Role of ET-1 in the regulation of coronary circulation

2003 ◽  
Vol 81 (6) ◽  
pp. 570-577 ◽  
Author(s):  
Michel Lavallée ◽  
Eric Thorin
Keyword(s):  
Coronary Vessels ◽  
Receptor Activation ◽  
Primary Objective ◽  
No Production ◽  
Metabolic Demand ◽  
Resistance Vessels ◽  
Secondary Phenomenon

Given that circulating ET levels in heart failure, in particular, may reach physiological threshold for coronary constrictor responses, the primary objective of the present review is to consider coronary vessels as an important target for circulating and locally produced endothelin(s). In healthy vessels, ET-1 causes biphasic coronary responses characterized by a transient dilation of large and small arteries followed by a sustained constriction. ETB receptors are pivotal in the early dilation of resistance vessels, whereas dilation of conductance vessels may be a secondary phenomenon triggered by flow increases. Exogenous ET-1 causes coronary constriction almost exclusively through ETA receptor activation. Human and canine large epicardial coronary vessels display significant baseline ET-1 dependent tone in vitro and in vivo, an ETA-dependent process. In contrast, ETB receptors located on smooth muscle cells are apparently less important for producing constrictor responses. NO production may serve as an important counter-regulatory mechanism to limit ET-dependent effects on coronary vessels. Conversely, in a dysfunctional endothelium, the loss of NO may augment ET-1 production and activity. By lifting the ET-dependent burden from coronary vessels, ET receptor blockade should help to ensure a closer match between cardiac metabolic demand and coronary perfusion.Key words: endothelin, ET receptors, coronary vessels, coronary blood flow, nitric oxide, shear stress, atherosclerosis, humans, animals.

Immunomodulation by 17β-estradiol in bivalve hemocytes

2006 ◽  
Vol 291 (3) ◽  
pp. R664-R673 ◽  
Author(s):  
Laura Canesi ◽  
Caterina Ciacci ◽  
Lucia Cecilia Lorusso ◽  
Michele Betti ◽  
Tiziana Guarnieri ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Hydrolytic Enzymes ◽  
Physiological Role ◽  
Estrogen Receptor Α ◽  
Nitrite Accumulation ◽  
No Production ◽  
17Β Estradiol

In mammals, estrogens have dose- and cell-type-specific effects on immune cells and may act as pro- and anti-inflammatory stimuli, depending on the setting. In the bivalve mollusc Mytilus, the natural estrogen 17β-estradiol (E2) has been shown to affect neuroimmune functions. We have investigated the immunomodulatory role of E2 in Mytilus hemocytes, the cells responsible for the innate immune response. E2 at 5–25 nM rapidly stimulated phagocytosis and oxyradical production in vitro; higher concentrations of E2 inhibited phagocytosis. E2-induced oxidative burst was prevented by the nitric oxide (NO) synthase inhibitor NG-monomethyl-l-arginine and superoxide dismutase, indicating involvement of NO and O2−; NO production was confirmed by nitrite accumulation. The effects of E2 were prevented by the antiestrogen tamoxifen and by specific kinase inhibitors, indicating a receptor-mediated mechanism and involvement of p38 MAPK and PKC. E2 induced rapid and transient increases in the phosphorylation state of PKC, as well as of a aCREB-like (cAMP responsive element binding protein) transcription factor, as indicated by Western blot analysis with specific anti-phospho-antibodies. Localization of estrogen receptor-α- and -β-like proteins in hemocytes was investigated by immunofluorescence confocal microscopy. The effects of E2 on immune function were also investigated in vivo at 6 and 24 h in hemocytes of E2-injected mussels. E2 significantly affected hemocyte lysosomal membrane stability, phagocytosis, and extracellular release of hydrolytic enzymes: lower concentrations of E2 resulted in immunostimulation, and higher concentrations were inhibitory. Our data indicate that the physiological role of E2 in immunomodulation is conserved from invertebrates to mammals.

scholarly journals Comparative analysis of biological aspects of Leishmania infantum isolates

