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PubMed1984

Endocrine control of the nasal salt glands in birds.

In birds, adrenocortical hormones probably sustain nasal salt gland (NSG) function, indirectly, through their influence on renal and cardiovascular function. Adrenalectomy blocks the response by duck NSG to hypertonic saline only if the ducks are maintained on freshwater. However, if adrenalectomized ducks are fed 0.9% NaCl ad libitum the NSG secrete fluid and osmolytes at the normal rate. Adrenalectomy did not prevent the significant functional hypertrophy of the NSG that always follows adaptation to saline. Mean arterial blood pressure was lower than normal two days after adrenalectomy. Stroke volume decreased by about 50% but there was a commensurate increase in cardiac frequency, so cardiac output was unchanged. There was no measurable change in total peripheral vascular resistance. There was at least a twentyfold increase in blood flow rate to the NSG when they were actively secreting fluid, but this increase was totally blocked after adrenalectomy. An inadequate supply of blood and not a corticosteroid deficiency in the secretory cells was the primary reason for NSG failure. Single intravenous injections of as little as 28 pm/kg bw of (Asp1,Val5)-angiotensin II (AII) had no measurable effect on mean arterial blood pressure in conscious ducks but did shut off the NSG for about 4 min; then the NSG switched on again. NSG blood flow decreased after AII.

Adrenal Glands↗

PubMed2000

Dextran sulfate sodium-induced murine colitis activates NF-kappaB and increases galanin-1 receptor expression.

Galanin is widely distributed in enteric nerve terminals and acts to modulate intestinal motility by altering smooth muscle contraction. This ligand causes Cl(-) secretion when colonic epithelial cells express the galanin-1 receptor (Gal1-R) subtype. Because Gal1-R expression by colonic epithelia is upregulated by the transcription factor nuclear factor-kappaB (NF-kappaB), increasingly appreciated as critical in the pathophysiology of inflammatory bowel disease, we wondered whether the diarrhea associated with this condition could be due to NF-kappaB-mediated increases in Gal1-R expression. To test this hypothesis, we provided oral dextran sulfate sodium (DSS) to C57BL/6J mice. Although Gal1-R are not normally expressed by epithelial cells lining the mouse colon, DSS treatment resulted in increased NF-kappaB activation and Gal1-R expression. Whereas galanin had no effect on murine colonic tissues studied ex vivo, it progressively increased short-circuit current and colonic fluid secretion in DSS-treated mice. Concomitant parenteral administration of the NF-kappaB inhibitor dexamethasone attenuated the activation of this transcription factor by DSS, inhibiting the increase in Gal1-R expression. Although Gal1-R-specific antagonists do not exist, intracolonic administration of commercially available galanin antibody diminished the DSS-induced increase in colonic fluid accumulation. Overall, these data demonstrate that a significant component of the excessive fluid secretion observed in DSS-treated mice is due to increased Gal1-R expression.

Animals↗

PubMedDate not supplied

Autosomal dominant polycystic kidney disease: clinical and genetic aspects.

