scholarly journals Heteromerization fingerprints between bradykinin B2 and thromboxane TP receptors in native cells

PLoS ONE ◽  
2019 ◽  
Vol 14 (5) ◽  
pp. e0216908 ◽  
Author(s):  
Oula K. Dagher ◽  
Miran A. Jaffa ◽  
Aïda Habib ◽  
Fuad N. Ziyadeh ◽  
Ayad A. Jaffa
Keyword(s):  
Tp Receptors

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.

TP receptors regulate renal hemodynamics during angiotensin II slow pressor response

2004 ◽  
Vol 287 (4) ◽  
pp. F753-F759 ◽  
Author(s):  
Noritaka Kawada ◽  
Kathryn Dennehy ◽  
Glenn Solis ◽  
Paul Modlinger ◽  
Rebecca Hamel ◽  
...  
Keyword(s):  
Pressor Response ◽  
Thiobarbituric Acid ◽  
Ang Ii ◽  
Wild Type ◽  
Thiobarbituric Acid Reactive Substances ◽  
Filtration Fraction ◽  
Arterial Blood ◽  
Tp Receptors ◽  
Prostaglandin H ◽  
Renal Vascular

We investigated the hypothesis that thromboxane A2 (TxA2)-prostaglandin H2 receptors (TP-Rs) mediate the hemodynamic responses and increase in reactive oxygen species (ROS) to ANG II (400 ng·kg−1·min−1 sc for 14 days) using TP-R knockout (TP −/−) and wild-type (+/+) mice. TP −/− had normal basal mean arterial blood pressure (MAP) and glomerular filtration rate but reduced renal blood flow and increased filtration fraction (FF) and renal vascular resistance (RVR) and markers of ROS (thiobarbituric acid-reactive substances and 8-isoprostane PGF2α) and nitric oxide (NOx). Infusion of ANG II into TP +/+ increased ROS and thromboxane B2 (TxB2) and increased RVR and FF. ANG II infusion into TP −/− mice reduced ANG I and increased aldosterone but caused a blunted increase in MAP (TP −/−: +6 ± 2 vs. TP +/+: +15 ± 3 mmHg) and failed to increase FF, ROS, or TxB2 but increased NOx and paradoxically decreased RVR (−2.1 ± 1.7 vs. +2.6 ± 0.8 mmHg·ml−1·min−1·g−1). Blockade of AT1 receptor of TP −/− mice infused with ANG II reduced MAP (−8 mmHg) and aldosterone but did not change the RVR or ROS. In conclusion, during an ANG II slow pressor response, AT1 receptors activate TP-Rs that generate ROS and prostaglandins but inhibit NO. TP-Rs mediate all of the increase in RVR and FF, part of the increase in MAP, but are not implicated in the suppression of ANG I or increase in aldosterone. TP −/− mice have a basal increase in RVR and FF associated with ROS.

Prostanoid and TP-receptors in atherothrombosis: Is there a role for their antagonism?

2010 ◽  
Vol 104 (11) ◽  
pp. 949-954 ◽  
Author(s):  
Chiara Giannarelli ◽  
M. Urooj Zafar ◽  
Juan Badimon
Keyword(s):  
Smooth Muscle ◽  
Endothelial Dysfunction ◽  
Platelet Activation ◽  
Critical Role ◽  
Clinical Manifestations ◽  
Plaque Burden ◽  
Platelet Activity ◽  
Tp Receptor ◽  
Tp Receptors ◽  
Plaque Stabilisation

