The reversible oral P2Y12 antagonist AZD6140 inhibits ADP-induced contractions in murine and human vasculature

Högberg, Carl; Svensson, Helen; Gustafsson, Ronny; Eyjolfsson, Atli; Erlinge, David

doi:10.1016/j.ijcard.2008.12.091

Cited by 51 publications

(51 citation statements)

References 18 publications

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“…The P2Y 12 receptor has previously been reported to mediate contraction of human internal mammary and pericardial fat arteries and mouse aorta (Wihlborg et al, 2004;Högberg et al, 2010), but not mouse mesenteric artery (Vial and Evans, 2002). If it has widespread contractile effects in the vasculature, then this could be of therapeutic importance.…”

Section: Discussionmentioning

confidence: 99%

“…P2Y 12 receptors have been reported to contract human isolated arteries (Wihlborg et al, 2004;Högberg et al, 2010); therefore, the effects of AR-C69931MX, a potent and selective P2Y 12 antagonist, were determined. AR-C69931MX (0.1 nM-10 M) had no effect on rat IPA basal tone, but inhibited contractions produced by ATP (300 M) in a concentrationdependent fashion, with an IC 50 of 9.9 nM (95% confidence limits of 2.0 -49.8 nM), Hill slope of 0.97, and maximum inhibition of 33.3 Ϯ 4.1% (Fig.…”

Section: Atp-sensitivementioning

confidence: 99%

“…In addition, nucleotides are rapidly dephosphorylated by ectoenzymes in vascular smooth muscle (Evans and Kennedy, 1994;Leff, 1995: Robson et al, 2006), which decreases their apparent potency and can lead to the production of metabolites that are active at other receptor subtypes. For example, the initial metabolite produced from ATP is ADP, an agonist at P2Y 12 receptors (Bodor et al, 2003), which were reported to mediate the contraction of human isolated arteries (Wihlborg et al, 2004;Högberg et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Identification of Contractile P2Y₁, P2Y₆, and P2Y₁₂Receptors in Rat Intrapulmonary Artery Using Selective Ligands

Mitchell

Syed

Tengah

et al. 2012

J Pharmacol Exp Ther

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ATP and UDP constrict rat intrapulmonary arteries, but which receptors mediate these actions is unclear. Here, we used selective agonists and antagonists, along with measurements of P2Y receptor expression, to characterize the receptor subtypes involved. Isometric tension was recorded from endotheliumdenuded rat intrapulmonary artery rings (i.d. 200 -500 m) mounted on a wire myograph. Expression of P2Y receptor subtype expression was determined by using reverse transcriptionpolymerase chain reaction with receptor-specific oligonucleotide primers. The selective P2Y 1 agonist (N)-methanocarba-2-methylthioadenosine-5Ј-O-diphosphate (MRS2365) induced small, concentration-dependent contractions that were inhibited by the P2Y 1 antagonist N 6 -methyl-2Ј-deoxyadenosine-3Ј,5Ј-bisphosphate (MRS2179). Contractions evoked by ATP were unaffected by MRS2179, but inhibited by approximately one-third by the P2Y 12 antagonist N 6 -(2-methylthiomethyl)-2-(3,3,3-trifluoropropylthio)dichloro-methylene ATP (AR-C69931MX). Combined blockade of P2X1 and P2Y 12 receptors virtually abolished the response to ATP. ADP also evoked contractions that were abolished by AR-C69931MX. The selective P2Y 6 receptor agonist 3-(2-oxo-2-phenylethyl)-UDP (PSB 0474) evoked concentrationdependent contractions and was approximately three times more potent than UDP, but the P2Y 14 agonist UDP-glucose had no effect. Contractions evoked by UDP were inhibited by the P2Y 6 receptor antagonist N,NЈ-1,4-butanediylbis-NЈ-(3-isothiocyanatophenyl)thiourea (MRS2578), but not the cysteinyl leukotriene 1 (CysL 1 ) antagonist 3-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)((3-dimethylamino-3-oxopropyl)thio)methyl)thiopropanoic acid (MK571). Higher concentrations of MRS2578 inhibited contractions to KCl, so they were not studied further. mRNA for P2Y 1 , P2Y 6 , and P2Y 12 receptors was identified. Our working model is that P2Y 12 and P2X1 receptors are present in rat intrapulmonary arteries and together mediate ATP-induced vasoconstriction. Contractile P2Y 6 , but not P2Y 14 or CysLT 1 , receptors are also present and are a major site through which UDP evokes constriction.