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited systemic disease caused by at least three different genes. The renal and extrarenal clinical manifestations, and the systemic complications due to cystic and non-cystic abnormalities in ADPKD patients have been widely investigated. Cellular and molecular aspects of cystogenetic mechanisms concern epithelial tubular cell proliferation, remodelling of extracellular matrix, fluid secretion and accumulation, and relations between cell proliferation and apoptosis. In vitro studies on cystogenesis suggest a key role of cell-to-cell or cell-to-matrix interactions. Surface proteins mediating cell-to-cell contact, such as E-cadherin (polycystin?), integrin interactions, growth factors, receptor expression, are involved in the process of differentiation of the cellular condition and of the extracellular matrix. Blocking any one of these complex mechanisms should influence the orientation and polarization of epithelial tubular cells and should mediate the inversion of fluid secretion which ends in renal cystogenesis. ADPKD comprises at least three phenotypically indistinguishable but genetically distinct entities, caused by mutations in three autosomal genes: PKD1 (chromosome 16p13.3) is present in about 85% of patients; PKD2 (chromosome 4q13q23) in 10%; PKD3 (unknown chromosome) in a few families. PCR-based mutation detection methods, automated DNA sequencing, and other "functional" methods are used to screen and analyse ADPKD patients. It is not yet known whether the mutations identified so far in PKD1 and PKD2 inactivate the genes or generate an aberrant product. The products of PKD1 and PKD2 genes have been called polycystin 1 and 2. Polycystins are members of a family of interactive proteins involved in complex adhesive cell-cell, cell-matrix, protein-protein, and protein-carbohydrate interactions in the extracellular compartment, and are involved in the same pathway (ion channel regulator? ion channel? pore?) where mutations in only one of the simple genes (PKD3 too?) may cause the ADPKD phenotype. Genotype-phenotype correlations, in terms of disease severity and/or progression to end-stage renal disease, probably depend on other factors, both genetic and environmental (for instance: DD genotype of the ACE gene in ADPKD hypertensive patients), that might influence the clinical course and progression of ADPKD. The hypothesis of the "two hits" has been proposed to explain at the molecular level the focal nature of cyst formation.

Genetic Counseling↗

PubMed1986

Enterotoxin production by Salmonella typhimurium strains of different virulence.

Six strains of Salmonella typhimurium (TML, W118, LT7, SL1027, M206 and Thax-1) of known virulence and ability to induce fluid secretion when inoculated into the rabbit ileum were examined for enterotoxin production. Enterotoxic activity, assayed in the rabbit ileal-loop test, was detected in polymyxin-B extracts from all strains (with the possible exception of Thax-1) cultured for 6 h in casamino acid-yeast extract medium. The extracts were inactive in tissue-culture assays with CHO, Y-1 adrenal and Vero cells, and in the infant mouse assay for enterotoxin. There was no correlation between enterotoxigenicity in vitro and the ability of whole organisms to induce fluid secretion in vivo. The significance of these results in relation to salmonellosis is discussed.

Animals↗

PubMed1998

Influence of high-dose pancreatic enzyme treatment on pancreatic function in healthy volunteers.

CONCLUSIONS: Adaptive changes in exocrine and endocrine pancreatic function, as well as changes in pancreas size and morphology, were not observed after 4-wk of oral pancreatic enzyme application. These findings suggest that the normal pancreas does not significantly adapt--either morphologically or functionally--to a 4-wk oral application of high-dose pancreatic enzymes. BACKGROUND: The control of exocrine pancreatic enzyme secretion is not completely understood. Although it has been established that exocrine pancreatic secretion is mainly regulated in the short-term by the amount of pancreatic enzymes in the proximal small intestine, it is not known whether long-term application of pancreatic enzymes causes changes in exocrine pancreatic secretion in humans. METHODS: Twelve healthy male volunteers (median age 27 yr) participated in a prospective, randomized, placebo-controlled, double-blind study. Six were placed in the treatment group and six in the placebo group. Over a 4-wk period, the six subjects in the treatment group took 18 capsules of Panzytrat (20,000 units of lipase, 18,000 units of amylase, and 1000 units of protease per capsule) daily. Before (wk 0), 4 wk following pancreatic enzyme application and 2 wk afterward, a secretin-cerulein test was carried out in all subjects to study exocrine pancreatic function (trypsin, chymotrypsin, bicarbonate content, and total pancreatic fluid secretion in the duodenum). One day following the secretin-cerulein test, a standard test meal was given to all subjects to analyze endocrine pancreatic function. Additionally, before starting the treatment, once per week during treatment and 2 wk afterward, an ultrasound examination of the pancreas was carried out to see whether there was any change in pancreas size and morphology. RESULTS: Trypsin content in the duodenal aspirates following simultaneous stimulation with secretin and cerulein after 4 wk of high-dose pancreatic enzyme application was 92% in the treatment group and 82% in the placebo group compared with the wk 0 test results (100%). Two weeks after enzyme application, the secretin/cerulein-stimulated trypsin content was 88% in the treatment group and 107% in the placebo group. None of these changes was statistically significant. The same results were seen for chymotrypsin content, amylase, and bicarbonate content as well as for total pancreatic fluid secretion. Additionally, no change in the endocrine pancreatic function could be observed after 4 wk of pancreatic enzyme treatment. Pancreas ultrasonography revealed no alteration in pancreas size or parenchymal structure during the 4 wk of treatment and the following 2 wk.

