Biomedical subjects

H Osswald

Publications and source records attributed to H Osswald.

At least 37 records · Page 2Linked to original sources

PubMed1998

Decreased HER-2 tyrosine kinase expression in rectal mucosa of FAP patients following low-dose sulindac chemoprevention.

As a part of the mechanisms of action in reversing FAP adenomas by the low-dose sulindac maintenance therapy (2 x 25 mg/patient per day), the extent of HER-2 proto-oncogene expression in the rectal mucosa seems to be of interest. Immunocytochemical analyses were performed in plasma and in rectal tissue of sulindac-treated FAP patients during an 18 months follow-up and compared with rectal tissue of patients with FAP, Crohn's disease, or rectal cancer or with healthy volunteers. HER-2 was significantly reduced and maintained in tissue under sulindac chemoprevention below base line levels of healthy individuals, but not in plasma. Therefore, a direct or indirect effect of sulindac as a tyrosine kinase inhibitor may be implicated. During NSAID treatment HER-2 protein expression as a prognostic tool seems to be of little clinical relevance.

Adenomatous Polyposis Coli↗

PubMed1998

Effects of ions on adenosine binding and enzyme activity of purified S-adenosylhomocysteine hydrolase from bovine kidney.

The present investigation was undertaken to determine the effect of various ions on the characteristics of S-adenosylhomocysteine (SAH) hydrolase from bovine kidney. The binding sites of [3H]-adenosine to purified SAH hydrolase were not influenced by phosphate, magnesium, potassium, sodium, chloride or calcium ions at physiological cytosolic concentrations. To test whether NAD+ in the SAH hydrolase is essential for adenosine binding, we prepared the apoenzyme by removing NAD+ with ammonium sulfate. The resulting apoenzyme did not exhibit any [3H]-adenosine binding. Since the apoenzyme was enzymatically inactive, it is suggested that adenosine binds to the active site and not to an allosteric site of the intact enzyme. The kinetics of the hydrolysis and the synthesis of SAH catalyzed by the enzyme SAH hydrolase were measured in the presence and absence of phosphate and magnesium. Phosphate increased the Vmax for both synthesis and hydrolysis. However, only the affinity of adenosine for SAH synthesis was significantly enhanced from 10.1+/-1.3 microM to 5.4+/-0.5 microM by phosphate. This effect was already maximal at a phosphate concentration of 1 mM. All other tested ions were without effect on the enzyme activity. Our results show that phosphate at physiological concentrations shifts the thermodynamic equilibrium of SAH hydrolase in the direction of SAH synthesis. These findings imply that SAH-sensitive transmethylation reactions are inhibited during renal hypoxia when intracellular levels of phosphate, adenosine, and SAH are elevated.

Adenosine↗

PubMed1998

Renal haemodynamic responses to exogenous and endogenous adenosine in conscious dogs.

1. Adenosine has been suggested to be the mediator of a metabolic feedback mechanism which transfers acute changes in the tubular load into opposite changes in renal blood flow (RBF). The goal of the present experiments was to assess the importance of endogenously formed adenosine as a 'homeostatic metabolite' during short-term changes in metabolic demand. 2. In nine chronically instrumented conscious foxhounds, both the direct effects of adenosine injections (10, 30 and 100 nmol) into the renal artery and the temporal changes of RBF after short renal artery occlusions (15, 30 and 60 s duration), the most widely used experimental model to study the metabolic feedback mechanism in vivo, were studied. 3. Intrarenal bolus injections of adenosine (10, 30 and 100 nmol) induced dose-dependent decreases of RBF (RBF: -34 +/- 5, -59 +/- 4 and -74 +/- 4 %, respectively). This vasoconstrictor effect of adenosine was significantly larger (RBF: -51 +/- 4, -68 +/- 4 and -83 +/- 3 %, respectively) when the dogs received a low salt diet. 4. The post-occlusive responses were characterized by a transient hyperaemia with no detectable drop of RBF below the preocclusion level. The post-occlusive responses were affected neither by changes in local angiotensin II levels, nor by intrarenal infusions of hypertonic NaCl or blockade of A1 adenosine receptors. 5. When intrarenal adenosine levels were elevated by infusion of the adenosine uptake inhibitor dipyridamole, a transient, although weak, post-occlusive vasoconstriction was detected. 6. In summary, the present data demonstrate that adenosine acts as a potent renal vasoconstrictor in the conscious dog. The endogenous production of adenosine during short-lasting occlusions of the renal artery, however, appears to be too small to induce a post-occlusive vasoconstrictor response of RBF. These results suggest that a metabolic feedback with adenosine as 'homeostatic metabolite' is of minor importance in the short-term regulation of RBF in the conscious, unstressed animal.