SummaryAtherosclerosis and its clinical manifestations (i.e. myocardial infarction, stroke) are major causes of mortality and morbidity in Western countries. Endothelial dysfunction is considered the first step in the cascade leading up to coronary events. Increasing evidence suggests that direct inhibition of thromboxane A2/prostaglandin (TP)-receptors may not only have anti-platelet effects but also impact endothelial dysfunction as well as inflammatory component of atherosclerosis. While TP-receptor involvement in platelet function has received the greatest attention, more recent findings support the critical role of TP-receptor in other pathophysiological aspects of atherothrombosis. Prostanoids (i.e. TxA2, F2-isoprostanes, prostaglandins endoperoxides PGG2/PGH2) are known to promote the initiation and progression of atherosclerosis, not only via platelet activation, but through leukocyte-endothelial interactions and vasoconstriction. Dysfunctional endothelium, characterised by increased COX-activity, releases prostanoids that promote endothelial exposure to adhesion molecules and induce smooth muscle cell contraction. Plaque macrophages synthesise PGH2/PGG2 via COX-2; these potent prostanoids can trigger platelet activation and aggregation despite COX-1 inhibition by aspirin. TP-receptor inhibition has been reported to exert anti-atherosclerotic effects in pre-clinical model of disease. Reduction of plaque burden was associated with plaque stabilisation documented by the reduction in the content of macrophages, apoptotic cells, MMPs and endothelin-1, and the increase in smooth muscle cells content. TP-receptor blockade might have an anti-athero-sclerotic and plaque stabilisation effect. The possibility of combining anti-platelet activity with an anti-atherosclerotic effect via selective TP-receptor inhibitors could have important implications especially in clinical conditions associated with increased production of prostanoids, such as diabetes.

Epinephrine correction of impaired platelet thromboxane receptor signaling

2000 ◽  
Vol 279 (6) ◽  
pp. C1760-C1771 ◽  
Author(s):  
Patricia C. Dunlop ◽  
Linda A. Leis ◽  
Gerhard J. Johnson
Keyword(s):  
G Protein ◽  
Human Platelet ◽  
Human Platelets ◽  
Binding Studies ◽  
G Protein Coupling ◽  
Protein Coupling ◽  
Thromboxane Receptor ◽  
Tp Receptor ◽  
Tp Receptors ◽  
Platelet Secretion

This study evaluated the mechanism of epinephrine potentiation of platelet secretion induced by thromboxane A2(TXA2). Dog platelets that do not secrete in response to TXA2alone (TXA2−) were compared with dog platelets that do secrete (TXA2+) and with human platelets. TXA2− platelets had impaired TXA2receptor (TP receptor)-G protein coupling, indicated by 1) impaired stimulated GTPase activity, 2) elevated basal guanosine 5′- O-(3-thiotriphosphate) binding, and 3) elevated Gαqpalmitate turnover that was corrected by preexposure to epinephrine. Kinetic agonist binding studies revealed biphasic dog and human platelet TP receptor association and dissociation. TXA2− and TP receptor-desensitized TXA2+ dog and human platelets had altered ligand binding parameters compared with untreated TXA2+ or human platelets. These parameters were reversed, along with impaired secretion, by epinephrine. Basal phosphorylation of TXA2− platelet TP receptors was elevated 60% and was normalized by epinephrine. Epinephrine potentiates platelet secretion stimulated by TXA2by reducing basal TP receptor phosphorylation and facilitating TP receptor-G protein coupling in TXA2− platelets and, probably, in normal platelets as well.

Prostaglandin I2 mediates weak vasodilatation in human placental microvessels

2020 ◽  
Vol 103 (6) ◽  
pp. 1229-1237
Author(s):  
Xueqin Feng ◽  
Yingying Zhang ◽  
Yumeng Zhang ◽  
Xiaojun Yang ◽  
Dongmei Man ◽  
...  
Keyword(s):  
Human Placenta ◽  
Functional Results ◽  
The Body ◽  
Prostaglandin I2 ◽  
Synthesis Inhibitor ◽  
Pharmacological Response ◽  
Tp Receptors ◽  
K Current ◽  
Crucial Information ◽  
Placental Microvessels