Adaptation, Physiological↗

PubMed1997

Identification of an active site in the antisecretory factor protein.

The antisecretory factor (AF) is a new regulatory protein, produced in the human pituitary gland, which reverses intestinal fluid secretion induced by cholera toxin. We have previously described the cDNA-cloning and characterization of the expressed gene. The aim of this study was to identify the region responsible for the antisecretory activity in the AF-molecule. The recombinant full-length AF has an increased ability to inhibit hypersecretion after treatment with trypsin, indicating that the activity of AF is achieved by smaller peptide fragments. To localize the active region of AF, we expressed truncated forms of the recombinant protein and examined their antisecretory activity against cholera toxin-induced fluid secretion in rat. Nine recombinant AF peptides and four smaller peptides made by solid phase synthesis were tested. Five of the peptides lacked all activity, whereas seven of them were highly active, a dose between 4 and 15 pmol causing a half-maximal inhibition. All the active peptides contained amino acid 36-42 of the AF sequence, whereas none of the inactive peptides contained this sequence. Our results suggest that the site of the antisecretory activity resides in a small region (I)VCHSKTR between position 35 and 42 of the AF molecule.

Amino Acid Sequence↗

PubMed1998

Freezing survival by isolated Malpighian tubules of the New Zealand alpine weta Hemideina maori.

The ability of isolated Malpighian tubules from a freeze-tolerant insect, the New Zealand alpine weta (Hemideina maori), to withstand freezing was assessed by measuring post-freeze membrane potentials and rates of fluid secretion. The hemolymph of cold-acclimated Hemideina maori was found to contain relatively high concentrations of the cryoprotectants trehalose (>300 mmol l-1) and proline (41 mmol l-1). Survival of isolated Malpighian tubules was correspondingly high when a high concentration of trehalose was present in the bathing saline. Tubules allowed to recover for 20 min from a 1 h freeze to -5 degrees C in saline containing 400 mmol l-1 trehalose had a basolateral membrane potential of -53 mV compared with a potential of -63 mV in tubules not exposed to a freeze/thaw cycle. Fluid secretion in tubules that had experienced a freeze/thaw cycle in saline containing 400 mmol l-1 trehalose was 9.9+/-2.6 nl h-1 compared with 18.7+/-5.0 nl h-1 (means +/- s.e.m., N=18) in tubules that had not been frozen. Tubules frozen in saline containing a lower concentration of trehalose (200 mmol l-1) or in glucose (400 mmol l-1) showed a similar ability to survive freezing to -5 degrees C. In contrast, freezing for 1 h at -5 degrees C in saline containing 400 mmol l-1 sucrose produced a 57 % decrease in membrane potential and an 88 % decrease in secretion rate. Tubules held in saline lacking high concentrations of sugars showed no survival after freezing to -5 degrees C for 1 h. When frozen to -15 degrees C, tubules appeared to survive best in saline with the highest trehalose concentration (400 mmol l-1). Freezing damage was not simply the result of exposure to cold, since tubules chilled (unfrozen) to -5 degrees C for 1 h were not compromised even when the bathing saline lacked a high sugar concentration. Exposure of tubules to a combination of low temperature and high osmolality mimicked damage caused by actual freezing: the membrane potential showed a 60 % recovery when the test was performed in saline containing trehalose, but showed no recovery in saline containing sucrose.

