Role of cyclooxygenase-1-mediated prostacyclin synthesis in endothelium-dependent vasoconstrictor activity of porcine interlobular renal arteries

2012 ◽  
Vol 302 (9) ◽  
pp. F1133-F1140 ◽  
Author(s):  
Bin Liu ◽  
Wenhong Luo ◽  
Yingzhan Zhang ◽  
Hui Li ◽  
Ningxia Zhu ◽  
...  
Keyword(s):  
Renal Artery ◽  
Force Measurement ◽  
Isometric Force ◽  
Receptor Antagonism ◽  
Vasomotor Reaction ◽  
Tp Receptor ◽  
Cyclooxygenase 1 ◽  
Vasoconstrictor Response ◽  
Tp Receptors ◽  
Cox 1

This study aimed to determine whether PGI2 would be evoked by the endogenous endothelial B2 receptor agonist bradykinin (BK) in the porcine interlobular renal artery and, if so, to determine how it would influence the vasomotor reaction, and the specific cyclooxygenase (COX) isoform(s) involved in its synthesis. The production of the PGI2 metabolite 6-keto-PGF1α was analyzed with HPLC-mass spectroscopy, while vasomotor reaction to PGI2 or BK was determined with isometric force measurement. Results showed that BK evoked an increase in the production of 6-keto-PGF1α, which was abolished by endothelial denudation that removed COX-1 expression, or was reduced by COX-1 inhibition. Interestingly, PGI2 evoked a potent contraction, which was prevented by antagonizing thromboxane-prostanoid (TP) receptors and was not enhanced by antagonizing the vasodilator PGI2 (IP) receptors. The IP receptor agonists MRE-269 and iloprost did not induce any relaxation. Moreover, iloprost, which is also a PGI2 analog, caused a contraction, which was sensitive to TP receptor antagonism, but was to a significantly lesser extent than that of PGI2. Indeed, IP receptors were not detected by RT-PCR or Western blotting in the vessel. Following nitric oxide synthase (NOS) inhibition, BK also evoked an endothelium-dependent contraction, which was blocked by TP receptor antagonism. In addition, inhibition of COX-1 (but not COX-2) impeded the vasoconstrictor activity of BK and expedited the relaxation induced by the agonist in NOS-intact vessels. These results demonstrate that in the porcine interlobular renal artery BK evokes endothelial COX-1-mediated PGI2 synthesis, which mainly leads to the activation of TP receptors and a vasoconstrictor response, possibly due to a scarcity of vasodilator activity mediated by IP receptors. Also, our data suggested that the effect of a PGI2 analog on TP receptors could be reduced compared with that of PGI2 due to modified structure as with iloprost.

A vasoconstrictor role for cyclooxygenase-1-mediated prostacyclin synthesis in mouse renal arteries

2013 ◽  
Vol 305 (9) ◽  
pp. F1315-F1322 ◽  
Author(s):  
Bin Liu ◽  
Yingzhan Zhang ◽  
Ningxia Zhu ◽  
Hui Li ◽  
Wenhong Luo ◽  
...  
Keyword(s):  
Vascular Function ◽  
Receptor Agonist ◽  
Underlying Mechanism ◽  
Renal Arteries ◽  
Receptor Antagonism ◽  
Renal Vasoconstriction ◽  
Tp Receptor ◽  
Cyclooxygenase 1 ◽  
Tp Receptors ◽  
Cox 1

This study was to determine whether prostacyclin [prostaglandin I2 (PGI2)] evokes mouse renal vasoconstriction and, if so, the underlying mechanism(s) and how its synthesis via cyclooxygenase-1 (COX-1) influences local vasomotor reaction. Experiments were performed on vessels from C57BL/6 mice and/or those with COX-1 deficiency (COX-1−/−). Results showed that in renal arteries PGI2 evoked contraction more potently than in carotid arteries, where COX-1 is suggested to mediate prominent endothelium-dependent contraction. A similar result was observed with the thromboxane-prostanoid (TP) receptor agonist U46619. However, in renal arteries TP receptor antagonism, which inhibited the contraction, did not result in any relaxation in response to PGI2. Moreover, we noted that the endothelial muscarinic receptor agonist ACh evoked an increase in the production of the PGI2 metabolite 6-keto-PGF1α, which was prevented by endothelial denudation or COX-1−/−. Interestingly, COX-1−/− was further found to abolish a force development that was sensitive to TP receptor antagonism and result in enhanced relaxation evoked by ACh following NO synthase inhibition. Also, in renal arteries the COX substrate arachidonic acid evoked a vasoconstrictor response, which was again abolished by COX-1−/−. Meanwhile, nonselective COX inhibition did not show any effect in vessels from COX-1−/− mice. Thus, in mouse renal arteries, high expression of TP receptors together with little functional involvement from the vasodilator PGI2 receptors results in a potent vasoconstrictor effect evoked by PGI2. Also, our data imply that endogenous COX-1-mediated PGI2 synthesis leads to vasoconstrictor activity and this could be an integral part of endothelium-derived mechanisms in regulating local renal vascular function.

