scholarly journals GR32191, a highly potent and specific thromboxane A2 receptor blocking drug on platelets and vascular and airways smooth muscle in vitro

1989 ◽  
Vol 97 (3) ◽  
pp. 783-794 ◽  
Author(s):  
P. Lumley ◽  
B.P. White ◽  
P.P.A. Humphrey
Keyword(s):  
Smooth Muscle ◽  
Thromboxane A2 ◽  
Blocking Drug ◽  
Thromboxane A2 Receptor ◽  
Receptor Blocking ◽  
Airways Smooth Muscle

THE EFFECTS OF GR32191, A NEW THROMBOXANE RECEPTOR BLOCKING DRUG,ON PLATELETS AND VASCULAR SMOOTH MUSCLE IN VITRO

1987 ◽  
Author(s):  
P Lumley ◽  
E W Collington ◽  
P Hallett ◽  
E J Hornby ◽  
p PA Humphrey ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Guinea Pig ◽  
Vascular Smooth Muscle ◽  
Inhibitory Activity ◽  
Whole Blood ◽  
Blocking Drug ◽  
Receptor Blocking ◽  
Thromboxane Receptor ◽  
Induced Aggregation

The effect of a new thromboxane receptor blocking drug GR32191 ([1R-[1α(Z),2β,3β,5α]]-(+)-7-[5-[[(1,1"-biphenyl)-4-yl]methoxy] -3-hydroxy-2-(l-piperidinyl)cyclopentyl]-4-heptenoic acid,hydrochloride) has been examined upon platelets and vascular smooth muscle. In human platelet-rich plasma (PRP), aggregation to thromboxane(Tx) A2, PGH2, arachidonic acid, collagen andU-46619 was antagonised by GR32191 (IC50 range 2-36 nM).Primary aggregation (PRP treated with aspirin 10 pM) to ADP, 5-HT and adrenaline were unaffected by concentrations of GR32191 up to 10 pM. In human PRP, U-46619-induced aggregation and 5-HT release were antagonised by GR32191(10-100 nM). In contrast, in theabsence of aspirin, ADP-induced 5-HT release,but not aggregation, was antagonised by the compound implicating a role for TXA2 in the release process. In human PRP GR32191 (up to 30μM) did not itself induce aggregation or, in the presence of EGTA (4 mM), induce detectable shape change. Up to 10 μM GR32191 was without effect upon the inhibitory activity of PGI2 or PGD2 and at 1μMhad no significant inhibitory activity upon fatty acid cyclooxygenase, thromboxane synthase, prostacyclin synthase, 12-lipoxygenase orphosphodiesterase. The effect of GR32191was quantified further in human platelets suspended in whole blood or physiological salt solution. Aggregation to U-46619 was antagonised byGR32191 with a pA2 (slope of the Schild regression) of 8.2 (1.3) in whole blood and 8.8 (1.3) in resuspended platelets. The compound competitively and specifically antagonised the contractions of strips of human isolatedpulmonary blood vessels and rat and guinea-pig aortic strips produced by U-46619 with pA2 (slope) values of 8.2 (1.1), 7.9 (0.9) and 8.7(0.9) respectively. In contrast contractions induced by KC1 and 5-HT (rat) orKC1and histamine (guinea-pig) were unaffectedbyconcentrations of GR32191 up to 30 μM.Thus GR32191 is a potent and specific thromboxane receptor blocking drug on platelets and vascular smooth muscle in vitro. It is orally active and long lasting in man (Thomas, M et al.,this meeting).

A Specific Thromboxane Receptor Blocking Drug, AH23848, Reduces Platelet Deposition on Vascular Grafts in Man

1990 ◽  
Vol 64 (03) ◽  
pp. 369-373 ◽  
Author(s):  
I F Lane ◽  
P Lumley ◽  
M F Michael ◽  
A M Peters ◽  
C N McCollum
Keyword(s):  
Thromboxane A2 ◽  
Mean Value ◽  
Blocking Drug ◽  
Antithrombotic Effect ◽  
Thromboxane A2 Receptor ◽  
Receptor Blocking ◽  
Treatment Groups ◽  
Thromboxane Receptor ◽  
Daily Rate ◽  
Platelet Deposition

SummaryThe antithrombotic effect of a specific thromboxane A2 receptor blocking drug, AH23848, on radio-labelled platelet deposition in mature Dacron aorto-bifemoral grafts has been evaluated in patients. Thirty patients were randomly allocated to AH23848 70 mg, aspirin 300 mg plus dipyridamole 75 mg or placebo 8-hourly for 9 days. AH23848 inhibited platelet aggregarion induced by the thromboxane ,A2 mimetic U-46619; no such effect was observed with aspirin plus dipyridamole. 111In-platelet uptake was measured as the thrombogenicity index (TI) which is a measure of the daily rate of accumulation of platelets by the graft. The mean (s.e. mean) value of 0.193 (0.029) on placebo was significantly reduced to 0.115 (0.022) by AH23848 (p <0.05) but only to 0.175 (0.028) by aspirin plus dipyridamole. There was no difference in mean platelet life span between the three treatment groups. The pronounced antithrombotic effect of AH23848 implicates thromboxane ,A2 in the process of platelet deposition in arterial prostheses and demonstrates the considerable promise of thromboxane receptor blocking drugs as antithrombotic therapy.