Abstract Human placental vessels (HPVs) play important roles in the exchange of metabolites and oxygen in maternal-fetal circulation. Endothelial-derived prostacyclin (prostaglandin I2, PGI2) is a critical endothelial vasodilator in the body. However, the physiological and pharmacological functions of endothelial PGI2 in the human placenta are still unclear. Human, sheep, and rat blood vessels were used in this study. Unlike non-placental vessels (non-PVs), the PGI2 synthesis inhibitor tranylcypromine (TCP) did not modify 5-hydroxytryptamine (5-HT)-induced vascular contraction, indicating that endothelial-derived PGI2 was weak in PVs. Vascular responses to exogenous PGI2 showed slight relaxation followed by a significant contraction at a higher concentration in HPV, which was inhibited by the thromboxane-prostanoid (TP) receptors antagonist SQ-29,548. Testing PVs and non-PVs from sheep also showed similar functional results. More TP receptors than PGI2 (IP) receptors were observed in HPVs. The whole-cell K+ current density of HPVs was significantly weaker than that of non-PVs. This study demonstrated the specific characteristics of the placental endogenous endothelial PGI2 system and the patterns of placental vascular physiological/pharmacological response to exogenous PGI2, showing that placental endothelial PGI2 does not markedly contribute to vascular dilation in the human placenta, in notable contrast to non-PVs. The results provide crucial information for understanding the endothelial roles of HPVs, which may be helpful for further investigations of potential targets in the treatment of diseases such as preeclampsia.

scholarly journals Loss of prostaglandin F2α, but not thromboxane, responsiveness in pregnant human myometrium during labour

2008 ◽  
Vol 197 (1) ◽  
pp. 171-179 ◽  
Author(s):  
Deborah P Fischer ◽  
Jonathon A Hutchinson ◽  
Diane Farrar ◽  
Peter J O'Donovan ◽  
David F Woodward ◽  
...  
Keyword(s):  
Spontaneous Activity ◽  
Isometric Force ◽  
Area Under The Curve ◽  
Prostaglandin F2α ◽  
Late Gestation ◽  
Human Myometrium ◽  
Uterine Contractility ◽  
Arithmetic Means ◽  
Tp Receptors ◽  
Labour Onset

Prostaglandins (PG) E2, PGF2α and thromboxane (TX) mediate uterine contractility by targeting prostonoid EP, FP and TP receptors respectively. The aim of this study was to elucidate the function of these receptors in isolated human myometrium taken at term gestation prior to and following labour onset. Lower segment myometrial strips were immersed in organ baths in oxygenated Krebs' solution at 37 °C and connected to isometric force transducers. After equilibration, spontaneous activity and concentration responses to PGE2, PGF2α and U46619 (a stable TX mimetic) were measured as area under the curve and expressed as a percentage of the final contraction induced by hypotonic shock. Results were expressed as arithmetic means±s.e.m. and analysed using two-way ANOVA with Bonferroni's post hoc test. Myometrium excised at late gestation displayed the greatest spontaneous activity compared with the tissues taken during labour (P<0.001). Excitation evoked by PGF2α (P<0.01) and PGE2 at 10−5 mol/l were attenuated after labour onset. U46619 consistently stimulated concentration-dependent contractions (P<0.001) and selective antagonists confirmed TP-mediated effects. The maintained responses to TX indicate crucial roles for TP receptors in the muscular tonus of the parturient uterus. This receptor and its secondary messenger system represent effective myometrial targets for tocolytic agents in both pregnancy and labour-associated disorders.

scholarly journals A role for the thromboxane receptor in l-NAME hypertension

2008 ◽  
Vol 295 (4) ◽  
pp. F1096-F1102 ◽  
Author(s):  
Helene Francois ◽  
Natalia Makhanova ◽  
Philip Ruiz ◽  
Jonathan Ellison ◽  
Lan Mao ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cardiac Hypertrophy ◽  
Weight Ratio ◽  
Kidney Injury ◽  
Lipid Mediator ◽  
Wild Type ◽  
Nitric Oxide Synthase Inhibitor ◽  
Tp Receptor ◽  
Tp Receptors ◽  
Synthase Inhibitor