Adenosine↗

PubMed1998

Eukaliuric natriuresis and diuresis in response to disprocynium24: studies on the tubular site of action.

We previously described that 1,1'-diisopropyl-2,4'-cyanine (disprocynium24, DP24) exerts an eukaliuric diuresis and natriuresis in the anesthetized rat. The purpose of the present study was to localize the tubular site of action of DP24. Employing micropuncture experiments in anesthetized rats, we first tested the effect of systemic application of DP24 (300 microg/kg + 300 microg/kg h, i.v.) on whole kidney excretion rates as well as on fluid, sodium and potassium ion delivery to the early distal tubule (V(ED), Na+(ED), K+(ED)). It was found that the eukaliuric diuresis and natriuresis in response to DP24 was accompanied by a substantial increase in V(ED) and Na+(ED), suggesting a predominant tubular site of action upstream to the early distal tubule, most likely in the proximal tubule. DP24 caused a comparable fractional, although minor absolute increase in K+(ED) as compared to Na+(ED). Second, application of DP24 into the first surface loop of the proximal tubule significantly increased V(ED) and Na+(ED) at a concentration of about 10(-7) M, indicating that DP24 may act from the intratubular site. Third, microperfusion of tubular segments revealed that effects of DP24 on the proximal convoluted tubule and the loop of Henle accounted for about 70 and 30%, respectively, of its diuretic and natriuretic action upstream to the early distal tubule. With regard to the loop of Henle, the quantitative effect of DP24 on fluid and Na+ reabsorption proposed a predominant effect on the straight part of the proximal tubule rather than the thick ascending limb. Intratubular DP24 did not affect reabsorption in the distal tubule. In summary, the present findings indicate that: (1) the diuretic and natriuretic effect of DP24 resides predominantly in the proximal tubule, and (2) DP24 may act from the intratubular site. Since DP24 increased V(ED) and Na+(ED) without apparently affecting sodium or potassium ion transport in the distal tubule, the mechanism of the eukaliuric response remains unclear.

Animals↗

PubMed1998

Potassium diet as a determinant for the renal response to systemic potassium channel modulation in anesthetized rats.

The role of potassium intake in the response of kidney function and plasma renin activity (PRA) to systemic application of U37883A (4-morpholinecarboximidine-N-1-adamantyl-N'-cyclohexyl-hydro chloride), a putative blocker of ATP-sensitive potassium channels (K(ATP)), and P1075 (N-cyano-N'-(1,1-dimethylpropyl)-N"-pyridylguanidine), an opener of K(ATP) channels, was studied in the anesthetized rat. It was found that under normal potassium diet (0.7% K), U37883A (15 mg/kg, i.v.) increased urinary flow rate (UV) and sodium excretion (UNaV), decreased urinary potassium excretion (UKV), and significantly diminished heart rate (HR) without affecting mean arterial blood pressure (MAP) or glomerular filtration rate (GFR). P1075 (10 microg/kg, i.v.) lowered UV, UNaV and UKV, at least in part due to the fall in MAP and GFR. PRA was diminished by U37883A and increased by P1075. Variation in potassium diet (0.04 or 2% K) left the response in MAP, HR or GFR to both potassium channel modulators essentially unchanged. The reduction in renal excretion rates to P1075 also appeared unaffected, further supporting a predominant role of the change in MAP and GFR in this response. Variation in potassium diet, however, elicited the following alterations: (1) under both low and high potassium diet U37883A did no longer cause a significant natriuresis; (2) U37883A elicited a significant kaliuresis under high potassium diet, whereas potassium excretion remained essentially unchanged on very low levels under low potassium diet; (3) the increase in PRA to P1075 was blunted under low potassium diet. Additional experiments provided evidence that P1075 releases renin from freshly isolated juxtaglomerular cells of rats on normal but not on low potassium diet. In summary, systemic potassium channel modulation employing U37883A or P1075, respectively, exerts distinct effects on blood pressure and heart rate independent of potassium diet. In contrast, potassium diet appears to be a determinant for the concomitant responses in plasma renin activity and renal sodium and potassium excretion.