2020 ◽  
Author(s):  
Taiana Ferreira-Paes ◽  
Karen S. Charret ◽  
Merienny R.S. Ribeiro ◽  
Raquel F. Rodrigues ◽  
Leon L. Leon
Keyword(s):  
Leishmania Infantum ◽  
No Production ◽  
Arginine Metabolism ◽  
Biological Behaviour ◽  
Biological Aspects ◽  
Oxide Synthase ◽  
Biological Differences

AbstractLeishmania infantum infantum (LII) is one of the species that causes visceral leishmaniasis (VL) in the Old World, while L. infantum chagasi (LIC), and is present in the New World. Few studies address the biological differences, as well as the behaviour of these strains during infection. These parasites live inside the cells of their hosts, continuously evading the microbicidal mechanisms and modulating the immune response of these cells. One of the mechanisms used by these protozoa involves the L-arginine metabolism. Given the importance of the understanding of differences between Leishmania species, as well as establishing a better murine model to study leishmaniases, the objectives of this work were to analyse the biological and molecular differences between two Leishmania infantum strains (LII and LIC) and the degree of susceptibility of mice with different genetic backgrounds to infection, as well as to understand the role of arginase (ARG)/nitric oxide synthase (NOS) in the parasite-host relationship. The infectivity in vivo and in vitro of LII and LIC was performed in BALB/c and Swiss Webster mice, as well the NOS and ARG activities. The LII strain showed more infective than the LIC strain both in vivo and in vitro. In animals infected by both strains, a difference in NOS and ARG activities occurred. In vitro, promastigotes of LII isolated from BALB/c and Swiss Webster mice showed higher ARG activity than the LIC during the growth curve, however, no difference was observed in intracellular NO production by promastigotes between these strains. A comparison of the sequences of the ARG gene was made and both strains were identical. However, despite the similarity, the strains showed different expression of this gene. It can be concluded that although L. chagasi strains are considered identical to L. infantum strains, both have different biological behaviour.

scholarly journals Involvement of Nitric Oxide in Iodine Deficiency-Induced Microvascular Remodeling in the Thyroid Gland: Role of Nitric Oxide Synthase 3 and Ryanodine Receptors

Endocrinology ◽  
2014 ◽  
Vol 156 (2) ◽  
pp. 707-720 ◽  
Author(s):  
J. Craps ◽  
C. Wilvers ◽  
V. Joris ◽  
B. De Jongh ◽  
J. Vanderstraeten ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Thyroid Gland ◽  
Mrna Expression ◽  
Iodine Deficiency ◽  
Ryanodine Receptors ◽  
No Production

Iodine deficiency (ID) induces microvascular changes in the thyroid gland via a TSH-independent reactive oxygen species-hypoxia inducible factor (HIF)-1α-vascular endothelial growth factor (VEGF) pathway. The involvement of nitric oxide (NO) in this pathway and the role of calcium (Ca2+) and of ryanodine receptors (RYRs) in NO synthase 3 (NOS3) activation were investigated in a murine model of goitrogenesis and in 3 in vitro models of ID, including primary cultures of human thyrocytes. ID activated NOS3 and the production of NO in thyrocytes in vitro and increased the thyroid blood flow in vivo. Using bevacizumab (a blocking antibody against VEGF-A) in mice, it appeared that NOS3 is activated upstream of VEGF-A. L-nitroarginine methyl ester (a NOS inhibitor) blocked the ID-induced increase in thyroid blood flow in vivo and NO production in vitro, as well as ID-induced VEGF-A mRNA and HIF-1α expression in vitro, whereas S-nitroso-acetyl-penicillamine (a NO donor) did the opposite. Ca2+ is involved in this pathway as intracellular Ca2+ flux increased after ID, and thapsigargin activated NOS3 and increased VEGF-A mRNA expression. Two of the 3 known mammalian RYR isoforms (RYR1 and RYR2) were shown to be expressed in thyrocytes. RYR inhibition using ryanodine at 10μM decreased ID-induced NOS3 activation, HIF-1α, and VEGF-A expression, whereas RYR activation with ryanodine at 1nM increased NOS3 activation and VEGF-A mRNA expression. In conclusion, during the early phase of TSH-independent ID-induced microvascular activation, ID sequentially activates RYRs and NOS3, thereby supporting ID-induced activation of the NO/HIF-1α/VEGF-A pathway in thyrocytes.

