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PubMed1991

How do loop diuretics act?

In the thick ascending limb of the loop of Henle, NaCl reabsorption is mediated by a Na+/2Cl-/K+ cotransport system, present in the luminal membrane of this nephron segment. Loop diuretics such as furosemide (frusemide), piretanide, bumetanide and torasemide bind reversibly to this carrier protein, thus reducing or abolishing NaCl reabsorption. This leads to a decrease in interstitial hypertonicity and thus to a reduced water reabsorption. In nephron segments other than the thick ascending limb, loop diuretics have no quantitative importance with respect to their saluretic and diuretic activities. Loop diuretics also reduce Ca++ and Mg++ reabsorption in the thick ascending limb in a way which is still not clear. Furthermore, these drugs increase the urinary K+ excretion by enhancing distal tubular K+ secretion and reducing K+ reabsorption in the loop of Henle. Finally, by reduction of active NaCl transport, loop diuretics drastically reduce the substrate requirement and oxygen dependence of the thick ascending limb cells. This renders these cells, which are characterised by high transport rates and only limited substrate reserves, less vulnerable in acute renal failure.

Animals↗
PubMed1991

Afferent loop syndrome: sonographic findings in seven cases.

We studied the sonographic findings in seven patients in whom afferent loop obstruction was first detected by sonography. All seven subsequently were proved at surgery to have afferent loop syndrome. The causes of the obstruction included internal hernia (n = 3), cancer recurrence (n = 2), marginal ulcer (n = 1), and development of cancer at the anastomosis site (n = 1). In all cases, the dilated afferent loop was seen on sonography as a tubular structure in the upper abdomen crossing transversely over the midline. The distal end of the afferent loop could be traced toward the anastomosis. The probable cause of the syndrome was predicted on the basis of sonography in two of three patients with cancer at the anastomosis. Our experience suggests that afferent loop syndrome can be diagnosed sonographically on the basis of the detection, location, and shape of the dilated afferent loop.

Adult↗
PubMed1975

Short chain fatty acids in rats with jejunal blind loops. I. Analysis of SCFA in small intestine, cecum, feces, and plasma.

The luminal and plasma levels of short chain fatty acids (SCFA), products of bacterial fermentation, were measured in rats with surgically produced, self-filling blind loops located in the proximal small intestine. High levels of acetic, propionic, and butyric acids were detected in the blind loop segment and in the distal small bowel, regions which in normal and sham-operated rats contain no SCFA. Isobutyric, isovaleric, and valeric acids were also present. Feeding or fasting made little difference in the amount or composition of luminal SCFA. Although the amount of SCFA in each animal varied, the ratio of these acids was relatively constant. The ceca of the blind loop rats had relatively less acetic acid (48% of total SCFA) than did normal rats (64%) and proportionately more isobutryic, isovaleric, and valeric acids. The concentrations of SCFA increased in the feces of blind loop rats. The acetic acid concentration was 50% higher in blind loop rat feces; propionic, isobutryic, and isovaleric acids were elevated to a greater extent. The total output of most of the SCFA was also of acetic acid (137 +/- 32 mug per ml), the rest being isovaleric (5.2 +/- 2.6 mug per ml) and isobutyric (1.4 +/- 0.7 mug per ml) acids. Blind loop animals had nearly twice the concentration of acetic acid in the plasma (240 +/- 29 mug per ml) as normal animals, while the other acids were unchanged. The present study suggests that endogenous substances may be important substrates for the production of SCFA in the intestinal lumen. The high levels of SCFA in the small intestine and in feces and the substantial increase in the concentration of acetic acid in thvergrowth syndrome if the same relationships were found in man.

Animals↗
PubMed1992

The effect of loop of Henle diuretics on the tubuloglomerular feedback mechanism.