Actions of the lipid mediator thromboxane (Tx) A2 acting through the TP receptor contribute to the pathogenesis of cardiovascular disease. To further explore the role of TxA2 in hypertension, we examined the consequences of deficiency of the TP receptor on the course of hypertension associated with endothelial dysfunction and salt sensitivity. To this end, the nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester (l-NAME) was administered to TP-deficient ( Tp−/−) and wild-type ( Tp+/+) control mice in drinking water for 21 wk along with a high-salt (HS; 6% NaCl) diet. Administration of l-NAME increased urinary excretion of TxB2 to a similar extent in both Tp+/+ and Tp−/− animals. l-NAME also caused significant and sustained elevations in blood pressure that reached a maximum between weeks 3 and 6. However, the severity of hypertension was attenuated in the Tp−/− mice throughout the study period ( P < 0.001). At the end of the study, the wild-type mice developed significant cardiac hypertrophy (23.6 ± 2% increase in heart-to-body weight ratio). The severity of cardiac hypertrophy was attenuated in the TP-deficient group (11.1 ± 2.6%; P < 0.05). In contrast, kidney hypertrophy was exaggerated in the Tp−/− mice compared with controls (37.1 ± 5.4 vs. 12.3 ± 2.3%; P < 0.01). Moreover, the severity of glomerulosclerosis, tubule vacuolization, and interstitial chronic inflammation was also enhanced in the Tp−/− group ( P < 0.01). Thus, in l-NAME hypertension, TP receptors contribute to elevated blood pressure and cardiac hypertrophy. In this model, TP receptors also provided unexpected protection against kidney injury.

scholarly journals Thromboxane A2 Induces Itch-Associated Responses through TP Receptors in the Skin in Mice

2007 ◽  
Vol 127 (8) ◽  
pp. 2042-2047 ◽  
Author(s):  
Tsugunobu Andoh ◽  
Yumi Nishikawa ◽  
Tomomi Yamaguchi-Miyamoto ◽  
Hiroshi Nojima ◽  
Shu Narumiya ◽  
...  
Keyword(s):  
Thromboxane A2 ◽  
Tp Receptors

Abstract 520: Thromboxane Receptors in Smooth Muscle Promote Hypertension, Vascular Remodeling and Sudden Death

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Matthew A Sparks ◽  
Natalia Makhanova ◽  
Robert C Griffiths ◽  
John N Snouwaert ◽  
Beverly Koller ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Sudden Death ◽  
Smooth Muscle Cells ◽  
Vascular Remodeling ◽  
Muscle Cells ◽  
Link Type ◽  
Tp Receptor ◽  
Induced Hypertension ◽  
Tp Receptors

The prostanoid thromboxane (TxA2) is a potent vasoconstrictor and platelet aggregant that has been implicated in the pathogenesis of cardiovascular diseases including hypertension. Actions of thromboxane (TP) receptors in platelets and the vasculature have both been implicated in cardiovascular pathogenesis. To distinguish the contributions of vascular TP receptors in isolation, we generated mice with cell-specific deletion of TP receptors in smooth muscle cells (TP-SMKOs) using Cre/Loxp technology. We used the KISM22α-Cre transgenic mouse line, with Cre recombinase “knocked-in” to the Sm22α gene locus, to excise the conditional Tp receptor allele specifically in smooth muscle. mRNA for the TP-receptor was easily detected in aortae from control mice, but not from TP-SMKOs (P<0.005). Similarly, TP receptor mRNA expression in mesenteric arteries, with intact endothelium and adventitia, was decreased by ≈80% in TP-SMKOs (P=0.05). In TP-SMKOs, acute vasoconstrictor responses to the TP agonist U46619 were dramatically attenuated by ≈60% in both the peripheral and renal circulations (P<0.05), whereas acute vascular responses to angiotensin II were unaffected. Infusion of high-dose U46619 caused circulatory collapse and death in a majority of control mice, but TP-SMKOs were completely protected from U46619 -induced sudden death (P<0.05). Baseline blood pressures measured by radiotelemetry were similar in TP-SMKOs (111±1 mmHg) and Controls (114±1 mmHg; P=NS). However, the absence of TP receptors in vascular smooth muscle cells caused significant attenuation of angiotensin II-induced hypertension (controls: 159±2 mm Hg; TP-SMKO: 145±8 mm Hg, P<0.05) and diminished aortic medial hypertrophy in TP-SMKOs (59±4 μm) vs. Controls (79±7 μm; P<0.05). Thus, vascular TP receptors play a major role in shock, angiotensin II-induced hypertension, and vascular remodeling.

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