Evidence for lack of a role of cGMP in effect of alpha-hANP on aldosterone inhibition

1987 ◽  
Vol 252 (5) ◽  
pp. E643-E647 ◽  
Author(s):  
H. Matsuoka ◽  
M. Ishii ◽  
Y. Hirata ◽  
K. Atarashi ◽  
T. Sugimoto ◽  
...  
Keyword(s):  
Inhibitory Effect ◽  
Minor Role ◽  
Dependent Manner ◽  
Free Medium ◽  
Adrenal Cells ◽  
Aldosterone Production ◽  
A Minor ◽  
Dose Dependent ◽  
Derivatives Of

To investigate the role of guanosine 3',5'-cyclic monophosphate (cGMP) in the inhibitory effect on aldosterone production of alpha-human atrial natriuretic polypeptide (alpha-hANP) we first compared the effects of the peptide with those of sodium nitroprusside (SNP) on the production of aldosterone and cGMP in dispersed adrenal capsular cells of rats, second, examined the effects of derivatives of cGMP on the production of aldosterone, and, third, studied the influence of potassium on the effects of alpha-hANP on the production of aldosterone and cGMP. alpha-hANP at concentrations of 3 X 10(-8) to 3 X 10(-7) M decreased the production of aldosterone in a dose-dependent manner, while markedly increasing the production of cGMP. On the other hand, although SNP at concentrations of 10(-5) to 10(-3) M increased the production of cGMP in a dose-dependent manner, it caused no significant changes in the production of aldosterone. Neither dibutyryl cGMP nor 8-bromo-cGMP affected the production of aldosterone in the adrenal cells. Although the aldosterone-inhibitory effect of alpha-hANP was lost in the potassium-free medium, the cGMP-stimulatory effect of the peptide was not altered by adding potassium to the incubation medium at concentrations of 0-5 meq/l. These results suggest that cGMP plays a minor role in the inhibitory effect of alpha-hANP on the production of aldosterone and that the production of cGMP stimulated by the peptide is not directly involved in the decrease in aldosterone production in adrenal capsular cells of rats.

L-type calcium channels in the renal microcirculatory response to endothelin

2005 ◽  
Vol 288 (4) ◽  
pp. F771-F777 ◽  
Author(s):  
David M. Pollock ◽  
John M. Jenkins ◽  
Anthony K. Cook ◽  
John D. Imig ◽  
Edward W. Inscho
Keyword(s):  
Rat Kidney ◽  
Inhibitory Effect ◽  
Minor Role ◽  
Channel Blockade ◽  
Drug Infusion ◽  
Vasoconstrictor Response ◽  
A Minor ◽  
Dose Dependent ◽  
Arteriolar Diameter

The signaling pathways of endothelin (ET)-1-mediated vasoconstriction in the renal circulation have not been elucidated but appear to be distinct between ETA and ETB receptors. The purpose of this study was to determine the role of L-type Ca2+ channels in the vasoconstrictor response to ET-1 and the ETB receptor agonist sarafotoxin 6c (S6c) in the rat kidney. Renal blood flow (RBF) was measured with an ultrasonic flow probe in anesthetized rats, and a microcatheter was inserted into the renal artery for drug infusion. All rats were given vehicle (0.9% NaCl) or three successive bolus injections (1, 10, and 100 pmol) of ET-1 or S6c at 30-min intervals ( n = 6 in each group). ET-1 and S6c produced dose-dependent decreases in RBF. The Ca2+ channel blocker nifedipine (1.5 μg) significantly attenuated the RBF response only at the highest doses of ET-1 and S6c. In the isolated blood-perfused juxtamedullary nephron preparation, Ca2+ channel blockade with diltiazem had a very small inhibitory effect on ET-1-induced decreases in afferent arteriolar diameter only at the lowest concentrations of ET-1. In vascular smooth muscle cells isolated from preglomerular vessels, ET-1 produced a typical biphasic Ca2+ response, whereas S6c had no effect on cytosolic Ca2+. Furthermore, Ca2+ channel blockade (diltiazem or Ni2+) had no effect on the peak or sustained increase in cytosolic Ca2+ produced by ET-1. These results support the hypothesis that L-type Ca2+ channels play only a minor role in the constrictor responses to ET-1 in the renal microcirculation.