Aspirin-Dependent Effects on Purinergic P2Y1 Receptor Expression

2019 ◽  
Vol 119 (05) ◽  
pp. 726-734 ◽  
Author(s):  
Isabella Massimi ◽  
Laura Alemanno ◽  
Maria Guarino ◽  
Raffaella Guerriero ◽  
Massimo Mancone ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Thromboxane A2 ◽  
Adenosine Diphosphate ◽  
Receptor Expression ◽  
P2y1 Receptor ◽  
Biochemical Pathway ◽  
Thromboxane A2 Receptor ◽  
Induced Aggregation

AbstractChronic treatment with aspirin in healthy volunteers (HVs) is associated with recovery of adenosine diphosphate (ADP)-induced platelet activation. The purinergic P2Y1 receptor exerts its effects via a Gq-protein, which is the same biochemical pathway activated by thromboxane-A2 receptor. We hypothesized that recovery of ADP-induced platelet activation could be attributed to increased P2Y1 expression induced by chronic aspirin exposure. We performed a multi-phase investigation which embraced both in vitro and in vivo experiments conducted in (1) human megakaryoblastic DAMI cells, (2) human megakaryocytic progenitor cell cultures, (3) platelets obtained from HVs treated with aspirin and (4) platelets obtained from aspirin-treated patients. DAMI cells treated with aspirin or WY14643 (PPARα agonist) had a significant up-regulation of P2Y1 mRNA, which was shown to be a PPARα-dependent process. In human megakaryocytic progenitors, in the presence of aspirin or WY14643, P2Y1 mRNA expression was higher than in mock culture. P2Y1 expression increased in platelets obtained from HVs treated with aspirin for 8 weeks. Platelets obtained from patients who were on aspirin for more than 2 months had increased P2Y1 expression and ADP-induced aggregation compared with patients on aspirin treatment for less than a month. Overall, our results suggest that aspirin induces genomic changes in megakaryocytes leading to P2Y1 up-regulation and that PPARα is the nuclear receptor involved in this regulation. Since P2Y1 is coupled to the same Gq-protein of thromboxane-A2 receptor, platelet adaptation in response to pharmacological inhibition seems not to be receptor specific, but may involve other receptors with the same biochemical pathway.

scholarly journals Epithelium-dependent regulation of airways smooth muscle function. A histamine-nitric oxide pathway

1998 ◽  
Vol 7 (6) ◽  
pp. 409-411 ◽  
Author(s):  
Konstantinos Gourgoulianis ◽  
Zoe Iliodromitis ◽  
Apostolia Hatziefthimiou ◽  
Paschalis-Adam Molyvdas
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Airway Epithelium ◽  
Muscle Function ◽  
Smooth Muscles ◽  
Airways Smooth Muscle ◽  
Smooth Muscle Function ◽  
No Release ◽  
Nos Inhibitor

The airway epithelium is responsible for the production of a number of arachidonic acid and nonprostanoid inhibitory factors. Epithelium synthesises nitric oxide (NO) which may be important in regulating the function of airways smooth muscles. We studiedin vitrothe effect of histamine (100 nM100 μ M) which increases the NO release on rabbit airway smooth muscles induced by 80 mM KCl in the presence or not of 10-5Methylene blue (MB) (inactivator of guanylate cyclase) or N(G)-monomethyl L-arginine (L-NMMA), a NOS inhibitor. All experiments were done in tracheal muscle strips from 28 rabbits with epithelium and after epithelium removal. The additional use of histamine (1 μ M) on KCl contraction induced a relaxation of 10% of the initial contraction. The additional use of L-NMMA decreased the relaxation to 5% of initial contraction. MB rather than L-NMMA increased the contraction significantly(p<0.01). Epithelium removal increased the contraction induced by KCl (80 mM) and histamine (1 μ M) by about 30%(p<0.001). NO release especially from epithelium regulates the airways smooth muscle functions. Damage to the epithelium may contribute to an increase in airways sensitivity, observed in asthma.