Adamantane↗

PubMed1998

Intratubular application of sodium azide inhibits loop of Henle reabsorption and tubuloglomerular feedback response in anesthetized rats.

Sodium azide (NaN3, AZ) is a potent inhibitor and uncoupler of oxidative phosphorylation as well as a nitrovasodilator after being converted to nitric oxide (NO). We studied the effect of intratubular application of AZ on loop of Henle reabsorption and tubuloglomerular feedback (TGF) employing renal micropuncture experiments in nephrons with superficial glomeruli of anesthetized Munich-Wistar-Fromter rats. During perfusion of Henle's loop downstream from an obstructing wax block, AZ (3x10(-5) mol/l and 3x10(-4) mol/l) concentration-dependently increased early distal tubular flow rate and sodium and potassium ion concentration (V(ED), [Na+]ED, [K+]ED). In comparison, application of furosemide (10(-4) mol/l), the action of which is restricted to the water-impermeable thick ascending limb of Henle's loop (TALH) and the macula densa, similarly increased [Na+]ED and [K+]ED, but did not affect V(ED). The effect of AZ on loop of Henle reabsorption appeared to be predominantly localized upstream to the TALH since (1) AZ significantly inhibited net fluid reabsorption (the latter being completely abolished at 3x10(-4) mol/l), (2) the effect of AZ on [Na+]ED and [K+]ED could be mimicked by perfusing the Henle's loop at a flow rate that caused a comparable increase in V(ED) (reflecting a comparable load to TALH), and (3) the effects of AZ and furosemide were additive. In spite of the increase in [Na+]ED and [K+]ED, intratubular application of AZ caused a concentration-dependent inhibition of TGF response, the latter being assessed as the fall in early proximal tubular stop flow pressure during perfusion of Henle's loop at increasing flow rate. Like AZ and furosemide, the NO donor sodium nitroprusside (10(-4) mol/l) blunted the TGF response, but in contrast to furosemide or AZ, it caused a minor decrease in V(ED), without changing [Na+]ED or [K+]ED. The inhibitory effect of AZ on TGF was abolished by the NO scavenger carboxy PTIO. In summary, AZ inhibits both reabsorption in the water-permeable segment of Henle's loop and the TGF response. The effect on reabsorption may be linked to metabolic inhibition rather than NO release, whereas the blunted TGF response appears to involve conversion to NO.

Absorption↗

PubMed1998

Renal effects of exogenous dopamine: modulation by renal nerves and dopamine receptor antagonists.