scholarly journals Effect of nitric oxide on rat adrenal zona fasciculata steroidogenesis

1998 ◽  
Vol 158 (2) ◽  
pp. 197-203 ◽  
Author(s):  
CB Cymeryng ◽  
LA Dada ◽  
EJ Podesta
Keyword(s):  
Nitric Oxide ◽  
Inhibitory Effect ◽  
Adrenocortical Function ◽  
Zona Fasciculata ◽  
Dependent Manner ◽  
Adrenal Cells ◽  
Corticosterone Secretion ◽  
Adrenal Zona Fasciculata ◽  
Dose Dependent

The present study was designed to investigate the role of nitric oxide (NO) in the regulation of adrenocortical function. Different NO donors, such as sodium nitroprusside (SNP), S-nitroso-L-acetyl penicillamine, diethylamine/NO complex sodium salt and diethylenetriamine NO adduct, significantly decreased corticosterone production both in unstimulated and in corticotropin-stimulated zone fasciculata adrenal cells, in a dose-dependent manner. The effect of SNP was reversed by ferrous hemoglobin. A selective inhibitor of NO synthase, L-NG-nitro-arginine significantly increased corticosterone secretion. The effect of SNP was not mediated by cGMP as permeable cGMP analogs did not reproduce its inhibitory effect. SNP significantly inhibited the steroidogenesis stimulated by 8Br-cAMP and 22(R)-OH-cholesterol, but was ineffective when corticosterone was produced in the presence of exogenously added pregnenolone. Moreover, the conversion of [3H]cholesterol to [3H]pregnenolone and the production of pregnenolone or progesterone (assessed by RIA) were significantly decreased by SNP. Taken together, these results suggest that NO may be a negative modulator of adrenal zona fasciculata steroidogenesis.

Role Of Cyclic Amp In The Inhibition Of Human Platelet Functions By Quercetin, A Flav0N0Id That Potentiates PGI2 Effect

1981 ◽  
Author(s):  
J P Cazenave ◽  
A Beretz ◽  
A Stierlé ◽  
R Anton
Keyword(s):  
Maximum Level ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Pde Inhibitors ◽  
Pde Inhibition ◽  
Induced Aggregation ◽  
Camp Levels ◽  
Dose Dependent

Injury to the endothelium (END) and subsequent platelet (PLAT)interactions with the subEND are important steps in thrombosis and atherosclerosis. Thus,drugs that protect the END from injury and also inhibit PLAT function are of interest. It has been shown that some flavonoids(FLA), a group of compounds found in plants, prevent END desquamation in vivo, inhibit cyclic nucleotide phosphodiesterases(PDE)and inhibit PLAT function. We have studied the structure-activity relationships of 13 purified FLA on aggregation and secretion of 14c-5HT of prelabeled washed human PLAT induced by ADP, collagen(COLL) and thrombin(THR). All the FLA were inhibitors of the 3 agents tested. Quercetin(Q), was the second best after fisetin. It inhibited secretion and aggregation with I50 of 330µM against 0.1 U/ML.THR, 102µM against 5µM ADP and 40 µM against COLL. This inhibitory effect is in the range of that of other PDE inhibitors like dipyridamole or 3-isobutyl-l- methylxanthine. The aggregation induced by ADP, COLL and THR is at least mediated by 3 mechanisms that can be inhibited by increasing cAMP levels. We next investigated if Q, which is a PDE inhibitor of bovine aortic microsomes,raises PLAT cAMP levels. cAMP was measured by a protein-binding method. ADP- induced aggregation(5µM) was inhibited by PGI2 (0.1 and 0.5 nM) . Inhibition was further potentiated(l.7 and 3.3 times) by lOµM Q, which alone has no effect on aggregation. The basal level of cAMP(2.2 pmol/108PLAT) was not modified by Q (50 to 500µM). Using these concentrations of Q,the rise in cAMP caused by PGI2(0.1 and 0.5nM) was potentiated in a dose dependent manner. Q potentiated the effect of PGI2 on the maximum level of cAMP and retarded its breakdown. Thus Q and possibly other FLA could inhibit the interaction of PLAT with the components of the vessel wall by preventing END damage and by inhibiting PLAT function through a rise in cAMP secondary to PDE inhibition and potentiation of the effect of vascular PGI2 on PLAT adenylate cyclase.