scholarly journals Increased Susceptibility of C1q-Deficient Mice to Salmonella enterica Serovar Typhimurium Infection

2002 ◽  
Vol 70 (2) ◽  
pp. 551-557 ◽  
Author(s):  
Joanna Warren ◽  
Pietro Mastroeni ◽  
Gordon Dougan ◽  
Mahdad Noursadeghi ◽  
Jonathan Cohen ◽  
...  
Keyword(s):  
Salmonella Enterica ◽  
Fluorescent Protein ◽  
Alternative Pathway ◽  
No Production ◽  
Classical Pathway ◽  
Serovar Typhimurium ◽  
Deficient Mice

ABSTRACT The role of the complement system in host defense against Salmonella infection is poorly defined. Bacterial cell wall O-antigen polysaccharide can activate the alternative pathway in vitro. No studies, however, have elucidated the role of the classical pathway in immunity to Salmonella spp. in vivo. C1q-deficient mice (C1qa −/−) on a 129/Sv genetic background and strain-matched controls were infected intraperitoneally and intravenously with Salmonella enterica serovar Typhimurium and monitored over a 14-day period. After inoculation by either route, the C1qa −/− mice were found to be significantly more susceptible to Salmonella infection. Hepatic and splenic bacterial counts, performed at various time points, showed increased numbers of colonies in complement-deficient mice compared to controls. Analysis of blood clearance showed no difference between the two experimental groups during the first 15 min. However, after 20 min and until 6 h postinfection, numbers of circulating bacteria were significantly higher in complement-deficient mice. In vitro experiments using either resident or thioglycolate-elicited peritoneal macrophages showed a significant increase in the number of bacteria inside C1q-deficient macrophages compared to controls irrespective of the serum used for opsonizing the bacteria. These findings could not be explained either by an increased bacterial uptake, analyzed in vitro and in vivo using green fluorescent protein-tagged salmonellae, or by a defect in the respiratory burst or in NO production. The data presented here suggest the possibility of novel pathways by which C1q may modulate the pathogenesis of infectious diseases caused by intracellular pathogens.

scholarly journals Renal medullary ETB receptors produce diuresis and natriuresis via NOS1

2008 ◽  
Vol 294 (5) ◽  
pp. F1205-F1211 ◽  
Author(s):  
Daisuke Nakano ◽  
Jennifer S. Pollock ◽  
David M. Pollock
Keyword(s):  
Renal Medulla ◽  
Urinary Sodium Excretion ◽  
Receptor Activation ◽  
No Production ◽  
Sprague Dawley ◽  
Receptor Stimulation ◽  
Water Excretion ◽  
Sprague Dawley Rats

Endothelin-1 (ET-1) plays an important role in the regulation of salt and water excretion in the kidney. Considerable in vitro evidence suggests that the renal medullary ETB receptor mediates ET-1-induced inhibition of electrolyte reabsorption by stimulating nitric oxide (NO) production. The present study was conducted to test the hypothesis that NO synthase 1 (NOS1) and protein kinase G (PKG) mediate the diuretic and natriuretic effects of ETB receptor stimulation in vivo. Infusion of the ETB receptor agonist sarafotoxin S6c (S6c: 0.45 μg·kg−1·h−1) in the renal medulla of anesthetized, male Sprague-Dawley rats markedly increased the urine flow (UV) and urinary sodium excretion (UNaV) by 67 and 120%, respectively. This was associated with an increase in medullary cGMP content but did not affect blood pressure. In addition, S6c-induced diuretic and natriuretic responses were absent in ETB receptor-deficient rats. Coinfusion of NG-propyl-l-arginine (10 μg·kg−1·h−1), a selective NOS1 inhibitor, suppressed S6c-induced increases in UV, UNaV, and medullary cGMP concentrations. Rp-8-Br-PET-cGMPS (10 μg·kg−1·h−1) or RQIKIWFQNRRMKWKK-LRK5H-amide (18 μg·kg−1·h−1), a PKG inhibitor, also inhibited S6c-induced increases in UV and UNaV. These results demonstrate that renal medullary ETB receptor activation induces diuretic and natriuretic responses through a NOS1, cGMP, and PKG pathway.

