PEROXIDE STIMULATION OF PGI3 AND DIHOMO-PGI2 IN ENDOTHELIUM

1987 ◽  
Author(s):  
J C Bordet ◽  
M Guichardant ◽  
M Lagarde
Keyword(s):  
Vascular Endothelium ◽  
Gas Chromatography Mass Spectrometry ◽  
Efficient Synthesis ◽  
Competitive Inhibitors ◽  
Silyl Derivatives ◽  
Adrenic Acid ◽  
High Peroxide ◽  
Prostacyclin Synthase ◽  
Docosatetraenoic Acid ◽  
Stimulation Of

Human umbilical endothelial cell (EC) monolayers incubated with eicosapentaenoic acid (EPA) produce small amounts of prostaglandin E3 (PGI3). We have previously shown that this metabolite is markedly enhanced in EC supernatant by co-incubating EPA with arachidonic acid (AA) (BBRC 135, 403, 1986). Moreover we found that PGF3a and PGE3 were similarly enhanced, and we concluded that such a stimulation occured at the cyclooxygenase rather than at the prostacyclin synthase level. It is generally assumed that cyclooxygenase is a peroxide-dependent enzyme and the present study shows that the potentiating effect of AA on EPA cyclooxygenation may be due to its hydroperoxy derivative, 15-HPETE. This has been established by measuring prostanoids of the trienoic series from (14-C)EPA and by detection of their metoxy-pentafluorobenzyl-trimethyl silyl derivatives from unlabelled EPA by gas chromatography-mass spectrometry. The potentiating effect of n-6 hydroperoxy derivative of linoleic acid (13-HPODE) was even higher than that of 15-HPETE. In addition, the cyclooxygenation of docosatetraenoic acid (DTA) or adrenic acid, was found to be also potentiated by 15-HPETE and 13-HPODE, but higher concentrations were required for the efficient synthesis of dihomo-PGI2. Concentrations of peroxides required for such potentiations were however far lower (−2μM) than those inhibiting prostacyclin synthase (≥100μM under our conditions). EPA and DTA, as competitive inhibitors of AA cyclooxygenation, appeared to need a higher peroxide tone than AA for their own metabolism. The biological relevance of DTA is not proved at this day, and dihomo-PGI2 has been found less active than PGI2. In contrast, PGI3 has been assumed to exhibit similar antiaggregatory effect than PGI2. EPA may then beneficially enhance the prostacyclin potential of vascular endothelium especially in conditions where a high peroxide tone is suspected like ageing or diabetes

scholarly journals Angiotensinergic stimulation of vascular endothelium in mice causes hypotension, bradycardia, and attenuated angiotensin response

2006 ◽  
Vol 103 (50) ◽  
pp. 19087-19092 ◽  
Author(s):  
R. Ramchandran ◽  
T. Takezako ◽  
Y. Saad ◽  
L. Stull ◽  
B. Fink ◽  
...  
Keyword(s):  
Vascular Endothelium ◽  
Stimulation Of

scholarly journals Contrasting effects of N5-substituted tetrahydrobiopterin derivatives on phenylalanine hydroxylase, dihydropteridine reductase and nitric oxide synthase

2000 ◽  
Vol 348 (3) ◽  
pp. 579-583 ◽  
Author(s):  
Ernst R. WERNER ◽  
Hans-Jörg HABISCH ◽  
Antonius C. F. GORREN ◽  
Kurt SCHMIDT ◽  
Laura CANEVARI ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Phenylalanine Hydroxylase ◽  
Neuronal Nitric Oxide Synthase ◽  
Dihydropteridine Reductase ◽  
Redox Active ◽  
Competitive Inhibitors ◽  
Oxide Synthase ◽  
Active Contribution ◽  
Stimulation Of