scholarly journals Downregulation of Thromboxane A2 Receptor Occurs Mainly via Nuclear Factor-KappaB Signaling Pathway in Rat Renal Artery

2017 ◽  
Vol 2017 ◽  
pp. 1-8
Author(s):  
Yaping Zhang ◽  
Man Mi ◽  
Yan-Hua Xie ◽  
Si-Wang Wang ◽  
Lars Edvinsson ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Renal Artery ◽  
Signaling Pathway ◽  
Contractile Response ◽  
Nuclear Factor Kappab ◽  
Nuclear Factor ◽  
Receptor Mrna ◽  
Tp Receptor ◽  
Tp Receptors ◽  
Specific Inhibitors

Thromboxane A2 (TXA2) acts on TXA2 receptors (TP) to regulate renal artery blood flow and subsequently contributes to the pathogenesis of renal ischemia. The present study was designed to examine if nuclear factor-kappaB (NF-κB) signaling pathway is involved in the downregulation of TP receptors in rat renal artery. Rat renal artery segments were organ cultured for 6 or 24 h. Downregulation of TP receptors was monitored using myograph (contractile function), real-time PCR (receptor mRNA), and immunohistochemistry (receptor protein). Specific inhibitors (MG-132 and BMS345541) for NF-κB signaling pathway were used to dissect the underlying molecular mechanisms involved. Compared to fresh (noncultured) segments, organ culture of the renal artery segments for 24 h induced a significant rightward shift of U46619 (TP receptor agonist) contractile response curves (pEC50: 6.89±0.06 versus 6.48±0.04, P<0.001). This decreased contractile response to U46619 was paralleled with decreased TP receptor mRNA and protein expressions in the renal artery smooth muscle cells. Specific inhibitors (MG-132 and BMS345541) for NF-κB signaling pathway significantly abolished the decreased TP protein expression and receptor-mediated contractions. In conclusion, downregulation of TP receptors in the renal artery smooth muscle cells occurs mainly via the NF-κB signaling pathway.

Interactions of gallic acid, resveratrol, quercetin and aspirin at the platelet cyclooxygenase-1 level Functional and modelling studies

2009 ◽  
Vol 102 (08) ◽  
pp. 336-346 ◽  
Author(s):  
Marilena Crescente ◽  
Gisela Jessen ◽  
Stefania Momi ◽  
Hans-Dieter Höltje ◽  
Paolo Gresele ◽  
...  
Keyword(s):  
Salicylic Acid ◽  
Platelet Aggregation ◽  
Gallic Acid ◽  
Molecular Modelling ◽  
In Silico Docking ◽  
Cyclooxygenase 1 ◽  
Modelling Studies ◽  
Cox 1

SummaryWhile resveratrol and quercetin possess antiplatelet activity, little is known on the effect of gallic acid on platelets.We studied the interactions of these three different polyphenols among themselves and with aspirin, at the level of platelet cyclooxygenase-1 (COX-1). Both functional (in vitro and in vivo) and molecular modelling approaches were used. All three polyphenols showed comparable antioxidant activity (arachidonic acid [AA]-induced intraplatelet ROS production); however, resveratrol and quercetin, but not gallic acid, inhibited AA-induced platelet aggregation. Gallic acid, similarly to salicylic acid, the major aspirin metabolite, prevented inhibition of AA-induced platelet function by aspirin but, at variance with salicylic acid, also prevented inhibition by the other two polyphenols. Molecular modelling studies, performed by in silico docking the polyphenols into the crystal structure of COX-1, suggested that all compounds form stable complexes into the COX-1 channel, with slightly different but functionally relevant interaction geometries. Experiments in mice showed that gallic acid administered before aspirin, resveratrol or quercetin fully prevented their inhibitory effect on serum TxB2. Finally, a mixture of resveratrol, quercetin and gallic acid, at relative concentrations similar to those contained in most red wines, did not inhibit platelet aggregation, but potentiated sub-inhibitory concentrations of aspirin. Gallic acid interactions with other polyphenols or aspirin at the level of platelet COX-1 might partly explain the complex,and possibly contrasting, effects of wine and other components of the Mediterranean diet on platelets and on the pharmacologic effect of lowdose aspirin.