scholarly journals Thykamine Extracts from Spinach Reduce Acute Inflammation In Vivo and Downregulate Phlogogenic Functions of Human Blood Neutrophils In Vitro

Biomedicines ◽  
2020 ◽  
Vol 8 (7) ◽  
pp. 219
Author(s):  
Vickie Beaupré ◽  
Nathalie Boucher ◽  
Isabel Desgagné-Penix
Keyword(s):  
In Vitro Models ◽  
No Production ◽  
Chlorophyll Pigments ◽  
Cellular Models ◽  
Blood Neutrophils ◽  
Anti Inflammatory ◽  
Botanical Extract

The anti-inflammatory and antioxidant role of Thykamine, a botanical extract of thylakoides obtained from spinach leaves, has been investigated in animal and cellular models. The oxidative properties have been proven by inhibiting NO production (>98%) in J774A.1 cells and by protecting a linoelic acid emulsion subjected to lipid peroxidation caused by AAPH. Thykamine injected intraperitoneally to rats reduced the inflammatory process of (TNBS)-induced colitis and carrageenan-induced paw edema. As neutrophils are the first cells to migrate to inflammatory sites, the influence of Thykamine on the primary neutrophil functions were studied. Thykamine dose-dependent reduced neutrophil chemiotaxis, phagocytosis, and degranulation. No change in the release of LDH by neutrophils on Thykamine was recorded. Thykamine inhibited by 85% the neutrophil production of O2−. A superoxide recovery activity was observed on a zymography demonstrating a SOD-like enzyme on Thykamine extracts. Spontaneous fluorescence provided by carotenoid and chlorophyll pigments (488/675 nm) detected Thykamine on the surface, in the cytoplasm (mainly central where Golgi are present) and weakly in the nucleus of neutrophils. The results argue that SOD and pigments found in Thykamine are part of its antioxidant and anti-inflammatory properties shown in in vivo and in vitro models of inflammation.

Regulation of vasopressin secretion by ETA and ETB receptors in compartmentalized rat hypothalamo-neurohypophysial explants

2004 ◽  
Vol 286 (4) ◽  
pp. E535-E541 ◽  
Author(s):  
Noreen F. Rossi
Keyword(s):  
Receptor Activation ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Posterior Pituitary ◽  
Unique Combination ◽  
Vasopressin Secretion ◽  
Hypothalamic Level

The endothelins (ET) have been implicated in vasopressin (AVP) release in vivo and in vitro. The effects of ET in this system are complex, and the net AVP secretory response likely depends on a unique combination of ET isoform, ET receptor subtype, and neural locus. The purpose of these studies was to examine the role of ET receptor subtypes at hypothalamic vs. neurohypophysial sites on somatodendritic and neurohypophysial AVP secretion. Experiments were done in cultured explants of the hypothalamo-neurohypophysial system of Long Evans rats. Either the whole explant (standard) or only the hypothalamus or posterior pituitary (compartmentalized) was exposed to log dose increases (0.01-10 nM) of the agonists ET-1 (ETA selective), ET-3 (nonselective), or IRL-1620 (ETB selective) with or without selective ETA (BQ-123, 2-200 nM) or ETB (IRL-1038, 6-600 nM) receptor antagonism. In standard explants, ET-1 and ET-3 dose-dependently increased, whereas IRL-1620 decreased net AVP release. Hypothalamic ETB receptor activation increased both somatodendritic and neurohypophysial AVP release. At least one intervening synapse was involved, as tetrodotoxin blocked the response. Activation of ETA receptors at the hypothalamic level inhibited, whereas ETA receptor activation at the posterior pituitary stimulated, neurohypophysial AVP secretion. Antagonism of hypothalamic ETA receptors potentiated the stimulatory effect of ET-1 and ET-3 on neurohypophysial secretion, an effect not observed with ETB receptor-induced somatodendritic release of AVP. Thus the response of whole explants reflects the net result of both stimulatory and inhibitory inputs. The integration of these excitatory and inhibitory inputs endows the vasopressinergic system with greater plasticity in its response to physiological and pathophysiological states.

