO) in adult male Munich Wistar rats 5-7 days after ipsilateral renal denervation (DNX). Renal micropuncture was used under euvolemic conditions before (period 1) and during (period 2) systemic inhibition of NO synthase (NOS) with NG-monomethyl-L-arginine (L-NMMA) in three groups. Group 1 served as a DNX control. In group 2, the alpha 2-adrenergic agonist B-HT 933 (BHT) was infused systemically throughout the experiment. In group 3, the AII-receptor blocker, Iosartan (LOS), was infused before period 2 as well as throughout infusion of BHT. L-NMMA increased blood pressure (BP) to a similar degree in all three groups. In group 1, infusion of L-NMMA did not affect glomerular hemodynamics or tubular function. With BHT in group 2, L-NMMA reduced absolute proximal tubular reabsorption (APR) and by reducing nephron plasma flow (SNPF) and glomerular ultrafiltration coefficient (LpA) caused nephron filtration rate (SNGFR) to decrease, a response described in innervated kidneys. LOS in group 3 abrogated the BHT-facilitated reduction of LpA and SNGFR but not of SNPF and APR in response to L-NMMA. In group 1, urinary sodium excretion (UNaV) did not change and urinary flow rate (UV) increased slightly in period 2. L-NMMA combined with BHT, however, exerted a profound diuresis and natriuresis in group 2. These effects were further exaggerated with LOS. In a fourth group of DNX rats. LOS given alone before period 2 did not affect SNGFR, SNPF, LpA, APR, UV, or UNaV. We conclude that after subacute renal denervation alpha 2-adrenergic activation sensitizes (a) LpA to reduction by NOS inhibition through an AII-dependent mechanism, and (b) SNPF and proximal tubular reabsorption to reduction by L-NMMA regardless of the AII activity. Furthermore, our results suggest a potential role for the alpha 2-adrenergic system and AII in the diuretic and natriuretic effect of systemic NOS inhibition.

Angiotensin II↗
PubMed1995

Glomerular and tubular interactions between renal adrenergic activity and nitric oxide.

Endothelium-dependent nitric oxide (EDNO) exerts control over the processes of glomerular filtration and tubular reabsorption. The importance of the renal nerves to the tonic influence of EDNO in the glomerular microcirculation and proximal tubule was tested by renal micropuncture in euvolemic adult male Munich-Wistar rats. The physical determinants of glomerular filtration and proximal reabsorption were assessed before and during administration of the nitric oxide synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA), in control animals and in animals 5-9 days after either ipsilateral surgical renal denervation (DNX) or after either sham surgery (SHX). L-NMMA caused single-nephron glomerular filtration rate to decline in control and SHX animals but not in DNX rats. L-NMMA caused a reduction in proximal reabsorption in control and SHX rats, which was prevented by prior DNX. DNX did not alter urinary guanosine 3',5'-cyclic monophosphate excretion, and, although DNX upregulates glomerular angiotensin II (ANG II) receptors, prior DNX did not alter intrarenal ANG II content as evaluated by radioimmunoassay. Some component of renal adrenergic activity is required for the full expression of the glomerular and tubular effects of blockade of nitric oxide synthase.

Analysis of Variance↗
PubMed1995

Homeostatic efficiency of tubuloglomerular feedback is reduced in established diabetes mellitus in rats.

We tested the hypothesis that the ability of the tubuloglomerular feedback (TGF) to stabilize renal function is impaired in rats with 7-8 wk of insulin-treated streptozotocin-diabetes. Proximal tubular flow was measured in free-flowing nephrons using a noninvasive optical technique. The homeostatic efficiency of TGF was determined from the fractional compensation for perturbations in ambient flow. Fractional compensation was substantially reduced in diabetic rats. To assess the roles of the proximal tubule and loop of Henle as determinants of TGF efficiency, we tested the effect of diabetes on proximal tubular reabsorption as determined by standard micropuncture and on the ionic content of early distal tubular fluid by employing a microelectrode for on-line measurement of electrical conductivity (TED). Diabetes caused glomerular hyperfiltration and increased fractional proximal tubular reabsorption (FPR), such that late proximal tubular flow (VLP) and early distal tubular flow were unaffected. The increase in FPR was a minor contributor to the overall effect on fractional compensation. Diabetes decreased the ambient TED without affecting the slope of the relationship between VLP and TED. These results demonstrate that the homeostatic, efficiency of the TGF system is reduced in diabetes and that this cannot be fully accounted for by changes in tubular reabsorption. Impaired TGF efficiency renders the diabetic glomerular microvasculature more susceptible to impact from fluctuations in systemic hemodynamics.