The modulation of the renal response to exogenous dopamine by renal denervation (DNX) and dopamine receptor antagonists was investigated in thiopental-anesthetized Sprague-Dawley rats. Experiments were performed after reaching stable systemic hemodynamics and urinary flow rate. These conditions were obtained with an infusion rate of approximately 1.2% of body weight per hour. In the vehicle group (VHC) i.v. infusion of dopamine (1, 3 and 9 microg kg(-1) min(-1) significantly increased glomerular filtration rate (GFR), assessed by renal clearance of [3H]inulin, by 14+/-1.5, 16+/-1.6 and 31+/-2.6%, respectively. Infusion of 1 and 3 microg kg(-1) min(-1) dopamine did not change systemic hemodynamics while the highest dose elevated heart rate, potentially contributing to the GFR increase. The specific D1 receptor antagonist SCH 23390 (10 microg kg(-l) min(-1) i.v.) did not affect the GFR response to dopamine infusion. In contrast, domperidone (DOM; 8 microg kg(-1) min(-1) i.v.), a specific, peripherally acting D2 antagonist, attenuated the glomerular hyperfiltration induced by the three doses of dopamine to 11+/-1.7, 13+/-2.2 and 16+/-2.6%, respectively. DNX diminished the GFR response to dopamine infusion to almost the same extent (11+/-2.8, 10+/-2.2 and 17+/-2.6%, respectively) as did DOM. When DNX animals were treated with DOM, the GFR responses to dopamine were further attenuated to non-significant increases. These additive effects of DOM and DNX suggest that two different mechanisms are involved. Both DNX and SCH 23390 decreased sodium excretion at baseline whereas DOM enhanced it. Under the present experimental condition, neither D1 nor D2 receptor blockade affected the natriuretic and diuretic response to dopamine. Whereas D1 receptors do not appear to be involved, both D2 receptors and renal nerves play a role in the renal hemodynamic response to dopamine, indicating involvement of both pre- and postsynaptical dopamine receptors.

Animals↗

PubMed1998

The immunoreactivity of glial fibrillary acidic protein in mesangial cells and podocytes of the glomeruli of rat kidney in vivo and in culture.

In this study the presence of glial fibrillary acidic protein (GFAP) in kidney is for the first time demonstrated in cryostat sections and cultures of isolated glomerular explants derived from rat kidneys. In double immunolabelling analysis of adult rat kidney sections using antiserum against GFAP and monoclonal antibody (mAb) against vimentin or desmin, the presence of immunoreactivity for GFAP could be observed in the glomerulus of the kidney and vascular cells situated in the peritubular space which expressed vimentin and desmin. Labelling of the sections with absorbed antiserum against GFAP completely abolished the staining in all these cells. The mAb against GFAP, clone GF12.24 which is known to label GFAP both in neural and non-neural cells, recognised its antigen only in the cells located in glomeruli. The investigations performed on early 2- or 3-day-old cultures from glomerular explants revealed different patterns of staining for GFAP in mesangial cells and podocytes: weak filamentous in mesangial cells and a strong non-filamentous perinuclear pattern in podocytes. Due to prominent perinuclear expression in podocytes GFAP may be considered as a marker of these cells. A different pattern of distribution of immunoreactivity for GFAP in podocytes and mesangial cells might be due to function-related posttranslational modifications of GFAP resulting in assembly or disassembly of GFAP filaments. The different pattern of staining for GFAP in the podocytes and mesangial cells, cells which exert a different influence on the capillaries of the glomeruli, suggests a role for GFAP in regulation of the tension and permeability of vascular walls. Previous investigations and present studies hint at GFAP as being a general marker of perivascular cells.

Animals↗

PubMed1998

Luminal signal in tubuloglomerular feedback: what about potassium?

Evidence suggests that a minimal luminal [K+] is required to elicit a full tubuloglomerular feedback (TGF) response, consistent with transmission of the TGF signal across the macula densa (MD) via the Na+-2Cl(-)-K+ cotransporter. Furthermore, it appears that luminal [K+] at the MD is close to the K+ affinity of the Na+-2Cl(-)-K+ cotransporter and changes in response to altering late proximal tubular flow rate (VLP), that is, a maneuver that induces a TGF response. These findings suggest that luminal [K+] (besides [Cl-]) could be rate limiting in TGF. In the thick ascending limb of Henle's loop (TALH), most of the luminal K+ is derived from recycling across the apical tubular membrane. Because changing VLP causes relatively greater alterations in the absolute Na+ and Cl- delivery to Henle's loop than in K+ load, the parallel changes of VLP and luminal [K+] at the MD, despite significant alteration in K+-dependent reabsorption of Na+ and Cl- via the Na+-2Cl(-)-K+ cotransporter, imply a transport-dependent adaptation of K+ recycling in TALH.

Animals↗

PubMed1998

Adenosine and extracellular volume in radiocontrast media-induced nephropathy.

