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P2Y1 Receptor Antagonist (p2y1 + receptor_antagonist)
Selected AbstractsInhibition of localized thrombosis in P2Y1 -deficient mice and rodents treated with MRS2179, a P2Y1 receptor antagonistJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 6 2003N. Lenain Summary., Previous studies in experimental models revealed a role for the P2Y1 platelet ADP receptor in systemic vascular thromboembolism models. In the present work, we used models of localized arterial and venous thrombosis to assess the role of the P2Y1 receptor in these processes. Arterial thrombosis was induced in one mesenteric arteriole of a mouse using FeCl3, while venous thrombosis was studied in a Wessler model adapted to rats. P2Y1 -deficient mice and mice treated with the P2Y1 antagonist MRS2179 displayed significantly less arterial thrombosis than their respective controls. Combination of P2Y1 deficiency with P2Y12 inhibition led to a significant additive effect. Venous thrombosis was slightly but significantly inhibited in MRS2179-treated rats. These results demonstrate a role for the P2Y1 receptor in both arterial and venous thrombosis, further establishing this receptor as a potential target for antithrombotic drugs. [source] Excitatory purinergic neurotransmission in smooth muscle of guniea-pig taenia caeciTHE JOURNAL OF PHYSIOLOGY, Issue 3 2005Yong Zhang Non-adrenergic, non-cholinergic (NANC) inhibitory neurotransmission has been an area of intense interest in gut motor physiology, whereas excitatory NANC neurotransmission has received less attention. In order to further explore excitatory NANC neurotransmission, we performed conventional intracellular recordings from guinea-pig taenia caeci smooth muscle. Tissue was perfused with oxygenated Krebs solution at 35°C and nerve responses evoked by either oral or aboral nerve stimulation (NS) (4 square wave pulses, 0.3 ms duration, 20 Hz). Electrical activity was characterized by slow waves upon which one to three action potentials were superimposed. Oral NS evoked an inhibitory junction potential (IJP) at either the valley or peak of the slow wave. Application of nifedipine (1 ,m) abolished slow waves and action potentials, but membrane potential flunctuations (1,3 mV) and IJPs remained unaffected. Concomitant application of apamin (300 nm), a small-conductance Ca2+ -activated K+ channel blocker, converted the IJP to an EJP that was followed by slow IJP. Further administration of NG -nitro- l -arginine methyl ester (l -NAME, 200 ,m), a nitric oxide synthase inhibitor, abolished the slow IJP without affecting the EJP, implying that the slow IJP is due to nitrergic innervation. The EJP was abolished by tetrodotoxin (1 ,m), but was not significantly affected by atropine (3 ,m) and guanethidine (3 ,m) or hexamethonium (500 ,m). Substance P (SP, 1 ,m) desensitization caused slight attenuation of the EJP, but the EJP was abolished by desensitization with ,,,-methylene ATP (50 ,m), a P2 purinoceptor agonist that is more potent than ATP at the P2X receptor subtype, suramin (100 ,m), a non-selective P2 purinoceptor antagonist, and pyridoxal-phosphate-6-azophenyl-2,,4,-disulphonic acid (PPADS, 100 ,m), a selective P2X purinoceptor antagonist. In contrast, the EJP was unaffected by MRS-2179 (2 ,m), a selective P2Y1 receptor antagonist. Aboral NS evoked an apamin- and l -NAME-sensitive IJP, but virtually no NANC EJP. These data suggest the presence of polarized excitatory purinergic neurotransmission in guinea-pig taenia caeci, which appears to be mediated by P2X purinoceptors, most likely the P2X1 subtype. [source] Effects of excitatory and inhibitory neurotransmission on motor patterns of human sigmoid colon in vitroBRITISH JOURNAL OF PHARMACOLOGY, Issue 7 2008M Aulí Background and purpose: To characterize the in vitro motor patterns and the