Amino Acids↗

PubMed2005

GCK-3, a newly identified Ste20 kinase, binds to and regulates the activity of a cell cycle-dependent ClC anion channel.

CLH-3b is a Caenorhabditis elegans ClC anion channel that is expressed in the worm oocyte. The channel is activated during oocyte meiotic maturation and in response to cell swelling by serine/threonine dephosphorylation events mediated by the type 1 phosphatases GLC-7alpha and GLC-7beta. We have now identified a new member of the Ste20 kinase superfamily, GCK-3, that interacts with the CLH-3b COOH terminus via a specific binding motif. GCK-3 inhibits CLH-3b in a phosphorylation-dependent manner when the two proteins are coexpressed in HEK293 cells. clh-3 and gck-3 are expressed predominantly in the C. elegans oocyte and the fluid-secreting excretory cell. Knockdown of gck-3 expression constitutively activates CLH-3b in nonmaturing worm oocytes. We conclude that GCK-3 functions in cell cycle- and cell volume-regulated signaling pathways that control CLH-3b activity. GCK-3 inactivates CLH-3b by phosphorylating the channel and/or associated regulatory proteins. Our studies provide new insight into physiologically relevant signaling pathways that control ClC channel activity and suggest novel mechanisms for coupling cell volume changes to cell cycle events and for coordinately regulating ion channels and transporters that control cellular Cl- content, cell volume, and epithelial fluid secretion.

Animals↗

PubMed1976

Sequence of events in the activation of adenylate cyclase by cholera toxin.

The toxin of Vibrio Cholera causes fluid secretion from the small intestine by stimulation of adenylate cyclase and elevation of intracellular cyclic AMP concentrations. The toxin is a protein composed of subunits responsible for binding to cell membranes and a subunit responsible for the activation of adenylate cyclase. The binding subunits (B) are non-covalently bonded to the active subunit (A). The latter is composed of two polypeptides A1 and A2 linked by a disulphide bridge. Exposure of the intestine to toxin results in rapid binding to the brush border membrane. Thence follows a gradual increase in adenylate cyclase activity, and stimulation of electrolyte and fluid secretion. Enzyme localization studies show that the brush border does not contain adenylate cyclase. Thus the stimulation of adenylate cyclase by toxin which interacts with the brush border must be indirect. From recent studies it seems that an activator of adenylate cyclase can be found in cytosol from toxin-treated cells. Incubation of toxin with cytosol or dithiothreitol results similarly in the formation of an activator. Preincubation of toxin with cytosol results in more rapid activation of adenylate cyclase in liver cell membranes than direct addition of cytosol and toxin. Preincubation of cholera toxin for activation, by cytosol, is presumed to be due to the splitting of the disulphide band between the A1 and A2 components of the active subunit. The stimulatory ability resides in A1 and both A1 and NAD are required for the activation of adenylate cyclase. The toxin-stimulated adenylate cyclase has similar characteristics to the enzyme stimulated by non-hydrolysable analogs of GTP such as guanylylimidodiphosphate (GppNHp). Stimulation by either cholera or GppNHp is irreversible, the responses to catecholamines are enhanced and the enzyme can be solubilized in the activated state.

Adenylyl Cyclases↗

PubMed1991

Oscillations of cytosolic sodium during calcium oscillations in exocrine acinar cells.

In acinar cells from rat salivary glands, cholinergic agonists cause oscillations in cytoplasmic free calcium concentration, which then drive oscillations of cell volume that reflect oscillating cell solute content and fluid secretion. By quantitative fluorescence ratio microscopy of an intracellular indicator dye for sodium, it has now been shown that large amplitude oscillations of sodium concentration were associated with the calcium and cell volume oscillations. Both calcium and sodium oscillations were dependent on the continued presence of calcium in the extracellular medium and were abolished by the specific sodium-potassium adenosine triphosphatase inhibitor ouabain. Thus, calcium oscillations in salivary acinar cells, by modulating the activities of ion transport pathways in the plasma membrane, can cause significant oscillations of monovalent ions that may in turn feed back to regulate calcium oscillations and fluid secretion.