P2 receptors in regulation of renal microvascular function

2001 ◽  
Vol 280 (6) ◽  
pp. F927-F944 ◽  
Author(s):  
Edward W. Inscho
Keyword(s):  
Mesangial Cells ◽  
Strong Support ◽  
Receptor Activation ◽  
P2 Receptors ◽  
Microvascular Function ◽  
Extracellular Nucleotides ◽  
P2 Receptor

In the last 10–15 years, interest in the physiological role of P2 receptors has grown rapidly. Cellular, tissue, and organ responses to P2 receptor activation have been described in numerous in vivo and in vitro models. The purpose of this review is to provide an update of the recent advances made in determining the involvement of P2 receptors in the control of renal hemodynamics and the renal microcirculation. Special attention will be paid to work published in the last 5–6 years directed at understanding the role of P2 receptors in the physiological control of renal microvascular function. Several investigators have begun to evaluate the effects of P2 receptor activation on renal microvascular function across several species. In vivo and in vitro evidence consistently supports the hypothesis that P2 receptor activation by locally released extracellular nucleotides influences microvascular function. Extracellular nucleotides selectively influence preglomerular resistance without having an effect on postglomerular tone. P2 receptor inactivation blocks autoregulatory behavior whereas responsiveness to other vasoconstrictor agonists is retained. P2 receptor stimulation activates multiple intracellular signal transduction pathways in preglomerular smooth muscle cells and mesangial cells. Renal microvascular cells and mesangial cells express multiple subtypes of P2 receptors; however, the specific role each plays in regulating vascular and mesangial cell function remains unclear. Accordingly, the results of studies performed to date provide strong support for the hypothesis that P2 receptors are important contributors to the physiological regulation of renal microvascular and/or glomerular function.

scholarly journals Endothelin contributes to blunted renal autoregulation observed with a high-salt diet

2015 ◽  
Vol 309 (8) ◽  
pp. F687-F696 ◽  
Author(s):  
Robert C. Fellner ◽  
Zhengrong Guan ◽  
Anthony K. Cook ◽  
David M. Pollock ◽  
Edward W. Inscho
Keyword(s):  
Receptor Activation ◽  
High Salt ◽  
Sprague Dawley ◽  
Dietary Salt ◽  
Renal Autoregulation ◽  
Sprague Dawley Rats ◽  
Afferent Arterioles

Autoregulation of renal blood flow (RBF) is an essential function of the renal microcirculation that has been previously shown to be blunted by excessive dietary salt. Endogenous endothelin 1 (ET-1) is increased following a high-salt (HS) diet and contributes to the control of RBF but the differential effects of ET-1 on renal microvessel autoregulation in response to HS remain to be established. We hypothesized that a HS diet increases endothelin receptor activation in normal Sprague-Dawley rats and blunts autoregulation of RBF. The role of ET-1 in the blunted autoregulation produced by a HS diet was assessed in vitro and in vivo using the blood-perfused juxtamedullary nephron preparation and anesthetized rats, respectively. Using highly selective antagonists, we observed that blockade of either ETA or ETB receptors was sufficient to restore normal autoregulatory behavior in afferent arterioles from HS-fed rats. Additionally, normal autoregulatory behavior was restored in vivo in HS-fed rats by simultaneous ETA and ETB receptor blockade, whereas blockade of ETB receptors alone showed significant improvement of normal autoregulation of RBF. Consistent with this observation, autoregulation of RBF in ETB receptor-deficient rats fed HS was similar to both ETB-deficient rats and transgenic control rats on normal-salt diets. These data support the hypothesis that endogenous ET-1, working through ETB and possibly ETA receptors, contributes to the blunted renal autoregulatory behavior in rats fed a HS diet.

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