Renal hemodynamic changes could play a key role in radiocontrast media-induced nephropathy (RCIN), although the pathophysiological mechanisms are unclear. We investigated the role of adenosine in RCIN caused by sodium diatrizoate (Urografin, 3 ml/kg) in nitro-L-Arg methyl ester (L-NAME)-hypertensive rats in different hydration states [eight weeks of L-NAME (50 mg/liter) in drinking water; high or low sodium intake for the last two weeks]. In clearance experiments under thiobutabarbital anesthesia in these previously mentioned animals, glomerular filtration rate (GFR), renal blood flow (RBF), and mean arterial pressure (MAP) were measured in the presence or absence of the adenosine A1-receptor antagonist 8-cyclopropyl-1,3-dipropylxanthine (DPCPX, 100 microg/kg bolus plus 10 microg/kg/hr). DPCPX or pretreatment did not change control hemodynamics. Contrast medium caused GFR and RBF to fall significantly in volume-depleted rats (from 0.29 +/- 0.02 to 0.21 +/- 0.02 ml/min/100 g and 5.4 +/- 0.3 to 4.0 +/- 0.4 ml/min, respectively) without change in MAP. In volume-expanded rats, changes were not significant (0.25 +/- 0.01 to 0.24 +/- 0.02 ml/min/100 g and 5.6 +/- 0.3 to 5.3 +/- 0.4 ml/min, respectively). In the volume-depleted rats, changes were prevented by DPCPX (0.27 +/- 0.02 to 0.24 +/- 0.02 ml/min/100 g and 4.8 +/- 0.1 to 5.0 +/- 0.1 ml/min, respectively). The acute hemodynamic effects elicited by contrast medium in L-NAME hypertensive rats thus can be prevented by volume expansion. Adenosine, via A1-receptors, contributes to the adverse effects of contrast media.

Acute Kidney Injury↗

PubMed1998

Isolated superfused juxtaglomerular cells from rat kidney: a model for study of renin secretion.

Freshly isolated rat juxtaglomerular cells (JGC) were superfused to study renin secretion rate (RSR) at the cellular level. Effluates from the superfusion chamber collected in 20-min intervals showed a time-dependent decline in RSR from 85.5 +/- 32 to 4.0 +/- 2.4 ng ANG I. ml-1. h-1. mg protein-1. min-1 within 100 min of collection (mean +/- SE, n = no. of JGC preparations/superfusion chambers = 9/18). Addition of adenosine deaminase type II (ADA II, 3 U/1.4 mg protein) to the superfusion medium increased RSR more than fourfold to 402 +/- 100 ng in the first collection period, which dropped to 237.5 +/- 67 ng ANG I. ml-1. h-1. mg protein-1. min-1 (n = 9/18) within 100 min. This ADA II effect was rapid in onset and fully reversible. When the purified ADA type VII, with a 40-fold higher specific activity, was added to the superfusate, RSR was increased only by 96 +/- 17.8% compared with controls. This ADA VII (5 U/30 microgram) effect could be mimicked by the selective adenosine A1-receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 10(-6) mol/l). Since albumin stimulated RSR in a concentration-dependent fashion, to an extent similar to that of ADA II, we assume that the ADA II effect was largely unspecific in nature. We conclude that 1) superfusion of isolated JGC from rats is suitable for investigations of renin secretion at the cellular level, 2) the increase in RSR by ADA II appears to be only in part due to deamination of endogenously generated adenosine, and 3) albumin in the superfusate induces a similar stimulatory effect as ADA II.

Adenosine↗

PubMed1997

Polymerized hemoglobin restores cardiovascular and kidney function in endotoxin-induced shock in the rat.