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Section: Discussionmentioning

confidence: 99%

Section: Atp-sensitivementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Identification of Contractile P2Y₁, P2Y₆, and P2Y₁₂Receptors in Rat Intrapulmonary Artery Using Selective Ligands

Mitchell

Syed

Tengah

et al. 2012

J Pharmacol Exp Ther

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“…12 In bench studies, high doses of oral clopidogrel treatment had no inhibitory effect, whereas ticagrelor added ex vivo inhibited P2Y12-mediated vasoconstriction in murine vessels, human internal mammary arteries, and small human arteries. 13 In a dog thrombosis model, animals treated with ticagrelor had significantly lower rates of reocclusion, less cyclic flow variation, and longer reflow duration compared with animals treated with clopidogrel, despite similar antiplatelet effects.…”

Section: Findings and Interpretationmentioning

confidence: 93%

Differential Effect of Ticagrelor Versus Prasugrel on Coronary Blood Flow Velocity in Patients With Non–ST-Elevation Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention

Alexopoulos¹,

Moulias²,

Koutsogiannis³

et al. 2013

Circ: Cardiovascular Interventions

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In the present study of patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) treated with percutaneous Background-Prasugrel and ticagrelor provide a superior anti-ischemic action than clopidogrel, with some of ticagrelor's benefits possibly attributed to adenosine-mediated mechanisms. We aimed to compare the effect of maintenance dose of ticagrelor versus prasugrel on coronary blood flow velocity (CBFV) during increasing doses of intravenously administered adenosine. Methods and Results-In a prospective, single-center, single-blind, crossover study, 56 patients with non-ST-elevation acute coronary syndrome undergoing percutaneous coronary intervention were randomized to receive either ticagrelor 90 mg BID or prasugrel 10 mg OD with a 15-day treatment period. At the end of each treatment period, CBFV by transthoracic Doppler echocardiography was assessed at baseline and under incremental doses (50 μg/kg per minute, 80 μg/kg per minute, 110 μg/kg per minute, and 140 μg/kg per minute) of adenosine infusion. Maximal CBFV area under the curve was higher for ticagrelor-treated than for prasugrel-treated patients, with a least squares mean difference of 7.16 (95% confidence interval, 2.61-11.7; P=0.003). Maximal CBFV/baseline CBFV ratio was higher with ticagrelor than prasugrel at 50, 80, and 110 μg/ kg per minute but not at 140 μg/kg per minute adenosine infusion rate, with mean difference (95% confidence interval) of 0.17 (0.08-0.26; P<0.001), 0.21 (0.02-0.41; P=0.03), 0.24 (0.01-0.47; P=0.04), and 0.14 (−0.12 to 0.4; P=0.3), respectively. Conclusions-In patients with non-ST-elevation acute coronary syndrome undergoing percutaneous coronary intervention, ticagrelor augments CBFV to a greater extent than prasugrel when incremental doses of adenosine are administered. Although exploratory, these results may represent a pleiotropic action of ticagrelor, possibly contributing to its beneficial effects in such patients. Clinical Methods Study ProtocolWe performed a prospective, single-center, single-blind, investigator-initiated, randomized, crossover study to compare the effect of ticagrelor versus prasugrel on adenosine-induced CBFV responses. Consecutive patients aged 18 to 75 years with NSTE-ACS undergoing PCI with drug-eluting stent implantation were included. Patients admitted with ST-elevation myocardial infarction were excluded to avoid possible influence of the infarcted myocardium and left ventricular remodeling to CBFV. 8 Other exclusion criteria were prior myocardial infarction, prior PCI, coronary artery bypass grafting, nonsinus rhythm, requiring hemodialysis, major periprocedural complications or suboptimal PCI result (residual stenosis >20% by visual assessment), contraindication for ticagrelor or prasugrel administration, weight <60 kg, age ≥75 years, risk for bleeding or bradycardic events, severe chronic obstructive pulmonary disease, requirement for oral anticoagulant, left ventricular ejection fraction <45%, left ventricular hypertrophy, diastolic dysfunction, severe valvular disease, an...

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“…The best explanation is that unlike platelets, P2Y 12 receptors are found in many cells including leukocytes, vascular smooth muscle cells, macrophages, microglial, specific subregions of the brain, and dendritic cells. This increases the number of potential effects of ticagrelor [8][9][10][11][12] . Furthermore, the "pleiotropic effects" of ticagrelor may also occur due to different mechanisms other than interaction with the P2Y 12 receptor [13] .…”

Section: Introductionmentioning

confidence: 99%

Böbrekte İskemi-Reperfüzyon Hasarında Ticagrelor’un Etkisi: Pleiotropik Etki Geçerli Bir Faktör mü?