Tetrahydrobiopterin [(6R)-5,6,7,8-tetrahydro-L-biopterin, H4biopterin] is one of several cofactors of nitric oxide synthases (EC 1.14.13.39). Here we compared the action of N5-substituted derivatives on recombinant rat neuronal nitric oxide synthase with their effects on dihydropteridine reductase (EC 1.6.99.7) and phenylalanine hydroxylase (EC 1.14.16.1), the well-studied classical H4biopterin-dependent reactions. H4biopterin substituted at N5 with methyl, hydroxymethyl, formyl and acetyl groups were used. Substitution at N5 occurs at a position critical to the redox cycle of the cofactor in phenylalanine hydroxylase/dihydropteridine reductase. We also included N2ʹ-methyl H4biopterin, a derivative substituted at a position not directly involved in redox cycling, as a control. As compared with N5-methyl H4biopterin, N5-formyl H4biopterin bound with twice the capacity but stimulated nitric oxide synthase to a lesser extent. Depending on the substituent used, N5-substituted derivatives were redox-active: N5-methyl- and N5-hydroxylmethyl H4biopterin, but not N5-formyl- and N5-acetyl H4biopterin, reduced 2,6-dichlorophenol indophenol. N5-Substituted H4biopterin derivatives were not oxidized to products serving as substrates for dihydropteridine reductase and, depending on the substituent, were competitive inhibitors of phenylalanine hydroxylase: N5-methyl- and N5-hydroxymethyl H4biopterin inhibited phenylalanine hydroxylase, whereas N5-formyl- and N5-acetyl H4biopterin had no effect. Our data demonstrate differences in the mechanism of stimulation of phenylalanine hydroxylase and nitric oxide synthase by H4biopterin. They are compatible with a novel, non-classical, redox-active contribution of H4biopterin to the catalysis of the nitric oxide synthase reaction.

scholarly journals The lux autoinducer-receptor interaction in Vibrio harveyi: binding parameters and structural requirements for the autoinducer

1995 ◽  
Vol 312 (2) ◽  
pp. 439-444 ◽  
Author(s):  
J G Cao ◽  
Z Y Wei ◽  
E A Meighen
Keyword(s):  
Light Emission ◽  
Vibrio Harveyi ◽  
Homoserine Lactone ◽  
Receptor Interaction ◽  
Binding Parameters ◽  
Acylhomoserine Lactone ◽  
Competitive Inhibitors ◽  
Function Relationship ◽  
Relationship Of ◽  
Stimulation Of

To assess the binding parameters and the structure-function relationship of the Vibrio harveyi lux autoinducer, N-(D-3-hydroxybutanoyl)homoserine lactone (D-HBHL), to light emission, a series of acylhomoserine lactone analogues were synthesized and their effects on the stimulation of luminescence of an autoinducer-deficient mutant of V. harveyi, D1, examined. Of the analogues with 3-hydroxyacyl chains, only N-(3-hydroxyvaleryl)homoserine lactone (HVHL) could act as an inducer, with about 85% of the potency of D-HBHL in stimulation of luminescence; the apparent Kd of the putative receptor for HVHL was 3.8 microM, close to that for the natural autoinducer (1.4 microM). Analogues with longer 3-hydroxyacyl chains, N-(3-hydroxyhexanoyl)homoserine lactone and N-(3-hydroxyheptanoyl)homoserine lactone, acted as competitive inhibitors of HBHL with apparent KI values of 77 and 53 microM respectively. Replacement of the 3-hydroxybutanoyl moiety with a 3-methylbutanoyl or 3-methoxybutanoyl group created weak competitive inhibitors, N-(isovaleryl)- and N-(3-methoxybutanoyl)- homoserine lactones, with apparent KI values of 150 and 360 microM respectively. Two other analogues, N-(2-hydroxybutanoyl)- and N-(4-hydroxybutanoyl)-homoserine lactone, could neither stimulate nor inhibit luminescence. The approach used in these studies to demonstrate binding of autoinducer analogues at the same site, as well as measurement of the relative dissociation constant, may be of value in analysing analogues activating or inhibiting luminescence and other processes that are under control of acylhomoserine lactone autoregulators.

Incorporation of arachidonic acid into lipids of the isolated perfused rat lung

1989 ◽  
Vol 66 (6) ◽  
pp. 2763-2771 ◽  
Author(s):  
F. H. Chilton ◽  
J. Y. Westcott ◽  
L. M. Zapp ◽  
J. E. Henson ◽  
N. F. Voelkel
Keyword(s):  
Arachidonic Acid ◽  
Molecular Species ◽  
Mass Spectrometry Analysis ◽  
Gas Chromatography Mass Spectrometry ◽  
Alveolar Type ◽  
Rat Lung ◽  
Spectrometry Analysis ◽  
Autoradiographic Analysis ◽  
Isolated Rat Lung ◽  
Stimulation Of