Animals↗

PubMed1998

CGRP upregulation in dorsal root ganglia and ileal mucosa during Clostridium difficile toxin A-induced enteritis.

We have previously reported that pretreatment of rats with capsaicin (an agent that ablates sensory neurons) or CP-96345 (a substance P receptor antagonist) dramatically inhibits fluid secretion and intestinal inflammation in ileal loops exposed to Clostridium difficile toxin A. The aim of this study was to determine whether calcitonin gene-related peptide (CGRP), a neuropeptide also found in sensory afferent neurons, participates in the enterotoxic effects of toxin A. Administration of toxin A was also found to increase CGRP content in dorsal root ganglia and ileal mucosa 60 min after toxin exposure. Furthermore, immunohistochemical studies demonstrated increased neuronal staining for CGRP 2 h after toxin A treatment. Pretreatment of rats with CGRP-(8-37), a specific CGRP antagonist, before instillation of toxin A into ileal loops significantly inhibited toxin-mediated fluid secretion (by 48%), mannitol permeability (by 83%), and histological damage. We conclude that CGRP, like substance P, contributes to the secretory and inflammatory effects of toxin A via increased production of this peptide from intestinal nerves, including primary sensory afferent neurons.

Animals↗

PubMed2025

Loss of STIM1 and STIM2 in Salivary Glands Disrupts ANO1 Function but Does Not Induce Sjogren's Disease.

Ca2+ signaling via the store-operated Ca2+ entry (SOCE) mediated by STIM1 and STIM2 proteins and the ORAI1 Ca2+ channel is important in saliva fluid secretion and has been associated with Sjogren's disease (SjD). However, there are no studies addressing STIM1/2 dysfunction in salivary glands or SjD in animal models. We report that mice lacking Stim1 and Stim2 [Stim1/2K14Cre(+)] in salivary glands exhibited reduced Ca2+ levels and hyposalivate. SOCE was functionally required for the activation of the Ca2+ activated Cl- channel ANO1. Ageing Stim1/2K14Cre(+) mice showed no evidence of lymphocytic infiltration or increased levels of autoantibodies characteristic of SjD, possibly associated with a downregulation of toll-like receptor 8 (Tlr8) expression. Salivary gland biopsies of SjD patients showed increased expression of STIM1 and TLR7/8. Our study shows that SOCE activates ANO1 function and fluid secretion in salivary glands and highlights a potential link between SOCE and TLR signaling in SjD.

Stromal Interaction Molecule 1↗

PubMed1999

Isolation, characterization and biological activity of a diuretic myokinin neuropeptide from the housefly, Musca domestica.

A competitive ELISA employing a polyclonal antiserum raised against leucokinin-I was used to isolate and purify a myokinin (muscakinin) from 1.05 kg of adult houseflies (Musca domestica). Following solid-phase purification, seven HPLC column steps were used to purify 4.8 nmol of leucokinin-immunoreactive material. Sequence analysis and mass spectrometry were consistent with the structure Asn-Thr-Val-Val-Leu-Gly Lys-Lys-Gln-Arg-Phe-His-Ser-Trp-Gly NH2. This peptide was synthesized and co-eluted with the natural peptide on three different HPLC columns. The activities of natural and synthetic muscakinin were identical, with both producing a 4-5 fold increase in fluid secretion by housefly Malpighian tubules at nanomolar concentrations. The presence of a pair of basic residues (Lys-Lys) suggested muscakinin might be processed further, with the peptide pGlu-Arg-Phe-His-Ser-Trp-Gly NH2 being produced by conversion of an N-terminal glutamine to pyroglutamic acid. However, this analog was 1000-fold less active than the intact peptide, comparable to the activity of AK-V which shares the same C-terminal pentapeptide sequence. The diuretic activity of muscakinin is more than double that of a previously identified CRF-related diuretic peptide (Musca-DP) from the housefly, and the two peptides act synergistically in stimulating fluid secretion. Muscakinin also increased the frequency and amplitude of contractions by housefly hindgut which might further contribute to the excretory process.