Increases in the delivery of solute to the loop of Henle result in increased reabsorption, vasoconstriction of the afferent arteriole, and a reduction in the glomerular filtration. Although the details of this tubuloglomerular feedback (TGF) mechanism are not completely worked out, it appears certain that alterations in reabsorption by the loop of Henle are critical to its operation. In the following study, we assessed the effect of several different loop of Henle diuretics on the response of the TGF mechanism. The function of TGF was monitored by measuring the stop-flow pressure (SFP) in the early proximal tubule in response to alterations in perfusion rate through the loop of Henle. All drugs were given directly into the loop of Henle in a concentration of 10(-4) M. With control solutions, SFP fell in a sigmoidal fashion over a perfusion range of 5 to 45 nl/min. When furosemide was added to the perfusate at a dose of 10(-4) M, SFP did not change. Bumetanide had an effect similar to furosemide, but muzolimine failed to inhibit the reduction in SFP over the perfusion range. Three experimental compounds were tested. All three cause diuresis when administered orally to animals. MK447 had no effect on SFP, but its metabolite, MK447-SO4, had an effect similar to furosemide. Another compound with modest diuretic effects, ICI 207,828, actually increased the response in SFP. Two distal diuretics, hydrochlorothiazide and amiloride, had no effect on SFP. The response of SFP to all these compounds correlated with its measured effect on loop reabsorption of sodium. Furosemide, bumetanide and MK447-SO4 significantly reduced sodium reabsorption.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Indomethacin antagonizes furosemide's intratubular effects during loop segment microperfusion.

To determine if indomethacin antagonizes the effect of intraluminal furosemide, superficial loop segments were microperfused from latest proximal to earliest distal tubules at 20 nl/min with 10(-5) M furosemide in rats treated with indomethacin or vehicle. Base-line loop chloride reabsorption was determined in the presence and absence of indomethacin in a third and fourth group perfused with a similar solution with furosemide omitted. Arterial pressure, whole kidney inulin clearance and urinary chloride excretion were not different among groups. Fractional loop chloride reabsorption was less (P less than .05) in vehicle-treated rats perfused with furosemide than in time control rats perfused without furosemide (30.8 +/- 2.8 vs. 50.3 +/- 2.8%). Fractional chloride reabsorption was greater (P less than .05) in furosemide-perfused loops of indomethacin-treated rats than furosemide-perfused loops of vehicle-treated rats (44.2 +/- 1.9 vs. 30.8 +/- 2.8%). Addition of 10(-4) M prostaglandin E2 to perfusate did not potentiate furosemide's effect in vehicle-treated rats but restored furosemide's potency in indomethacin-treated rats. Thus, indomethacin had no effect on base-line loop chloride uptake but attenuated furosemide's luminal effect. This response could be reversed by luminal prostaglandin E2. This study demonstrates that indomethacin antagonizes furosemide's tubular effects in the absence of furosemide-induced vasodilatation.

Absorption↗
PubMed1984

Effects of enantiomers of indacrinone (MK-196) on cation transport by the loop of Henle and distal tubule studied by microperfusion in vivo.

We have studied the effects of the two enantiomeric forms of the diuretic agent, indacrinone (MK-196), upon transport of sodium and potassium by the loop of Henle and distal tubule, using the technique of continuous microperfusion, in vivo, of individual tubular segments in the rat kidney. In the loop of Henle, both the (+)-and (-)-enantiomers, when included in the tubular perfusion fluid at a concentration of 5 X 10(-4) M, inhibited the reabsorption of sodium and potassium, but the (-)-enantiomer was significantly more effective in this regard than the (+)-enantiomer. Although loop sodium reabsorption was incompletely blocked by either form of the drug, potassium reabsorption by the loop was on average abolished by (-)-MK-196 and was actually converted in some experiments to an appreciable net secretory flux. In the distal tubule, both enantiomers inhibited net sodium reabsorption, but neither affected the control level of potassium secretion. These experiments provide direct evidence that the natriuretic effect of this agent is due to actions on sodium transporting sites in the loop of Henle and distal tubule. Furthermore, because potassium transport was affected only in the loop, they suggest that the nature of the cellular cation transport mechanism influenced by the drug may be different at the two nephron sites studied.