Altered TP receptor function in isolated, perfused kidneys of nondiabetic and diabetic ApoE-deficient mice

2008 ◽  
Vol 294 (1) ◽  
pp. F120-F129 ◽  
Author(s):  
Frédéric Michel ◽  
Serge Simonet ◽  
Christine Vayssettes-Courchay ◽  
Florence Bertin ◽  
Patricia Sansilvestri-Morel ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Kidney Disease ◽  
Renal Diseases ◽  
Receptor Ligands ◽  
Tp Receptor ◽  
Vasodilator Activity ◽  
Tp Receptors ◽  
Apoe Ko Mice ◽  
Apoe Ko ◽  
Biphasic Responses

Early manifestations of kidney disease occur in atherosclerosis and activation of TP (thromboxane A2) receptors is implicated in atherosclerotic, diabetes, and renal diseases. The purpose of the present study was to analyze, in isolated, perfused mouse kidneys, the participation of TP receptors in renal vasoconstrictions and vasodilatations. In kidneys, taken from wild-type C57BL6, apolipoprotein E-deficient (ApoE-KO) and diabetic ApoE-KO mice, changes in perfusion pressure were recorded. Constrictions to TP receptor ligands U 46619, arachidonic acid, PGH2, and 8-iso-PGF2α, but not those to angiotensin II, endothelin, or norepinephrine, were inhibited by the selective TP receptor antagonist Triplion (S 18886; 10 nM). Acetylcholine and prostacyclin evoked biphasic responses during methoxamine constrictions; the constrictor part was blocked by Triplion. In ApoE-KO mouse kidneys, compared with C57BL6, a specific decrease in norepinephrine response and no modification in dilator responses were observed. In diabetic ApoE-KO mouse kidneys, constrictions to U 46619 and those to 8-iso-PGF2α were significantly and selectively augmented, without modification in the expression of the TP receptor, and again without any significant change in vasodilator activity. Thus TP receptors are functional, and their activation is not involved in norepinephrine, endothelin, and angiotensin II vasoconstrictions but is implicated in the unusual vasoconstrictions to acetylcholine and prostacyclin. Increased responsiveness of TP receptors occurs in diabetic ApoE-KO mouse kidneys. Thus early changes in TP receptor-mediated vasoconstrictor activity may participate in the development of kidney disease in atherosclerosis and diabetes.

scholarly journals Differential expression of cyclooxygenase 1 and cyclooxygenase 2 in the bovine oviduct

2006 ◽  
Vol 191 (1) ◽  
pp. 263-274 ◽  
Author(s):  
Simone Odau ◽  
Christoph Gabler ◽  
Christoph Holder ◽  
Ralf Einspanier
Keyword(s):  
Mrna Expression ◽  
Estrous Cycle ◽  
Luteal Phase ◽  
Cellular Level ◽  
Differential Distribution ◽  
Cyclooxygenase 1 ◽  
Epithelial Cell Layer ◽  
Cox 2 ◽  
Cycle Dependent ◽  
Cox 1

The aim of the present study was to investigate the enzymes for the local prostaglandin (PG) biosynthesis present in the bovine oviduct during the estrous cycle to influence early reproductive events. Bovine oviducts were classified into four phases: pre-ovulatory, post-ovulatory, early-to-mid luteal, and late luteal phase, subdivided further into ipsi- or contralateral site and separated into ampulla or isthmus. Oviductal cells were gained by flushing the oviductal regions. Quantitative real-time reverse transcriptase-PCR was performed for the secretory and cytosolic phospholipases A2 (sPLA2IB, cPLA2α, and cPLA2β) and cyclooxygenases (COX-1 and COX-2) as the first step enzymes of PG synthesis. COX-1 and cPLA2β showed significant highest mRNA expression around and before ovulation compared with the luteal phase respectively. sPLA2IB and cPLA2α mRNA expression was unregulated during the estrous cycle. Regional differences in mRNA content were found for sPLA2IB with higher mRNA expression in the ampulla than in the isthmus. Western blot analysis revealed the highest COX-1 protein content in the early-to-mid luteal phase. Immunohistochemistry demonstrated that COX-1 was localized in epithelial and smooth muscle cells, whereas COX-2 was only localized in epithelial cells. COX-2 showed a differential distribution within the epithelial cell layer suggesting a regulation on a cellular level, although the COX-2 mRNA and protein amounts did not vary throughout the estrous cycle. A COX activity assay of oviductal cells revealed that COX activity originated predominantly from COX-1 than from COX-2. Treatment of primary oviductal cells with 10 pg/ml 17β-estradiol or 10 ng/ml progesterone resulted in a higher expression of COX-2 and cPLA2α, but not of the other enzymes. The expression pattern of these enzymes suggests that an estrous-cycle dependent and region-specific PG synthesis in the bovine oviduct may be required for a successful reproduction.