Amino Acid Sequence↗

PubMed1986

Effects of taurodeoxycholate on in vivo water and solute transport in rat jejunum in absence and presence of calcium.

Bile acids and fatty acids enhance the permeability of brush-border membrane vesicles for calcium. It has been postulated that increased influx of calcium into the enterocyte might be responsible for the fluid secretion induced by dihydroxy bile acids and fatty acids. During in vivo perfusion studies of the rat jejunum, 15 mM taurodeoxycholate induced secretion of electrolytes and water (P less than 0.001), reduced glucose absorption (P less than 0.001), and enhanced the absorption of mannitol (P less than 0.0125) and calcium (P less than 0.001). Calcium absorption continued to be enhanced during perfusion of a CaCl2-containing solution following the perfusion with taurodeoxycholate (P less than 0.05). In view of the previously demonstrated enhanced permeability of the apical brush-border membrane in the presence of bile acids, it is very likely that some calcium enters the enterocyte along the steep concentration gradient in the presence of taurodeoxycholate. In spite of enhanced calcium absorption, 15 mM CaCl2 had no effect on control absorption rates or on fluid secretion induced by taurodeoxycholate. The data indicate that the effects of bile acids on intestinal transport are not mediated by an influx of calcium into the enterocyte.

Absorption↗

PubMed2001

Absence of all components of the flagellar export and synthesis machinery differentially alters virulence of Salmonella enterica serovar Typhimurium in models of typhoid fever, survival in macrophages, tissue culture invasiveness, and calf enterocolitis.

In this study, we constructed an flhD (the master flagellar regulator gene) mutant of Salmonella enterica serovar Typhimurium and compared the virulence of the strain to that of the wild-type strain in a series of assays that included the mouse model of typhoid fever, the mouse macrophage survival assay, an intestinal epithelial cell adherence and invasion assay, and the calf model of enterocolitis. We found that the flhD mutant was more virulent than its parent in the mouse and displayed slightly faster net growth between 4 and 24 h of infection in mouse macrophages. Conversely, the flhD mutant exhibited diminished invasiveness for human and mouse intestinal epithelial cells, as well as a reduced capacity to induce fluid secretion and evoke a polymorphonuclear leukocyte response in the calf ligated-loop assay. These findings, taken with the results from virulence assessment assays done on an fljB fliC mutant of serovar Typhimurium that does not produce flagellin but does synthesize the flagellar secretory apparatus, indicate that neither the presence of flagella (as previously reported) nor the synthesis of the flagellar export machinery are necessary for pathogenicity of the organism in the mouse. Conversely, the presence of flagella is required for the full invasive potential of the bacterium in tissue culture and for the influx of polymorphonuclear leukocytes in the calf intestine, while the flagellar secretory components are also necessary for the induction of maximum fluid secretion in that enterocolitis model. A corollary to this conclusion is that, as has previously been surmised but not demonstrated in a comparative investigation of the same mutant strains, the mouse systemic infection and macrophage assays measure aspects of virulence different from those of the tissue culture invasion assay, and the latter is more predictive of findings in the calf enterocolitis model.

Animals↗

PubMed2004

Essential involvement of IFN-gamma in Clostridium difficile toxin A-induced enteritis.