The BAFF Inhibitor AMG523 Blocks Adhesion and Survival of Human Multiple Myeloma Cells in the Bone Marrow Microenvironment: Clinical Implication.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3452-3452 ◽  
Author(s):  
Yu-Tzu Tai ◽  
Jiangchun Xu ◽  
Xian-Feng Li ◽  
Iris Breitkreutz ◽  
Klaus Podar ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Survival ◽  
Mononuclear Cells ◽  
Flow Cytometric Analysis ◽  
Inhibitory Effect ◽  
Bone Marrow Microenvironment ◽  
Minor Role ◽  
Dependent Manner ◽  
Growth And Survival

Abstract We previously identified a role of B-cell activating factor (BAFF), a member of the tumor necrosis factor superfamily, in localization and survival of MM cells in the BM microenvironment (Cancer Res2006, 66:6675–82). In the present study, we examined the potential therapeutic utility of the BAFF inhibitor, AMG523, for treating human MM using MM lines, either sensitive or resistant to conventional chemotherapy, as well as freshly isolated patient MM cells, in the presence or absence of bone marrow stromal cells (BMSCs). AMG523 induces modest cytotoxicity in MM cell lines and patient MM cells, suggesting a minor role of autocrine mechanism of BAFF for MM growth and survival. In the presence of BMSCs, AMG523 significantly decreased growth and survival in dexamethasone (Dex)-sensitive MM1S, Dex-resistant MM1R, INA6 MM cells and in patient MM cells (n=7), in a dose-dependent manner (0.1–10 μg/ml). BAFF-augmented MM adhesion to BMSCs is also blocked by AMG523 at 0.1 mg/ml in MM lines (MM1S, 28PE, INA6), as well as in freshly isolated patient MM cells (n=4). BAFF protects MM cells against dex- and lenalidomide-induced cytotoxicity; conversely, AMG523 blocks BAFF-induced protection against drug-induced apoptosis. Importantly, pretreatment of AMG523 blocks BAFF-induced activation of AKT, nuclear factor kB, and ERK in MM cells, confirming its inhibitory effect on BAFF-mediated adhesion and survival. We next asked whether AMG523 enhances Dex-, bortezomib-, Lenalidomide-induced MM cell cytotoxicity. AMG523 augments the inhibitory effect of Dex and lenalidomide in patient MM cells in the presence of BMSCs. Since osteoclasts (OCLs) secrete BAFF in the bone marrow microenvironment, we further asked whether AMG523 inhibits protection by MM-OCL interaction. OCLs were derived from peripheral blood mononuclear cells from MM patients after 2-week culture with M-CSF and RANKL, and MM cells were added in the presence or absence of AMG523. OCLs significantly increased MM cell survival, evidenced by annexin V and PI staining followed by flow cytometric analysis; conversely, AMG523 blocked MM cell survival by coculture with OCLs. Taken together, our data demonstrate that the novel therapeutic AMG523 blocks the interaction between BAFF and its receptors in human MM, thereby providing the rationale for clinical trials of AMG523 to improve patient outcome in MM.

Effects of corticostatin-I on rat adrenal cells in vitro

1990 ◽  
Vol 125 (2) ◽  
pp. 287-292 ◽  
Author(s):  
T. Tominaga ◽  
J. Fukata ◽  
Y. Naito ◽  
Y. Nakai ◽  
S. Funakoshi ◽  
...  
Keyword(s):  
Specific Binding ◽  
Corticosterone Level ◽  
Inhibitory Effect ◽  
Zona Glomerulosa ◽  
Dependent Manner ◽  
Minimum Effective Concentration ◽  
Adrenal Cells ◽  
Aldosterone Production ◽  
The Media