neurotransmitters released by enteric motor neurons (EMNs) in the human sigmoid colon. Experimental approach: Sigmoid circular strips were studied in organ baths. EMNs were stimulated by electrical field stimulation (EFS) and through nicotinic ACh receptors. Key results: Strips developed weak spontaneous rhythmic contractions (3.67±0.49 g, 2.54±0.15 min) unaffected by the neurotoxin tetrodotoxin (TTX; 1 ,M). EFS induced strong contractions during (on, 56%) or after electrical stimulus (off, 44%), both abolished by TTX. Nicotine (1,100 ,M) inhibited spontaneous contractions. Latency of off-contractions and nicotine responses were reduced by NG -nitro- L -arginine (1 mM) and blocked after further addition of apamin (1 ,M) or the P2Y1 receptor antagonist MRS 2179 (10 ,M) and were unaffected by the P2X antagonist NF279 (10 ,M) or ,-chymotrypsin (10 U mL,1). Amplitude of on- and off-contractions was reduced by atropine (1 ,M) and the selective NK2 receptor antagonist Bz-Ala-Ala-D-Trp-Phe-D-Pro-Pro-Nle-NH2 (1 ,M). MRS 2179 reduced the amplitude of EFS on- and off-contractions without altering direct muscular contractions induced by ACh (1 nM,1 mM) or substance P (1 nM,10 ,M). Conclusions and implications: Latency of EFS-induced off-contractions and inhibition of spontaneous motility by nicotine are caused by stimulation of inhibitory EMNs coreleasing NO and a purine acting at muscular P2Y1 receptors through apamin-sensitive K+ channels. EFS-induced on- and off-contractions are caused by stimulation of excitatory EMNs coreleasing ACh and tachykinins acting on muscular muscarinic and NK2 receptors. Prejunctional P2Y1 receptors might modulate the activity of excitatory EMNs. P2Y1 and NK2 receptors might be therapeutic targets for colonic motor disorders. British Journal of Pharmacology (2008) 155, 1043,1055; doi:10.1038/bjp.2008.332; published online 1 September 2008 [source] Neurally released ATP mediates endothelium-dependent hyperpolarization in the circular smooth muscle cells of chicken anterior mesenteric arteryBRITISH JOURNAL OF PHARMACOLOGY, Issue 7 2005Marwan Draid The object of the present study was to clarify the neurotransmitter(s) controlling membrane responses to electrical field stimulation (EFS) in the circular smooth muscle cells of first-order branches of chicken anterior mesenteric artery. EFS (five pulses at 20 Hz, 1 ms) evoked a hyperpolarization of amplitude ,21.6±1.2 mV, total duration 21.8±1.2 s and latency 641.7±81.9 ms. The response was tetrodotoxin-sensitive and nonadrenergic noncholinergic (NANC) in nature. The NANC response was blocked by the nonspecific purinergic antagonist, suramin, indicating that the response is mediated by the neurotransmitter adenosine 5,-triphosphate (ATP). Either desensitization or blockade of P2Y receptor with its putative agonist 2-methylthioATP (1 ,M for 30 min) or with its antagonist cibacron blue F3GA (10 ,M), respectively, abolished the purinergic hyperpolarization. PPADS at concentrations up to 100 ,M had no effect on the EFS-induced response, indicating that this response is mediated through P2Y, but not P2X, receptor. In addition, the response was completely abolished by two specific P2Y1 receptor antagonists, namely, MRS 2179 (300 nM) and A3P5PS (10 ,M). Removal of the endothelium abolished the purinergic hyperpolarization, which was converted, in some preparations, to a small depolarization, indicating that the hyperpolarizing response is endothelium-dependent. The present study suggests that in first-order branches of chicken anterior mesenteric artery, ATP released from perivascular nerves may diffuse to the endothelium-activating P2Y1 receptor to induce release of an inhibitory substance that mediates hyperpolarization in the circular smooth muscle. British Journal of Pharmacology (2005) 146, 983,989. doi:10.1038/sj.bjp.0706413 [source] | ||||||||||