Clostridium difficile has emerged as the important causative agent of antibiotics-associated pseudomembranous colitis; especially its toxin A is presumed to be responsible for the colitis. We examined the pathophysiological roles of IFN-gamma in toxin A-induced enteritis using IFN-gamma knockout (KO) mice. When toxin A of C. difficile was injected into the ileal loops of BALB/c wild-type (WT) mice, massive fluid secretion, disruption of intestinal epithelial structure, and massive neutrophil infiltration developed within 4 h after the injection. IFN-gamma protein was faintly detected in some CD3-positive lymphocytes in the lamina propria and submucosa of the ileum of untreated WT mice. On the contrary, at 2 and 4 h after toxin A injection, IFN-gamma protein was detected in infiltrating neutrophils and to a lesser degree in CD3-positive lymphocytes. In the ileum of WT mice, toxin A treatment markedly enhanced the gene expression of TNF-alpha, macrophage inflammatory protein-1alpha and -2, KC, and ICAM-1 >2 h after treatment. In contrast, the histopathological changes were marginal, without enhanced fluid secretion in the ileum of toxin A-treated IFN-gamma KO mice. Moreover, toxin A-induced gene expression of TNF-alpha, neutrophil chemotactic chemokines, and ICMA-1 was remarkably attenuated in IFN-gamma KO mice. Furthermore, pretreatment of WT mice with a neutralizing anti-IFN-gamma Ab prevented toxin A-induced enteritis. These observations indicate that IFN-gamma is the crucial mediator of toxin A-induced acute enteritis and suggest that IFN-gamma is an important molecular target for the control of C. difficile-associated pseudomembranous colitis.

Animals↗

PubMed1991

Effects of somatostatin analog SMS 201-995 on enterotoxigenic diarrhea.

Somatostatin analog SMS 201-995 causes a dose-related suppression of the release and/or action of several gastrointestinal hormones and impairs several anterior pituitary functions. Some patients with illness involving abnormal hormonal activity have responded to treatment with SMS 201-995, including resolution of severe secretory diarrhea. This study examined SMS 201-995 inhibition of Escherichia coli heat-stable enterotoxin STa (STa) effects and effects of the analog in the rabbit RITARD model with enterotoxigenic Escherichia coli. SMS 201-995 did not alter STa binding to its receptor on piglet brush border membranes. The analog, at concentrations of 0.1 micrograms/ml (0.1 microM) and 1 microgram/ml (1 microM) did not significantly alter STa activation of intestinal epithelial cell particulate guanylate cyclase. At maximal dosing the analog significantly reduced intestinal fluid secretion in suckling mice that was induced by either 8-bromo cyclic GMP or STa. In piglets, the analog reduced by 37-44% the amount of diarrhea induced by STa. However, even with maximal dosing, the piglets still had significant diarrhea, although of a lesser amount. In the rabbit RITARD model the drug failed to alter the severe diarrheal response seen when dosing the animals with enterotoxigenic Escherichia coli. Overall, SMS 201-995 had a significant but incomplete effect in reducing the STa effects seen in the various assays. Additionally, in the RITARD model the analog did not alter the clinical responses to various enterotoxigenic bacteria. SMS 201-995 should be useful as a probe into the mechanisms involved in intestinal fluid secretion, but a clinical role in enterotoxigenic gastrointestinal disease was not supported by this study.

Animals↗

PubMed1986

Peptide nature of two mosquito natriuretic factors.

High-pressure liquid chromatography (HPLC) of saline extracts of Aedes aegypti heads yields three fractions (from a total of 108) that affect transepithelial voltage and/or fluid secretion in isolated Aedes Malpighian tubules. In this study we investigated the physical and chemical nature of the active materials in these fractions. Gel-filtration chromatography revealed that the molecular weights of the three fractions were between 1,900 and 2,700. To test their thermostability the fractions were repeatedly frozen and thawed over a period of 110 days without loss of biological activity. Boiling at 100 degrees C for 5 min failed to significantly reduce their biological effects in isolated Malpighian tubules. In contrast, treatment with the proteolytic enzyme mixture, pronase, destroyed activity in all three. Fraction I no longer depolarized the transepithelial voltage of in vitro perfused Malpighian tubules, and fractions II and III completely lost their ability to stimulate fluid secretion and to affect transepithelial voltage. We conclude that our HPLC isolation yields a heterogeneous group of three polar low-molecular weight peptides. Expression of their biological activities in Malpighian tubules depends on intact peptide bonds.

Aedes↗