Human bronchial smooth muscle cell proliferation via thromboxane A2 receptor

2004 ◽  
Vol 71 (6) ◽  
pp. 375-382 ◽  
Author(s):  
Yusuke Suzuki ◽  
Koichiro Asano ◽  
Yoshiki Shiraishi ◽  
Tsuyoshi Oguma ◽  
Tetsuya Shiomi ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Thromboxane A2 ◽  
Smooth Muscle Cell Proliferation ◽  
Bronchial Smooth Muscle ◽  
Thromboxane A2 Receptor

Increased in vitro airway responsiveness in sheep following repeated exposure to antigen in vivo

1985 ◽  
Vol 59 (6) ◽  
pp. 1874-1878 ◽  
Author(s):  
E. M. Wagner ◽  
S. R. Kleeberger ◽  
E. W. Spannhake ◽  
G. K. Adams
Keyword(s):  
Smooth Muscle ◽  
Thromboxane A2 ◽  
Airway Responsiveness ◽  
Tracheal Smooth Muscle ◽  
Prostaglandin F2 Alpha ◽  
Peripheral Airway ◽  
Exposure In Vivo ◽  
Thromboxane A2 Analogue

We have studied the effect of repeated in vivo antigen exposure on in vitro airway responsiveness in sensitized sheep. Fourteen sheep underwent five biweekly exposures to aerosolized Ascaris suum antigen or saline. Following this exposure regimen, the animals were killed and tracheal smooth muscle and lung parenchymal strips were prepared for in vitro studies of isometric contraction in response to histamine, methacholine, prostaglandin F2 alpha, and a thromboxane A2 analogue. No alteration in tracheal smooth muscle responsiveness was observed between saline- and antigen-exposed tissue. In contrast, by use of lung parenchymal strips as an index of peripheral airway responsiveness, significant increases in responsiveness to histamine and a thromboxane A2 analogue (10(-6) and 10(-5) M) were observed in antigen-exposed tissue compared with saline controls. These results demonstrate that repeated antigen exposure in vivo selectively increase the responsiveness of peripheral lung smooth muscle to certain chemical mediators of anaphylaxis.

scholarly journals Deficiency of the MicroRNA-31–MicroRNA-720 Pathway in the Plasma and Endothelial Progenitor Cells From Patients With Coronary Artery Disease

2014 ◽  
Vol 34 (4) ◽  
pp. 857-869 ◽  
Author(s):  
Hsei-Wei Wang ◽  
Tse-Shun Huang ◽  
Hung-Hao Lo ◽  
Po-Hsun Huang ◽  
Chih-Ching Lin ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Progenitor Cells ◽  
Endothelial Progenitor Cells ◽  
Thromboxane A2 ◽  
Endothelial Progenitor ◽  
Α Subunit ◽  
Thromboxane A2 Receptor ◽  
Artery Disease

Objective— Defects in angiogenesis/vasculogenesis or vessel repair are major complications of coronary artery disease (CAD). Endothelial progenitor cells (EPCs) play a fundamental role in postnatal vascular repair and CAD. The role of microRNAs in CAD pathogenesis and their potential as biomarkers remain to be elucidated. Approach and Results— MicroRNA-31 (miR-31) level in both the plasma and EPCs of patients with CAD is found lower. miR-31 regulates EPC activities by targeting FAT atypical cadherin 4 and thromboxane A2 receptor, which show increased expression in CAD EPCs. Overexpressing miR-31 in CAD EPCs rescued their angiogenic and vasculogenic abilities both in vitro and in vivo. When exploring approaches to restore endogenous miR-31, we found that far-infrared treatment enhanced the expression of not only miR-31, but also miR-720 in CAD EPCs. miR-720, which was also decreased in EPCs and the plasma of patients with CAD, stimulated EPC activity by targeting vasohibin 1. The miR720–vasohibin 1 pair was shown to be downstream of FAT atypical cadherin 4, but not of thromboxane A2 receptor. FAT atypical cadherin 4 inhibited miR-720 expression via repression of the planar cell polarity signaling gene four-jointed box 1 ( FJX1 ), which was required for miR-720 expression through a hypoxia-inducible factor 1, α subunit–dependent mechanism. Restoring miR-720 level strengthened activity of CAD EPCs. The miR-31–miR-720 pathway is shown critical to EPC activation and that downregulation of this pathway contributes to CAD pathogenesis. Circulating levels of miR-31, miR-720, and vasohibin 1 have the potential to allow early diagnosis of CAD and to act as prognosis biomarkers for CAD and other EPC-related diseases. Conclusions— Manipulating the expression of the miR-31–miR-720 pathway in malfunction EPCs should help develop novel therapeutic modalities.

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