Sepsis and its complications, hypotension, shock, and multiorgan failure continue to represent a significant cause of mortality among hospitalized patients, affecting approximately 200,000 patients per year in the US and 100,000 in Europe (Dal Nogare, A.R. 1991. Am. J. Med. Sci. 302:50-65.). Incidence rates appear to be increasing, probably due to an increase in the population with risk factors such as diabetes or invasive procedures. Activation of cytokines by endotoxins and subsequent formation of nitric oxide is of central pathogeneic importance in sepsis. In this study we show that polymerized bovine hemoglobin (Biopure 2) restores both cardiovascular and renal functions in an endotoxin-induced shock model in rats. These effects are compared to those of the nitric oxide synthase inhibitor N(G)-nitro-L-arginine, and hydroxyethyl starch, the latter currently in clinical use for intravenous volume replacement. Our results clearly indicate that polymerized hemoglobin but not nitric oxide synthase inhibition or volume replacement normalize cardiovascular and kidney function in acute septic shock. This new therapeutic approach is readily applicable to controlled clinical trials because polymerized hemoglobin has been tested in humans and is therefore available for such studies.

Animals↗

PubMed1997

Clinical and genomic influence of sulindac on rectal mucosa in familial adenomatous polyposis.

PURPOSE: A study was performed to evaluate the antiproliferative effects of low doses of the nonsteroidal drug, sulindac, on adenomas and rectal mucosa in familial adenomatous polyposis and to analyze the influence on tumor-suppressor genes and on apoptosis. METHODS: This was a prospective, controlled, nonrandomized Phase II dose-finding study for sulindac. The study group (n = 28) and control group (n = 10) underwent colectomy and ileorectal anastomoses, with repeated proctoscopy with endoluminal ultrasound and biopsies every three months. Dose-reduction of sulindac according to adenoma reversion was predetermined. Proliferation marker, Ki-67 (MIB1 and 5), on frozen or paraffin sections evaluated the antiproliferative effects; mutant p21ras, pantropic p53, mutant p53, and anti-bcl-2 were performed as enzyme-linked immunosorbent assay procedures and/or immunohistochemistry on paraffin sections. RESULTS: All patients responded to sulindac after 24 weeks (at the latest). There was a significant reduction of adenomas and dose reduction to 67 mg/day after three years of therapy (Mann's test for trend, P < 0.001). Results consisted of 78 percent complete reversions, 22 percent partial reversions of adenomas at latest re-examination, and no influence on upper gastrointestinal tract adenomas. No influence was detected on repeated hemograms, liver, or renal function at high or low doses. There was a permanent antiproliferative effect (Ki-67) of low-dose sulindac, significant blocking of ras mutation activation, and a significant difference of untreated and treated mucosa in mutant p53 content (Wilcoxon's or Kruskal-Wallis each, P < 0.05). Reverse correlation of anti-bcl-2 and p53 immunostaining on mucosa sections was an indication of adenoma relapse. CONCLUSIONS: Low-dose antiproliferative sulindac therapy is highly effective in adenoma reversion in familial adenomatous polyposis patients. Sulindac shows influence on tumor-suppressor genes and on apoptosis markers. An immunostaining correlation indicates adenoma relapse in flat microadenomas in advance of macroscopic appearance. Low-dose sulindac treatment may develop into an additive permnanent therapy for colectomized familial adenomatous polyposis patients.

Adenomatous Polyposis Coli↗

PubMed1997

Disprocynium24 induces a dopamine-independent, eukaliuric diuresis and natriuresis in the anaesthetized rat.

In the anaesthetized rat, intravenous administration of the isocyanine 1,1'-diisopropyl-2,4'-cyanine (disprocynium24) at doses up to 600 microg/kg resulted in marked diuresis and natriuresis without affecting urinary potassium excretion. Fractional sodium excretion was increased over 10-fold indicating a high ceiling-diuretic action. The effects of disprocynium24 on renal function were accompanied by a dose-dependent reduction in heart rate (HR) and mean arterial blood pressure (MAP). Acute administration of 600 microg/kg disprocynium24 decreased MAP by 25% and, in addition, caused a fall in glomerular filtration rate (GFR). Since i) disprocynium24 has been shown to interfere with urinary dopamine excretion (UDAV) and ii) dopamine has been implicated with the regulation of renal sodium excretion, we hypothesized that the effects of disprocynium24 might be mediated by its effects on renal dopamine handling. The following findings, however, argue against this hypothesis. First, administration of disprocynium24 in single doses up to 600 microg/kg caused a diuresis and natriuresis, but did not significantly affect U(DA)V. Second, neither the systemic nor the renal response to disprocynium24 were markedly altered by pretreatment with the dopamine D1- or D2-receptor blockers SCH23390 (10 microg x kg(-1) x min[-1]) or S(-)sulpiride (15 microg x kg(-1) x min[-1]), respectively.