Bağcıoğlu¹,

Kocaaslan²,

Uslu³

et al. 2017

Kafkas Univ Vet Fak Derg

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Citation of This ArticleBağcıoğlu M, Kocaaslan R, Uslu M, Fındık Güvendi G: The effect of ticagrelor on ischemia-reperfusion injury of kidney: Is the pleiotropic effect a valid factor? Kafkas Univ Vet Fak Derg, 23 (6): 917-924, 2017. DOI: 10.9775/kvfd.2017 AbstractThe goal of this study was to determine the protective effect of ticagrelor against ischemia-reperfusion injury in the kidney of rats via histological examination, biochemical parameters, and immunohistochemical analysis. Thirty male rats were randomized into five groups. The animals received ticagrelor 5 mg/kg, 10 mg/kg and 20 mg/kg or normal saline 0.1 mL/kg (control) orally before the procedure. The shame group only had laparatomy. An ischemia-reperfusion injury was done by clamping the renal hilus. There was less malondealdehyde assay (MDA) in ticagrelor groups than the control group, and this decrease was statistically significant (P=0.001 in all ticagrelor received groups). The glutathione peroxidase (GPx) and glutathione reductase (GR) were elevated in ticagrelor groups at all doses. Similar findings were observed in all treatment groups. The 5 mg ticagrelor treated group had no changes in glomerules and tubules relative to the control group via histology. Dilated tubular structures were similar to the sham group-both at 10 and 20 mg ticagrelor. Caspas-3 and NF-KB activity was similar in ticagrelor treated groups to sham group. Our study showed that ticagrelor is an effective agent to protect kidney from renal ischemia-reperfusion injury. Ticagrelor may protect the tissues by reducing the concentration of reactive oxygen species and inducing the antioxidant system-especially with the pleiotropic effect. Keywords: Kidney, Ischemia, Reperfusion, Injury, TicagrelorBöbrekte İskemi-Reperfüzyon Hasarında Ticagrelor'un Etkisi: Pleiotropik Etki Geçerli Bir Faktör mü? ÖzetBu çalışmada, ticagrelor'un ratların böbreğinde oluşturulan iskemi-reperfüzyon hasarına karşı koruyucu etkisinin histolojik, biyokimyasal ve immünohistokimyasal yöntemler kullanılarak tanımlanması amaçlanmıştır. Bu amaçla, 30 erkek rat rastgele olarak 5 gruba ayırılmıştır. Bu hayvanlara, yapılacak işlemlerden önce ticagrelor 5 mg/kg, 10 mg/kg ve 20 mg/kg dozlarında, kontrol grubuna da 0.1 mL/kg serum fizyolojik oral olarak verilmiştir. Sham grubunda ise sadece laparatomi yapılmıştır. İskemi-reperfüzyon hasarı renal hilusun klemplenmesi yoluyla yapılmıştır. Ticagrelor verilen gruplarda saptanan malondialdehit (MDA) düzeyinin kontrol grubundan daha az olduğu ve bu düşüklüğün istatistiksel olarak anlamlı olduğu tespit edildi (tüm ticagrelor grupları için P=0.001). Glutatyonperoksidaz (GPx) ve glutatyonredüktaz (GR) düzeyleride ticagrelor verilen tüm gruplarda artmış olarak bulundu. Histopatolojik incelemelerde, tedavi verilen tüm gruplarda benzer sonuçlar gözlendi. Ancak 5 mg ticagrelor verilen grupta glomerul ve tübül yapısında kontrol grubu arasında fark olmadığı belirlendi. 10 ve 20 mg ticagrelor verilen gruplarda, sham grubuna benzer özellikte dilate tübüler yapılar olduğu gözlendi. C...

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The reversible oral P2Y12 antagonist AZD6140 inhibits ADP-induced contractions in murine and human vasculature

Cited by 51 publications

References 18 publications

Identification of Contractile P2Y₁, P2Y₆, and P2Y₁₂Receptors in Rat Intrapulmonary Artery Using Selective Ligands

Identification of Contractile P2Y₁, P2Y₆, and P2Y₁₂Receptors in Rat Intrapulmonary Artery Using Selective Ligands

Differential Effect of Ticagrelor Versus Prasugrel on Coronary Blood Flow Velocity in Patients With Non–ST-Elevation Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention

Böbrekte İskemi-Reperfüzyon Hasarında Ticagrelor’un Etkisi: Pleiotropik Etki Geçerli Bir Faktör mü?

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The reversible oral P2Y12 antagonist AZD6140 inhibits ADP-induced contractions in murine and human vasculature

Cited by 51 publications

References 18 publications

Identification of Contractile P2Y1, P2Y6, and P2Y12Receptors in Rat Intrapulmonary Artery Using Selective Ligands

Identification of Contractile P2Y1, P2Y6, and P2Y12Receptors in Rat Intrapulmonary Artery Using Selective Ligands

Differential Effect of Ticagrelor Versus Prasugrel on Coronary Blood Flow Velocity in Patients With Non–ST-Elevation Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention

Böbrekte İskemi-Reperfüzyon Hasarında Ticagrelor’un Etkisi: Pleiotropik Etki Geçerli Bir Faktör mü?

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Identification of Contractile P2Y₁, P2Y₆, and P2Y₁₂Receptors in Rat Intrapulmonary Artery Using Selective Ligands

Identification of Contractile P2Y₁, P2Y₆, and P2Y₁₂Receptors in Rat Intrapulmonary Artery Using Selective Ligands