The C50T polymorphism of the cyclooxygenase-1 gene and the risk of thrombotic events during low-dose therapy with acetyl salicylic acid

2008 ◽  
Vol 100 (07) ◽  
pp. 70-75 ◽  
Author(s):  
Martijn G. H. van Oijen ◽  
Santosh Sundaresan ◽  
Marc A. Brouwer ◽  
Rene H. M. te Morsche ◽  
Wessel Keuper ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Platelet Aggregation ◽  
Primary Endpoint ◽  
Low Dose ◽  
Cardiovascular Death ◽  
Hazard Ratio ◽  
Cyclooxygenase 1 ◽  
Thromboxane Production ◽  
The Common ◽  
Cox 1

SummaryAspirin prevents thrombotic events by inhibiting platelet cyclooxygenase-1 (COX-1), thus reducing thromboxane A2 formation and platelet aggregation. The C50T polymorphism of COX-1 is associated with an impaired inhibition of both thromboxane production and in-vitro platelet aggregation by aspirin. We studied whether this polymorphism is also associated with the risk of clinical thrombotic events in patients using aspirin. We included 496 patients admitted to our Coronary Care Unit for various indications treated with aspirin 80 mg daily. Genotyping for the C50T polymorphism demonstrated that 86.7% of the patients had the common genotype, and 13.3% had the variant (12.5% heterozygous, 0.8% homozygous). Baseline variables were well balanced, except that patients with the common genotype more frequently used aspirin prior to admission compared to those patients with the variant genotype. The composite primary endpoint of myocardial infarction, stroke, and/or cardiovascular death occurred in 98 patients (19.8%). Myocardial infarction occurred in 9.6% of patients, stroke in 1.6%, and cardiovascular death in 12.1%.The unadjusted hazard ratio (95% CI) for the primary endpoint for patients with the variant versus the common genotype was 1.07 (0.62–1.85), p=0.8.The adjusted hazard ratio was 0.86 (0.49–1.50), p=0.6. In prior laboratory studies the COX-1 C50T polymorphism was associated with an impaired inhibitory effect of aspirin on thromboxane production and platelet function. However, in this cohort of patients using low-dose aspirin for secondary prevention the polymorphism was not associated with a higher risk of atherothrombotic events.

Functional coupling between the Na+/Ca2+ exchanger and nonselective cation channels during histamine stimulation in guinea pig tracheal smooth muscle

2007 ◽  
Vol 293 (1) ◽  
pp. L191-L198 ◽  
Author(s):  
Paola Algara-Suárez ◽  
Catalina Romero-Méndez ◽  
Tom Chrones ◽  
Sergio Sánchez-Armass ◽  
Ulises Meza ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Guinea Pig ◽  
Force Measurement ◽  
Isometric Force ◽  
Sustained Response ◽  
Functional Coupling ◽  
Channel Activation ◽  
Histamine Stimulation ◽  
Nonselective Cation Channels ◽  
Intracellular Ca

Airway smooth muscle (ASM) contracts partly due to an increase in cytosolic Ca2+. In this work, we found that the contraction caused by histamine depends on external Na+, possibly involving nonselective cationic channels (NSCC) and the Na+/Ca2+ exchanger (NCX). We performed various protocols using isometric force measurement of guinea pig tracheal rings stimulated by histamine. We observed that force reached 53 ± 1% of control during external Na+ substitution by N-methyl-d-glucamine+, whereas substitution by Li+ led to no significant change (91 ± 1%). Preincubation with KB-R7943 decreased the maximal force developed (52.3 ± 5.6%), whereas preincubation with nifedipine did not (89.7 ± 1.8%). Also, application of the nonspecific NCX blocker KB-R7943 and nifedipine on histamine-precontracted tracheal rings reduced force to 1 ± 3%, significantly different from nifedipine alone (49 ± 6%). Moreover, nonspecific NSCC inhibitors SKF-96365 and 2-aminoethyldiphenyl borate reduced force to 1 ± 1% and 19 ± 7%, respectively. Intracellular Ca2+ measurements in isolated ASM cells showed that KB-R7943 and SKF-96365 reduced the peak and sustained response to histamine (0.20 ± 0.1 and 0.19 ± 0.09 for KB-R, 0.43 ± 0.16 and 0.47 ± 0.18 for SKF, expressed as mean of differences). Moreover, Na+-free solution only inhibited the sustained response (0.54 ± 0.25). These data support an important role for NSCC and NCX during histamine stimulation. We speculate that histamine induces Na+ influx through NSCC that promotes the Ca2+ entry mode of NCX and CaV1.2 channel activation, thereby causing contraction.