Animals↗

PubMed1997

Role of renal nerves and endogenous dopamine in amino acid-induced glomerular hyperfiltration.

The present study was performed to clarify whether urinary dopamine excretion (UDAV) and renal nerves are involved in the increase in glomerular filtration rate (GFR) induced by amino acid (AA) infusion. In thiopental-anesthetized rats, L-phenylalanine-free solutions of 10 AA (10%) either with (AATyr, n = 10) or without (AA0, n = 10) L-tyrosine (0.5%) were infused. Compared with baseline values, AATyr increased GFR from 0.83 +/- 0.05 to 1.00 +/- 0.04 ml.min-1.100 g-1 (P < 0.01) and UDAV almost fivefold from 5.81 +/- 0.46 to 28.1 +/- 7.4 pmol.min-1.100 g-1 (P < 0.01). In contrast, infusion of AAo increased GFR as did AATyr but did not significantly change UDAV. The DA2-receptor antagonist S(-)-sulpiride dose-dependently (0.5 to 15 micrograms.min-1.100 g-1) inhibited the GFR response to AA infusion but did not affect UDAV. In rats that had undergone chronic bilateral renal denervation (DNX), the AA-induced hyperfiltration was abolished completely, regardless of whether L-tyrosine was present. DNX did not affect basal UDAV, but the increase in UDAV in response to AATyr was attenuated compared with rats with innervated kidneys. Renal sodium excretion was increased almost twofold due to AA infusion and did not correlate with UDAV significantly. The data suggest 1) that urinary dopamine does not play a significant role in the regulation of kidney function, 2) that renal innervation is essential in the GFR response to systemic AA infusion, and 3) that a dopaminergic mechanism apart from tubular dopamine excretion is involved as well.

Amino Acids↗

PubMed1997

Adenosine and tubuloglomerular feedback.

During the past 16 years numerous studies have shown that adenosine is present in the normoxic kidney and accumulates when ATP hydrolysis prevails over ATP synthesis. Adenosine can induce renal vasoconstriction and a fall in glomerular filtration rate (GFR). The tubuloglomerular feed-back (TGF) mechanism refers to a series of events whereby changes in the NaCl concentration in the tubular fluid at the end of the thick ascending limb of Henle's loop are sensed by the macula densa which then elicits a twofold response in the juxtaglomerular apparatus: a change in the afferent arteriolar tone and GFR and an alteration in renin secretion from granular cells. While an increase in late proximal tubular flow rate, which increases the NaCl concentration and probably transport across the macula densa, lowers GFR and renin secretion, a low NaCl concentration at the macula densa elicits the opposite effects. One important role of the TGF response is to keep the fluid and electrolyte delivery to the distal tubule within certain limits, so that this part of the nephron can accomplish the fine adjustments in reabsorption to meet body needs. In this regard the TGF mechanism serves to establish an appropriate balance between nephron filtration rate and reabsorption in the proximal tubule and loop of Henle. Among several factors, adenosine is considered to be a potential candidate for mediating the TGF response from macula densa to extraglomerular mesangial cells, afferent arteriole, and granular cells. The TGF-mediated vasoconstriction and reduction in renin release following an elevation of the NaCl concentration at the macula densa can be blocked by theophylline and other adenosine-A1-receptor-specific antagonists. Furthermore, the TGF is potentiated by substances that can elevate extracellular adenosine concentrations such as dipyridamole. These and other findings support the concept that adenosine as a metabolic mediator may couple energy metabolism (ATP hydrolysis for tubular Na+ transport) with the control of renin secretion and GFR.