ABSTRACT We have examined the mechanism by which corticostatin-I (CS-I) acts to attenuate ACTH-induced steroidogenesis in rat adrenal cells. CS-I inhibited ACTH-induced corticosterone production in a dosedependent manner, without any effects on the basal corticosterone level in adrenal cells. When the cells were stimulated by 100 pg ACTH/ml, the minimum effective concentration of CS-I was 100 ng/ml, and 0.3–1.0 μg CS-I/ml produced a 50% reduction of the stimulated corticosterone production. The inhibitory effect of CS-I on ACTH-stimulated corticosterone production became apparent within 15 min of incubation, and the effect was reversed quickly by the removal of CS-I from the media. CS-I had no effect on angiotensin II-stimulated aldosterone production by adrenal zona glomerulosa cells. CS-I also did not affect cyclic AMP- or forskolin-stimulated corticosterone production. In an in-vitro binding study using 125I-labelled CS-I, CS-I showed considerable specific binding to rat adrenal cells, and the binding competed with ACTH in a dose-dependent manner. These experiments suggest that CS-I competes with ACTH on their binding sites and exerts an inhibitory effect on the adrenal cells. Journal of Endocrinology (1990) 125, 287–292

Role of Intracellular Ca2+Stores in the Inhibitory Effect of Halothane on Airway Smooth Muscle Contraction 

1998 ◽  
Vol 89 (1) ◽  
pp. 165-173 ◽  
Author(s):  
Michiaki Yamakage ◽  
Shinji Kohro ◽  
Takashi Matsuzaki ◽  
Hideaki Tsuchida ◽  
Akoyoshi Namiki
Keyword(s):  
Smooth Muscle ◽  
Sarcoplasmic Reticulum ◽  
Airway Smooth Muscle ◽  
Muscle Tension ◽  
Inhibitory Effect ◽  
Intracellular Concentration ◽  
Dependent Manner ◽  
Release Channel ◽  
Dose Dependent

Background Halothane directly inhibits contraction of airway smooth muscle, mainly by decreasing the intracellular concentration of free Ca2+ ([Ca2+]i). The role of intracellular Ca2+ stores, sarcoplasmic reticulum, is still unclear. We investigated the role of sarcoplasmic reticulum in the inhibitory effect of halothane on contraction of airway smooth muscle by measuring [Ca2+]i and intracellular concentration of inositol 1,4,5-triphosphate ([IP3]i), a second messenger for release of Ca2+ from sarcoplasmic reticulum. Methods [Ca2+]i was monitored by measuring the 500-nm light emission ratio (F340/F380) of a Ca2+ indicator fura-2 with isometric tension of canine tracheal smooth muscle strip. During Ca2+-free conditions, carbachol (10(-5) M) was introduced with pretreatment of halothane (0-3%). During Ca2+-free conditions, 20 mM caffeine, a Ca2+-induced Ca2+ release channel opener, was introduced with or without halothane. We measured [IP3]i during exposure to carbachol and halothane by radioimmunoassay technique. Results Pretreatment with halothane significantly diminished carbachol-induced increases in [Ca2+]i by 77% and muscle tension by 83% in a dose-dependent manner. Simultaneous administration of halothane significantly enhanced caffeine-induced transient increases in [Ca2+]i and muscle tension in a dose-dependent manner, by 97% and 69%, respectively. Pretreatment with halothane abolished these responses. Rapid increase in [IP3]i produced by carbachol was significantly inhibited by 32% by halothane in a dose-dependent manner. Conclusions Halothane, during Ca2+-free conditions, inhibits transient contraction of airway smooth muscle induced by muscarinic receptor stimulation, mainly by attenuating the increase in [Ca2+]i. Depletion of Ca2+ from sarcoplasmic reticulum via Ca2+-induced Ca2+ release channels also may contribute to the attenuation of the increase in [Ca2+]i by halothane.

scholarly journals σB Modulates Virulence Determinant Expression and Stress Resistance: Characterization of a Functional rsbU Strain Derived from Staphylococcus aureus 8325-4