This study has attempted to identify the cells and phosphoglyceride molecular species associated with the rapid turnover of arachidonic acid (AA) in the isolated rat lung. In initial studies, AA complexed to trace amounts of albumin was added to the perfusate of rat lungs for 15 min and the incorporation of [3H]AA into various cells and phosphoglyceride molecular species was determined. Autoradiographic analysis revealed that the AA had labeled endothelial cells but also had already escaped from the intravascular space and labeled epithelial cells including alveolar type II cells. In addition, [3H]AA was found to be incorporated into various phosphoglycerides: phosphatidylcholine (PC) greater than phosphatidylethanolamine (PE) greater than phosphatidylinositol (PI). The majority of this [3H]AA was incorporated into 1-acyl-2-arachidonoyl-sn-glycero-3-PC, -PE, and -PI during the 15-min labeling period. In subsequent experiments, AA remodeling in the lung was examined by pulse labeling with [3H]AA for 15 min, washing unbound AA with albumin, and perfusing for an additional 120 min. In these lungs, some of the [3H]AA was remodeled into 1-alk-1-enyl-acyl-sn-glycero-3-PE. Gas chromatography-mass spectrometry analysis revealed that the largest pools of endogenous AA in the lung are found in PE associated with 1-alk-1-enyl-linked molecular species. On ionophore stimulation of lungs labeled for 15 min, labeled leukotriene (LT) B4, leukotriene C4, and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) were produced. LTC4 had a profoundly different radiospecific activity compared with LTB4 and 6-keto-PGF1 alpha, suggesting a different source of AA as contributing to the production of this eicosanoid.(ABSTRACT TRUNCATED AT 250 WORDS)

ATP and acetylcholine interact to modulate vascular tone and α1-adrenergic vasoconstriction in humans

2021 ◽  
Author(s):  
Janée D. Terwoord ◽  
Matthew L. Racine ◽  
Christopher M. Hearon ◽  
Gary J. Luckasen ◽  
Frank A. Dinenno
Keyword(s):  
Blood Flow ◽  
Vascular Endothelium ◽  
Vascular Tone ◽  
Complex Signal ◽  
Similar Response ◽  
Vascular Conductance ◽  
Arterial Infusion ◽  
Vasoconstrictor Response ◽  
Forearm Vascular Conductance ◽  
Stimulation Of

The vascular endothelium senses and integrates numerous inputs to regulate vascular tone. Recent evidence reveals complex signal processing within the endothelium, yet little is known about how endothelium-dependent stimuli interact to regulate blood flow. We tested the hypothesis that combined stimulation of the endothelium with adenosine triphosphate (ATP) and acetylcholine (ACh) elicits greater vasodilation and attenuates α1‑adrenergic vasoconstriction compared to combination of ATP or ACh with the endothelium-independent dilator sodium nitroprusside (SNP). We assessed forearm vascular conductance (FVC) in young adults (6F, 7M) during local intra-arterial infusion of ATP, ACh, or SNP alone and in the following combinations: ATP+ACh, SNP+ACh, and ATP+SNP wherein the second dilator was co-infused after attaining steady-state with the first dilator. By design, each dilator evoked a similar response when infused separately (ΔFVC, ATP: 48±4; ACh: 57±6; SNP: 53±6 ml·min-1·100 mmHg-1; P≥0.62). Combined infusion of the endothelium-dependent dilators evoked greater vasodilation than combination of either dilator with SNP (ΔFVC from first dilator, ATP+ACh: 45±9 vs. SNP+ACh: 18±7 and ATP+SNP: 26±4 ml·min-1·100 mmHg-1, P<0.05). Phenylephrine was subsequently infused to evaluate α1‑adrenergic vasoconstriction. Phenylephrine elicited less vasoconstriction during infusion of ATP or ACh vs. SNP (ΔFVC, -25±3 and -29±4 vs. -48±3%; P<0.05). The vasoconstrictor response to phenylephrine was further diminished during combined infusion of ATP+ACh (-13±3%; P<0.05 vs. ATP or ACh alone) and was less than that observed when either dilator was combined with SNP (SNP+ACh: -26±3%; ATP+SNP: -31±4%; both P<0.05 vs. ATP+ACh). We conclude that endothelium-dependent agonists interact to elicit vasodilation and limit α1‑adrenergic vasoconstriction in humans.

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