Absorption↗
PubMed1995

Renal hemodynamics and plasma and kidney angiotensin II in established diabetes mellitus in rats: effect of sodium and salt restriction.

Six weeks after the onset of insulin-treated streptozotocin diabetes (STZ) in Munich-Wistar rats, the effect of a low-sodium (LNa) and a low-salt (LNaCl) diet on renal function and on plasma and kidney tissue angiotensin II (AIIp, AIIk) was tested. Clearance experiments were performed in anesthetized rats 7 days after starting on LNa or LNaCl. On a control diet, STZ exhibited an increase in GFR, RBF, and kidney weight (KW) and a reduction in renal vascular resistance (RVR) and AIIk, but no change in AIIp, compared with nondiabetic normal rats (CON). Although sodium restriction reduced and salt restriction increased AIIk in CON, both diets increased AIIp without affecting renal hemodynamics or KW. In diabetic rats, both salt and sodium restriction further increased GFR and RBF by reducing RVR, increased KW, and changed AIIk and AIIp in a similar pattern, but at significantly lower values compared with CON. Daily treatment of STZ-LNa with the AII-receptor blocker losartan (20 mg/L, in drinking water) did not affect the reduction in RVR and the increase in KW but slightly reduced RBF because of a decrease in mean arterial blood pressure and further increased GFR. It was concluded that (1) AIIk but not AIIp is affected differently by LNa compared with LNaCl in both CON and STZ; (2) LNaCl and LNa change AIIp and AIIk in a similar pattern but at significant lower values in STZ compared with CON; and (3) with regard to renal hemodynamics and KW, the response to LNa and LNaCl is different in CON compared with rats 6 wk after the onset of diabetes mellitus, the latter exhibiting a further increase in renal hyperfiltration and KW by a mechanism that is not directly AII receptor dependent.

Angiotensin II↗
PubMed1995

Role of angiotensin in the regulation of renal response to proteins.

Intrarenal and extrarenal humoral factors have been proposed as mediators and modulators of the renal hyperemic response to amino acid infusion. Among the potential modulators, angiotensin II (AII) constitutes the most important candidate due to its critical role in the control of glomerular and tubular function. The modulatory effect of AII has been assessed by (1) measuring the changes in plasma renin activity (PRA)/AII during the normal hyperemic response, and (2) by assessing the levels of PRA/AII and the response to AII-suppressing agents in conditions with no vasodilatory response during amino acid infusion. Administration of a protein load in normal animals or humans does not modify PRA/AII. Absence of a vasodilatory response in various experimental conditions (nitric oxide blockade in normal rats, experimental models of hypertension, diabetes mellitus, chronic glomerulonephritis, cyclosporine administration) is characterized by a significant decrease in proximal tubular reabsorption during amino acid infusion. Converting enzyme inhibitors or AII receptor antagonist restore normal tubular function and the increase in glomerular filtration rate during amino acid infusion. Absence of a vasodilatory response is also associated with increases in kidney AII levels in some of these conditions. These results suggest that (1) AII modulates the amino acid-induced hyperemia through its inhibitory effect on proximal tubular reabsorption and activation of the tubuloglomerular feedback system, and (2) that the expression of the modulatory effect of AII may depend on the interaction between AII and other intrarenal systems like nitric oxide.

Amino Acids↗
PubMed1994

Glomerular hemodynamics in cell-free and erythrocyte-perfused isolated rat kidney.