2002 ◽  
Vol 184 (19) ◽  
pp. 5457-5467 ◽  
Author(s):  
Malcolm J. Horsburgh ◽  
Joanne L. Aish ◽  
Ian J. White ◽  
Les Shaw ◽  
James K. Lithgow ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Minor Role ◽  
Gene Encoding ◽  
Phenotypic Properties ◽  
Relative Level ◽  
General Stress Response ◽  
A Minor ◽  
Derivatives Of

ABSTRACT The accessory sigma factor σB controls a general stress response that is thought to be important for Staphylococcus aureus survival and may contribute to virulence. The strain of choice for genetic studies, 8325-4, carries a small deletion in rsbU, which encodes a positive regulator of σB activity. Consequently, to enable the role of σB in virulence to be addressed, we constructed an rsbU + derivative, SH1000, using a method that does not leave behind an antibiotic resistance marker. The phenotypic properties of SH1000 (8325-4 rsbU +) were characterized and compared to those of 8325-4, the rsbU mutant, parent strain. A recognition site for σB was located in the promoter region of katA, the gene encoding the sole catalase of S. aureus, by primer extension analysis. However, catalase expression and activity were similar in SH1000 (8325-4 rsbU +), suggesting that this promoter may have a minor role in catalase expression under normal conditions. Restoration of σB activity in SH1000 (8325-4 rsbU +) resulted in a marked decrease in the levels of the exoproteins SspA and Hla, and this is likely to be mediated by reduced expression of agr in this strain. By using Western blotting and a sarA-lacZ reporter assay, the levels of SarA were found to be similar in strains 8325-4 and SH1000 (8325-4 rsbU +) and sigB mutant derivatives of these strains. This finding contrasts with previous reports that suggested that SarA expression levels are altered when they are measured transcriptionally. Inactivation of sarA in each of these strains resulted in an expected decrease in agr expression; however, the relative level of agr in SH1000 (8325-4 rsbU +) remained less than the relative levels in 8325-4 and the sigB mutant derivatives. We suggest that SarA is not likely to be the effector in the overall σB-mediated effect on agr expression.

scholarly journals Evaluation of the role of inositol trisphosphate in IgE-dependent exocytosis

1990 ◽  
Vol 270 (3) ◽  
pp. 685-689 ◽  
Author(s):  
G Gat-Yablonski ◽  
R Sagi-Eisenberg
Keyword(s):  
Inositol Trisphosphate ◽  
Close Correlation ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Physiological Conditions ◽  
Similar Range ◽  
Ige Mediated ◽  
Dose Dependent ◽  
Basophilic Leukemia

A close correlation exists between inhibition by 12-O-tetradecanoylphorbol 13-acetate (TPA) of inositol trisphosphate (InsP3) formation and the rise in internal Ca2+ concentrations in IgE-stimulated rat basophilic leukemia (RBL-2H3) cells. Inhibition of both processes is dose-dependent, with half-maximal and maximal inhibition occurring at 1.5 and 10 ng of TPA/ml respectively. At a similar range of concentrations TPA does not inhibit, but rather enhances, IgE-dependent secretion. When added to antigen-activated cells. EGTA immediately abrogates secretion and stimulates InsP3 production. In contrast, EGTA has only a small inhibitory effect on IgE-induced secretion from TPA-activated cells. In antigen-activated cells, EGTA partially inhibits InsP1 formation, suggesting that, unlike InsP3, InsP1 may in part be formed directly from phosphatidylinositol in a Ca2(-)-dependent manner. Together, these findings suggest that under physiological conditions the stimulated formation of InsP3 is insufficient for triggering secretion, and that Ca2+ influx is essential. Moreover, InsP3 formation is not obligatory for IgE-mediated exocytosis, provided that the cells are activated by TPA. Secretion from TPA-activated cells, which is independent of InsP3 formation and the rise in internal Ca2+, does not require the presence of external Ca2+, implying that the presence of external Ca2+ during IgE-induced secretion is required for producing the Ca2+ signal and not for exocytosis per se.

scholarly journals MicroRNA-106a Inhibits Autophagy Process and Antimicrobial Responses by Targeting ULK1, ATG7, and ATG16L1 During Mycobacterial Infection