Animals↗
PubMed1981

Protein-losing enteropathy in the human and experimental rat blind-loop syndrome.

Protein-losing enteropathy in 2 human subjects with small intestine bacterial overgrowth is reported. Partial improvement in 1 and complete normalization in the 2nd, during long-term antibiotic therapy, demonstrate for the first time antibiotic reversibility of protein-losing enteropathy in the human blind-loop syndrome. Studies in rats with experimental jejunal blind loops revealed depressed serum protein levels and excessive fecal excretion of intravenously administered 51Cr as compared with nonoperated and surgical controls. Comparison of protein loss of rats with blind loops present for varying lengths of time and paired comparison of rats tested for protein loss at two different times revealed a relatively stable degree of protein loss once it was manifest. Reversal of protein loss with antibiotic therapy was accomplished in only a small percentage of rats, and in those only after prolonged therapy. Surgical extirpation of the blind loop from rats with protein-losing enteropathy consistently corrected the protein loss, although this correction was delayed up to 9 wk from the time of corrective surgery. These studies demonstrate (a) significant protein loss as one etiologic factor for protein metabolic disturbances in the human and experimental rat blind-loop syndrome, (b) the occurrence of intestinal protein loss as a manifestation of functionally significant mucosal injury in the contaminated nonstagnant small bowel as well as the stagnant part of the small intestine affected by bacterial overgrowth, and (c) the difficulty of reversing functionally significant mucosal injury in the blind-loop syndrome once it has been manifest.

Animals↗
PubMed1995

[Diagnosis and treatment of afferent loop syndrome].

In the period from 1981 to 1990, 43 patients were treated for the afferent loop syndrome. Their ages ranged from 20 to 76 years. Hofmeister-Finsterer gastric resection was the most frequent (81.40%) primary operation, in four patients (9.30%), primary resection was performed with anterocolonic anastomosis on a long loop after Braun. In two patients (4.65%) the syndrome had developed after Roux resection. In 12 patients (27.90%), the afferent loop syndrome was combined with the dumping syndrome, and in 24 (55.81%) with peptic ulcer of the gastrojejunoanastomosis, which along with other causes was the etiologicl al factor of the syndrome due to stenosis and deformity of the intestine. The afferent loop syndrome was classified into two degrees of severity according to the need for operative treatment and the presence of other diseases, "postgastroectomy syndromes", for which surgery was also needed. There were 8 patients (18.6%) with a mild afferent loop syndrome and 35 (81.40%) with the severe form. Patients of the last-named group were subjected to various reconstructive operations. Reconstruction of the anastomosis after Billroth-I is the method of choice in the afferent loop syndrome, particularly in patients with concurrent dumping syndrome (they were treated also by reconstructive gastrojejunoduodenoplasty). In patients with concomitant peptic ulcer of the anastomosis the creation of Braun anastomosis and resection after Roux are sometimes ineffective.

Adult↗
PubMed1994

A structure/activity study of calcium affinity and selectivity using a synthetic peptide model of the helix-loop-helix calcium-binding motif.

The acid pair hypothesis predicts the calcium affinity of the helix-loop-helix calcium-binding motif based on the number and location of acidic amino acid residues in chelating positions of the calcium-binding loop region. This study investigates the effects of the number and position of acidic residues in the loop region on calcium affinity and selectivity using 33-residue synthetic models of single helix-loop-helix calcium-binding motifs. Increasing the number of acidic residues in the octahedrally arranged chelating positions of the loop region from 3 to 4 by replacing an asparagine in the +y position with an aspartic acid increases the calcium affinity of the models between 2- and 38-fold. Differences in affinities are more pronounced in the models containing an x axis acid pair. The calcium affinities of peptide models containing 3 or 4 acidic residues in chelating positions of the loop region and an x axis acid pair are reduced when the residue in the +z position is changed from asparagine to serine. A similar reduction in calcium affinity occurs in the z axis acid paired peptides when the -x chelating residue is changed from serine to asparagine. Models with 3 acidic residues in chelating positions containing a z axis acid pair have greater calcium affinity than comparable peptide models with an x axis acid pair. The presence of x or z axis acid pairs in comparable peptides containing 4 acidic residues in chelating positions does not greatly alter calcium affinity. Calcium selectivity resides in x axis acid paired peptides, whereas z axis acid paired peptides exhibit both magnesium- and calcium-induced structural changes. This ion selectivity may be explained by postulating that the z axis residue side chains produce the initial, rate-limiting interactions with the cation, causing hydration shell destabilization and initiating the subsequent ligand interactions.