The cell-free isolated perfused kidney (IPK) is characterized by normal glomerular filtration rate (GFR) and very low filtration fraction (FF). Addition of erythrocytes to the perfusate (IEPK) increases FF while maintaining "normal" GFR levels. Micropuncture studies were performed in IPK and IEPK to establish the determinants of the glomerular ultrafiltration process responsible for low FF in IPK and to evaluate the impact of the addition of erythrocytes on these determinants. Nephron filtration rate was similar in IPK and IEPK (40 +/- 4 vs. 39 +/- 4 nl/min), whereas nephron perfusate flow was significantly higher in IPK (1,247 +/- 100 vs. 112 +/- 13 nl/min), leading to a superficial nephron FF of 3.4 +/- 0.2% in IPK and 36 +/- 2% in IEPK. Glomerular hydrostatic pressure (PG) and transcapillary hydrostatic pressure gradient (delta P) were 53 +/- 2 and 33 +/- 1 mmHg, respectively, in IPK and 51 +/- 3 and 34 +/- 2 mmHg in IEPK, all normal values. Glomerular arteriolar resistances were significantly lower in IPK than in IEPK, and the glomerular ultrafiltration coefficient (LpA) was significantly lower in IPK (0.053 +/- 0.010 vs. 0.100 +/- 0.020 nl.s-1.mmHg-1), but both values are within the normal in vivo range. These results demonstrate that low FF in IPK is not due to decreased delta P or LpA values but to the high renal perfusion rate required to maintain normal PG and delta P values. Addition of erythrocytes increases glomerular arteriolar resistances and restores glomerular hemodynamics to a pattern nearly identical to in vivo conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Vascular biology: relevance of nitric oxide in vascular and nonvascular tissue with normal and decreased renal function.

Nitric oxide has been recognized as an important paracrine or autocrine system during the past decade. The generalized importance of this rather simple molecule has been demonstrated in of a variety of neural, epithelial, vascular and immune systems. The degree to which alterations in nitric oxide metabolism contribute to the physiologic and pathophysiologic status of patients with end-stage renal disease remains to be fully defined in both experimental animals and in humans afflicted with renal disease.

Amino Acid Oxidoreductases↗
PubMed1994

Water and protein permeability is regulated by the glomerular epithelial slit diaphragm.

The glomerular barriers to water and macromolecular movement were examined 2 and 24 h after the administration of a monoclonal antibody (mAb) specific to an antigen located on the epithelial slit diaphragm and the external aspect of the glomerular basement membrane. By micropuncture techniques 2 h after mAb administration, single-nephron GFR (SNGFR) and plasma flow were unchanged but the glomerular capillary hydrostatic pressure gradient and glomerular capillary hydrostatic pressure were increased and the glomerular ultrafiltration coefficient (LpA) decreased to values that were 50% of the normal control. There was no increase in urinary protein excretion at 2 h. However, at 24 h after mAb, nephron plasma flow (SNPF) and SNGFR increased and the glomerular ultrafiltration coefficient returned to values indistinguishable from the normal control. At 24 h, there was a marked increase in protein excretion. The administration of meclofenamate decreased values for SNGFR and SNPF to normal. Immunoglobulin G was exclusively bound to glomerular capillary walls in a linear or continuous fashion at 2 h, but in a discontinuous, granular pattern at 24 h. These studies suggest that after mAb, important limiting glomerular barriers for hydraulic conductivity and protein excretion reside on the epithelial aspect of the glomerular capillary basement membrane, specifically at the level of the slit diaphragm. Studies also suggest that alterations in glomerular capillary hydraulic conductivity can be effectively separated from increases in macromolecular permeability.

Animals↗
PubMed1994

Glycine prevents toxic tubular cell injury.

Glycine prevents tubular injury as suggested by in vitro cell culture studies, studies in the isolated perfused kidney, and in vivo studies. We have previously demonstrated that intratubular administration of uranyl nitrate (UN) produces proximal tubular cell injury and decreases proximal tubular reabsorption (APR). The decrease in APR activates tubuloglomerular feedback and lowers nephron filtration rate (SNGFR). This study was designed to evaluate if glycine administration could prevent the decrease in SNGFR after UN administration and if maintenance of SNGFR was due to tubular cell cytoprotection or suppression of the tubuloglomerular feedback. Administration of 0.65 ng of UN into the early proximal tubule was associated with a decrease in distal SNGFR (SNGFRD) from 29 +/- 2 to 24 +/- 2 nL/min (p < .05) and late proximal SNGFR (SNGFRLP) from 37 +/- 2 to 26 +/- 2 nL/min, and APR from 14 +/- 1 to 10 +/- 1 nL/min. Systemic administration of glycine (20 g/dL, 1.4 mL/h) was associated with significant increases in SNGFRD and SNGFRLP, and APR (38 +/- 3, 44 +/- 3, and 15 +/- 2 nL/min). UN administration did not affect APR or SNGFR in glycine-treated rats. These findings demonstrate that glycine prevents UN-induced decreases in SNGFR through a cytoprotective effect on proximal tubular cells.

Animals↗