Adenosine↗

PubMed1997

Effect of intratubular application of angiotensin 1-7 on nephron function.

Cleavage of the C-terminal tripeptide of angiotensin I (Ang I) by neutral endopeptidase 24.11 releases angiotensin 1-7 (Ang 1-7). Because Ang I and neutral endopeptidase 24.11 are present in proximal tubular fluid and brush border, respectively, Ang 1-7 could be released into proximal tubular fluid to affect nephron function. Therefore, we studied the effect of intratubular Ang 1-7 (10(-12) to 10(-8) M) on nephron function employing in vivo renal micropuncture in inactin-anesthetized Munich-Wistar-Frömter rats. We observed that: (i) Intratubular application of Ang 1-7 for 3, 15, or 30 min did not affect reabsorption in the microperfused proximal convoluted tubule determined as net fluid reabsorption. (ii) During perfusion of Henle's loop for 15 min with artificial tubular fluid (time control), we observed a decline in fluid, potassium and sodium reabsorption by 20, 18 and 5%, respectively. A similar decline in reabsorption was seen with intratubular application of Ang 1-7 in a concentration of 10(-12) or 10(-10) M. In contrast, intratubular application of Ang 1-7 in a concentration of 10(-8) M increased fluid, potassium and sodium reabsorption in that nephron segment by 11, 9 and 3%, respectively. The latter response was completely abolished by AT1 angiotensin II receptor antagonist losartan (10[-6] M). (iii) Intratubular application of Ang 1-7 did not affect net sodium, potassium, or fluid reabsorption in the distal tubule. (iv) TGF response assessed by measuring proximal tubular stop-flow pressure or single nephron filtration rate during orthograde open-loop perfusion of Henle's loop was not significantly altered by intratubular application of Ang 1-7. These findings show that intratubular application of Ang 1-7 in concentrations which possibly cover the physiological range does not significantly alter (i) tubular reabsorption in proximal convoluted or distal tubule, or (ii) TGF response. Intratubular Ang 1-7 at a concentration of 10(-8) M appears to increase reabsorption in Henle's loop by an AT1 angiotensin II receptor-mediated mechanism, the physiological relevance of which remains to be established.

Absorption↗

PubMed1997

Potential role of luminal potassium in tubuloglomerular feedback.

Transport through the Na+-2Cl(-)-K+ cotransporter in the luminal membrane of macula densa cells is considered critical for tubuloglomerular feedback (TGF). Although various studies could support the importance of luminal Na+ and Cl-, the role of luminal K+ in TGF has not been thoroughly addressed. The study presented here examines this issue in nephrons with superficial glomeruli of anesthetized male Munich-Wistar-Frömter rats. Ambient Na+ concentration in early distal tubular fluid was approximately 22 mM, suggesting collection sites relatively close to the macula densa segment. First, it was found that ambient early distal tubular K+ concentration is approximately 1.3 mM, i.e., close to the K+ affinity of the Na+-2Cl(-)-K+ cotransporter in the thick ascending limb. Second, it was observed that a change in late proximal tubular flow rate, i.e., a maneuver that is known to induce a TGF response, significantly alters early distal tubular K+ concentration. Third, previous experiments failed to show an inhibition in TGF response during retrograde perfusion of the macula densa with K+-free solutions. Because of a potential K+ influx into the lumen between the perfusion site and the macula densa, however, the K+ channel blocker U37883A was added to the K+-free perfusate. TGF response was assessed as the fall in nephron filtration rate in response to retrograde perfusion of the macula densa segment from early distal tubular site. It was observed that luminal U37883A (100 microM) significantly attenuated TGF. Because adding 5 mM KCl to the perfusate restored TGF in the presence of U37883A and because the inhibitory action of U37883A on tubular K+ secretion was confirmed, the effect of U37883A on TGF was most likely caused by inhibition of K+ influx into the perfused segment, which decreased luminal K+ concentration at the macula densa. The present findings support a potential role for luminal K+ in TGF, which is in accordance with a transmission of the TGF signal across the macula densa via Na+-2Cl(-)-K+ cotransporter.

Adamantane↗