2021 ◽  
Vol 11 ◽  
Author(s):  
Kunmei Liu ◽  
Dantong Hong ◽  
Fan Zhang ◽  
Xin Li ◽  
Meng He ◽  
...  
Keyword(s):  
Immune Response ◽  
Electron Microscope ◽  
Mycobacterial Infection ◽  
Inhibitory Effect ◽  
Innate Immune ◽  
Negative Regulator ◽  
Dependent Manner ◽  
Transmission Electron ◽  
Dose Dependent

Autophagy is a key element of innate immune response against invading pathogens including Mycobacterium tuberculosis (M. tuberculosis). The emerging roles of microRNAs in regulating host antimicrobial responses against M. tuberculosis have gained widespread attention. However, the process by which miRNAs specifically influence antibacterial autophagy during mycobacterial infection is largely uncharacterized. In this study, we demonstrate a novel role of miR-106a in regulating macrophage autophagy against M. tuberculosis. H37Ra infection leads to downregulation of miR-106a in a time- and dose-dependent manner and concomitant upregulation of its three targets (ULK1, ATG7, and ATG16L1) in THP-1 macrophages. MiR-106a could inhibit autophagy activation and antimicrobial responses to M. tuberculosis by targeting ULK1, ATG7, and ATG16L1. Overexpression of miR-106a dramatically inhibited H37Ra-induced activation of autophagy in human THP-1 macrophages, whereas inhibitors of miR-106a remarkably promoted H37Ra-induced autophagy. The inhibitory effect of miR-106a on autophagy process during mycobacterial infection was also confirmed by Transmission Electron Microscope (TEM) observation. More importantly, forced expression of miR-106a increased mycobacterial survival, while transfection with miR-106a inhibitors attenuated the survival of intracellular mycobacteria. Taken together, these data demonstrated that miR-106a functioned as a negative regulator in autophagy and antimicrobial effects by targeting ULK1, ATG7, and ATG16L1 during M. tuberculosis infection, which may provide a potential target for developing diagnostic reagents or antibacterials against tuberculosis.

Bradykinin increases cytosolic free [Ca2+] in proximal tubule cells

1988 ◽  
Vol 255 (3) ◽  
pp. F486-F493 ◽  
Author(s):  
A. Aboolian ◽  
E. P. Nord
Keyword(s):  
Proximal Tubule ◽  
Dependent Manner ◽  
Ang Ii ◽  
Transduction Pathway ◽  
Free Medium ◽  
Proximal Tubule Cells ◽  
Heterologous Desensitization ◽  
Tubule Cells ◽  
Dose Dependent

The role of bradykinin (BK) as a calcium-mobilizing agonist in cells of renal proximal tubule origin was examined. Experiments were performed on confluent cultures of rabbit proximal tubule cells in primary culture and changes in cytosolic free Ca2+ concentration, [Cai2+], were monitored by use of the Ca2+-sensitive fluorescent probe fura-2. Under steady-state conditions, [Cai2+] was 210 +/- 7 nM in a Ca2+-replete medium vs. 135 +/- 5 nM in a medium devoid of Ca2+. Acute challenge with BK resulted in a transient increment in [Cai2+], which peaked at 150% the resting value within 10 s and was independent of medium [Ca2+]. The K0.5 for the process was 2.5 X 10(-10) M. The BK receptor displayed properties of the beta 2-variety. In a Ca2+-free medium 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate (TMB-8) blocked the BK-elicited Ca2+ transient in a time- and dose-dependent manner. In contrast to TMB-8, the Ca2+-channel inhibitor, verapamil, was without effect. Prior exposure of cells to ionomycin completely obviated the BK-induced Ca2+ transient. Cells challenged with BK were nonresponsive to subsequent challenge by a second Ca2+-mobilizing agonist, angiotensin II (ANG II). In summary, these data suggest that BK is an extremely sensitive activator of the phosphoinositol transduction pathway in rabbit proximal tubule cells. Furthermore, the heterologous desensitization between BK and ANG II, in terms of elevating [Cai2+], suggests that these two agonists release Ca2+ from a common intracellular store.

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