Involvement of calcitonin gene-related peptide in control of human fetoplacental vascular tone

2004 ◽  
Vol 286 (1) ◽  
pp. H230-H239 ◽  
Author(s):  
Yuan-Lin Dong ◽  
Sujatha Vegiraju ◽  
Madhu Chauhan ◽  
Pandu R. R. Gangula ◽  
Gary D. V. Hankins ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Human Placenta ◽  
Vascular Tone ◽  
Umbilical Artery ◽  
Force Measurement ◽  
Isometric Force ◽  
Calcitonin Gene Related Peptide ◽  
Immunofluorescent Staining ◽  
Related Peptide ◽  
Calcitonin Gene

Calcitonin gene-related peptide (CGRP), one of the most potent endogenous vasodilators known, has been implicated in vascular adaptations and placental functions during pregnancy. The present study was designed to examine the existence of CGRP-A receptor components, the calcitonin receptor-like receptor (CRLR) and receptor activity-modifying protein 1 (RAMP1), in the human placenta and the vasoactivity of CGRP in the fetoplacental circulation. Immunofluorescent staining of the human placenta in term labor using polyclonal anti-CRLR and RAMP1 antibodies revealed that labeling specifically concentrated in the vascular endothelium and the underlying smooth muscle cells in the umbilical artery/vein, chorionic artery/vein, and stem villous vessels as well as in the trophoblast layer of the placental villi. In vitro isometric force measurement showed that CGRP dose dependently relaxes the umbilical artery/vein, chorionic artery/vein, and stem villous vessels. Furthermore, CGRP-induced relaxation of placental vessels are inhibited by a CGRP receptor antagonist (CGRP8–37), ATP-sensitive potassium (KATP) channel blocker (glybenclamide), and cAMP-dependent protein kinase A inhibitor (Rp-cAMPS) and partially inhibited by a nitric oxide inhibitor ( Nω-nitro-l-arginine methyl ester). We propose that CGRP may play a role in the control of human fetoplacental vascular tone, and the vascular dilations in response to CGRP may involve activation of KATP channels, cAMP, and a nitric oxide pathway.

Characterization of the postocclusive response of renal blood flow in the cat

1978 ◽  
Vol 235 (4) ◽  
pp. F286-F290 ◽  
Author(s):  
W. S. Spielman ◽  
H. Osswald
Keyword(s):  
Blood Flow ◽  
Angiotensin Ii ◽  
Renal Artery ◽  
Renal Blood Flow ◽  
Artery Occlusion ◽  
Renal Nerves ◽  
Vasoconstrictor Response ◽  
Renal Artery Occlusion ◽  
Chronic Denervation

In contrast to the postocclusive hyperemia of brain, heart, and skeletal muscle, the hemodynamic response of the kidney following renal artery occlusion is highly variable in that both hyperemia and ischemia have been reported. The present study evaluates the factors influencing the renal response to complete renal artery occlusion (5-60 s) in the anesthetized cat. Marked postocclusive vasoconstriction could only be domonstrated in meclofenamate-treated (10 mg/kg) cats. The delta% renal blood flow (RBF) (30-s occlusion) was 16 +/- 4 in controls and 54 +/- 4 after meclofenamate (n= 10; P less than 0.001). Chronic denervation of the kidney, alpha-adrenergic receptor blockade, or infusion of [Sar1, Ile8]angiotensin II(2 microgram/min per kg) did not affect the postocclusive reduction of RBF, indicating that the vasoconstriction was independent of renal nerves, catecholamines, and circulating angiotesin II. Adenosine injected into the renal artery of five cats caused a dose-dependent transient fall of RBF. A dose of 100 nmol adenosine reduced RBF by 44 +/- 6% whereas after meclofenamate only 1 nmol produced the same degree of vasoconstriction. In summary, this study demonstrates a marked potentiation of the postocclusive vasoconstrictor response and the vasoconstrictive action of adenosine by meclofenamate in the anesthetized animal. No evidence was obtained to support a role for the sympathetic nervous system or circulating angiotensin II in mediating the postocclusive vasoconstriction.

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