Amino Acid Sequence↗
PubMed1977

Brush border peptidases and arylamidases in the experimental blind loop syndrome of the rat.

Peptidase and arylamidase activities were assessed in purified brush borders from jejunum of rats with surgically created blind loops. The blind loop segment and the jejunum proximal and distal to the blind loop were studied. Comparable jejunal segments from control rats were also studied. The blind loop syndrome was documented by presence of macrocytic anemia. Enzyme activities were determined on purified brush borders. In rats with the blind loop syndromes enzymatic activities hydrolizing sucrose, L-Leucyl-beta-naphthylamide, L-lysyl-beta-naphthylamide, alpha-L-glutamyl-beta-naphthylamide, L-phenylalanyl-alanine and L-leucyl-glycine were significantly reduced as compared to controls (P less than 0.001). After a short course of antibiotic therapy enzymatic activities returned to normal. Our findings suggest a reversible intestinal mucosa damage in the rat with blind loop syndrome.

Aminopeptidases↗
PubMed1999

Subtotal pancreatoduodenectomy: use of a defunctionalized loop for pancreatic stump drainage.

BACKGROUND: Since its introduction, pancreaticoduodenal resection for periampullary cancer has undergone numerous modifications. As a result, there has been a dramatic decline in the mortality rate. However, a high morbidity rate, mainly due to pancreatic fistula formation, is still reported. OBJECTIVE: To evaluate the results of the use of a defunctionalized jejunal loop in patients undergoing pancreatoduodenectomy to minimize both the frequency and severity of anastomotic leak. SETTING: Second Surgical Department, Athens University, Aretaieon Hospital, Athens, Greece. DESIGN: A series of retrospective cases from February 1990 to December 1997. PATIENTS: One hundred five patients who underwent pancreatoduodenectomy and had the pancreatic stump drained in a defunctionalized jejunal loop. METHODS: To avoid problems related to fistula formation due to erosion of the anastomoses from activated pancreatic enzymes, a defunctionalized jejunal loop was constructed and the pancreatic stump was invaginated into the end of this loop. RESULTS: Using the defunctionalized jejunal loop, the mean (+/-SD) hospitalization was 7.57+/-1.42 days, the morbidity rate was 11.2%, and the mortality rate was 0.95%. CONCLUSIONS: A modification of pancreatoduodenectomy for the treatment of pancreatic cancer resulted in an improvement in the immediate results of subtotal pancreatoduodenectomy. Careful detachment of the posterior surface of the pancreas from the anterior surface of the portal vein and performance of pancreaticojejunal anastomosis to a defunctionalized jejunal loop results in lower mortality and morbidity rates, thus making pancreatoduodenectomy a safe procedure.

Adult↗
PubMed1999

Effect of salt-dependent stiffness on the conformation of a stressed DNA loop containing initially coplanar bends.

Closed DNA loops containing one or more bent regions are important structures that occur in the regulation of gene expression. We analyze the response of structures of this type to a change in applied rotation (change in linking deficiency, delta Lk). Our results apply to a closed loop formed from an elastic rod that is intrinsically bent in Nb discrete, 20 degrees steps up to a maximum of 240 degrees, the bent regions being initially coplanar with the plane of the relaxed DNA loop. We determine the effect of changing the intrinsic elastic resistance of the DNA loop to bending and torsional deformations. This relative resistance is expressed by Poisson's ratio v, which depends upon the ratio of bending stiffness to torsional rigidity. Poisson's ratio is primarily a function of salt type and concentration. We find that the tertiary structure of DNA loops changes with delta Lk, but that the geometric response can be either of two quite different types, depending upon the precise (Nb, v) pair. For combinations of Nb and v that are above a critical curve (the Fickel curve), the response to increasing delta Lk is nonmonotonic (NMT region): the distance between the loop closure point and its diametric opposite first decreases, then increases, as delta Lk increases. For combinations of Nb and v that are below the Fickel curve (NMT region), the corresponding diameter never increases, but always decreases with increasing delta Lk. In addition to these results, we define and implement a new measure of tertiary structure in closed DNA: the absolute writhe, AWr.

Animals↗
PubMed2003

T cell receptor CDR3 loop length repertoire is determined primarily by features of the V(D)J recombination reaction.

The third complementarity-determining region (CDR) of the TCR alpha and beta chains forms loops that engage amino acid residues of peptides complexed with MHC. This interaction is central to the specific discrimination of antigenic-peptide-MHC complexes by the TCR. The TCRbeta chain CDR3 loop is encoded by the Dbeta gene segment and flanking portions of the Vbeta and Jbeta gene segments. The joining of these gene segments is imprecise, leading to significant variability in the TCRbeta chain CDR3 loop length and amino acid composition. In marked contrast to other pairing antigen-receptor chains, the TCR beta and alpha chain CDR3 loop size distributions are relatively narrow and closely matched. Thus, pairing of TCR alpha and beta chains with relatively similar CDR3 loop sizes may be important for generating a functional repertoire of alpha beta TCR. Here we show that the TCRbeta chain CDR3 loop size distribution is minimally impacted by TCRbeta chain or alpha beta TCR selection during thymocyte development. Rather, this distribution is determined primarily at the level of variable-region gene assembly, and is critically dependent on unique features of the V(D)J recombination reaction that ensure Dbeta gene segment utilization.

Alleles↗
PubMed1984

Lampbrush chromosome loop-specificity of transcript morphology in spermatocyte nuclei of Drosophila hydei.

The transcript morphology in the lampbrush chromosome loop pairs ;threads' and ;pseudonucleolus' of the Y chromosome in primary spermatocytes of Drosophila hydei has been investigated by the Miller spreading technique. Each loop pair carries giant transcripts with a secondary structure characteristic of the respective loop. The lengths of the transcribed regions are in the range 500-1500 kb or even larger. The results of our experiments are discussed in the context of loop ultrastructure, molecular structure and loop function. The high degree of secondary structure may be required to assemble specifically loop-specific proteins.

Journal Article↗
PubMed1988

Conformational and receptor binding properties of human EGF and TGF-alpha second loop fragments.

The solution conformation of the second loop fragment of human EGF, [Ala20] EGF (14-31), was determined using two-dimensional NMR homonuclear Hartmann-Hahn and rotating frame nuclear Overhauser enhancement spectroscopy. The results are compared with the conformation of the second loop fragment of human TGF-alpha, [Ala21] TGF-alpha(16-32), and with that of the second loop of intact EGF. Comparison of the two experimentally determined structures of the second loop fragments shows significant differences in the turn regions of each peptide. For the EGF fragment, hydrophobic side chain groups protrude away from the ring, whereas for the TGF-alpha fragment hydrophilic groups are directed away from the ring. Although these turn regions represent the putative receptor binding sites, neither second loop fragment binds to the EGF receptor. The biological activity is discussed in terms of the conformational differences found for the two second loop fragments.

Amino Acid Sequence↗
PubMed2005

Mutations on the FG surface loop of human papillomavirus type 16 major capsid protein affect recognition by both type-specific neutralizing antibodies and cross-reactive antibodies.

The aim of this study was to further characterize the conformational neutralizing epitopes present on the surface-exposed FG loop of human papillomavirus (HPV) type 16 L1 major capsid protein. We have generated previously two chimeric L1 proteins by insertion of a foreign peptide encoding an epitope of the hepatitis B core (HBc) antigen within the FG loop. In addition, three other chimeric L1 proteins were obtained by replacing three different FG loop sequences by the HBc motif and three others by point mutations. All these chimeric L1 proteins retained the ability to self-assemble into virus-like particles (VLPs), with the exception of the mutant with substitution of the L1 sequence 274-279 by the HBc motif. The eight chimeric VLPs were then analyzed for differential reactivity with a set of six HPV-16 and HPV-31 monoclonal antibodies that bound to conformational and linear epitopes. The binding patterns of these monoclonal antibodies confirmed that the FG loop contained or contributed to neutralizing conformational epitopes. The results obtained suggested that the H31.F7 antibody, an anti-HPV-31 cross-reacting and neutralizing antibody, recognized a conformational epitope situated before the 266-271 sequence. In addition, H16.E70 neutralizing antibody reactivity was reduced with L1 VLPs with an Asn to Ala point mutation at position 270, suggesting that Asn is a part of the epitope recognized by this antibody. This study contributes to the understanding of the antigenic structure of HPV-16 and -31 L1 proteins by confirming that the FG loop contributes to neutralizing epitopes and suggesting the existence of both type-specific and cross-reactive conformational epitopes within the FG loop.

Antibodies, Monoclonal↗
PubMed1998

Thermodynamic and structural consequences of flexible loop deletion by circular permutation in the streptavidin-biotin system.

A circularly permuted streptavidin (CP51/46) has been designed to remove the flexible polypeptide loop that undergoes an open to closed conformational change when biotin is bound. The original termini have been joined by a tetrapeptide linker, and four loop residues have been removed, resulting in the creation of new N- and C-termini. Isothermal titration calorimetric studies show that the association constant has been reduced approximately six orders of magnitude below that of wild-type streptavidin to 10(7) M(-1). The deltaH degrees of biotin association for CP51/46 is reduced by 11.1 kcal/mol. Crystal structures of CP51/46 and its biotin complex show no significant alterations in the binding site upon removal of the loop. A hydrogen bond between Ser45 and Ser52 found in the absence of biotin is broken in the closed conformation as the side-chain hydroxyl of Ser45 moves to hydrogen bond to a ureido nitrogen of biotin. This is true in both the wild-type and CP51/46 forms of the protein, and the hydrogen bonding interaction might thus help nucleate closure of the loop. The reduced entropic cost of binding biotin to CP51/46 is consistent with the removal of this loop and a reduction in entropic costs associated with loop closure and immobilization. The reduced enthalpic contribution to the free energy of binding is not readily explainable in terms of the molecular structure, as the binding contacts are nearly entirely conserved, and only small differences in solvent accessible surfaces are observed relative to wild-type streptavidin.

Binding Sites↗
PubMed2001

Protein folding: looping from hydrophobic nuclei.

Protein structure can be viewed as a compact linear array of nearly standard size closed loops of 25-30 amino acid residues (Berezovsky et al., FEBS Letters 2000; 466: 283-286) irrespective of details of secondary structure. The end-to-end contacts in the loops are likely to be hydrophobic, which is a testable hypothesis. This notion could be verified by direct comparison of the loop maps with Kyte and Doolittle hydropathicity plots. This analysis reveals that most of the ends of the loops are hydrophobic, indeed. The same conclusion is reached on the basis of positional autocorrelation analysis of protein sequences of 23 fully sequenced bacterial genomes. Hydrophobic residues valine, alanine, glycine, leucine, and isoleucine appear preferentially at the 25-30 residues distance one from another. These observations open a new perspective in the understanding of protein structure and folding: a consecutive looping of the polypeptide chain with the loops ending primarily at hydrophobic nuclei.

Amino Acid Sequence↗