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A. Basics
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07. Syncope and Bradycardia
08. Ventricular Arrhythmias and Sudden Cardiac Death (SCD)
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The ATP-sensitive P2X4 receptor is a new therapeutic target for heart rate control
Session:
Sessão de Comunicações Orais - Ciência Básica
Speaker:
Bruno Bragança
Congress:
CPC 2020
Topic:
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Theme:
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Subtheme:
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Session Type:
Comunicações Orais
FP Number:
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Authors:
Bruno Miguel Martins Bragança; Sílvia Nogueira-Marques; Fátima Ferreirinha; Ana Patrícia Fontes-Sousa; Paulo Correia-de-Sá
Abstract
<p>Increased heart rate (HR) is negatively correlated with cardiovascular outcome. Negative chronotropic drugs that change prognosis of heart failure (HF) are currently limited to beta-blockers and ivabradine. Combining negative chronotropic drugs are often needed for patients that do not tolerate single-agent escalating dosage and lack adequate HR control. Thus, novel well-tolerated negative chronotropic drugs are urgently needed. Adenosine slows down HR through A1 receptors (A1R) activation in the human sinoatrial node (SAN). Contrary to adenosine, activation of ATP-sensitive P2X4 receptors (P2X4R) increase ventricular contraction strength, but their role in the SAN is unknown. </p> <p>ATP (pEC50=4.05) concentration-dependently reduced HR in rat spontaneously beating atria. Inhibition of NTPDases with POM-1 enhanced the negative chronotropic effect of ATP (pEC50=5.10; p<0.05). ATP and ATPγS (100 µM) were equipotent in decreasing HR (−19±5% vs −18±5%, p>0.05). PPADS (10 µM) antagonized the ATP effect on HR (−20±2% vs −11±4%, p<0.05); the same occurred by blocking the P2X4R with 5-BDBD (10 µM; −31±7% vs −17±5%, p<0.05), but not with the A1R antagonist, DPCPX (3 nM; −19±3% vs −21±4%, p>0.05). Positive allosteric modulation of P2X4R with ivermectin (30 µM) enhanced the negative chronotropic effect of ATP (pEC50=4.99; p<0.05). CTP (1 mM) mimicked the negative chronotropic action of ATP (-22±1%) in a 5-BDBD (10 µM)-sensitive manner (−12±2%, n=5, p<0.05). Inhibition of the Na+/Ca2+ exchanger (NCX) with KB-R7943 (3 µM; −19±4% vs −8±3%, p<0.05) or ORM-10103 (3 µM; −29±4% vs −17±5%, p<0.05), attenuated ATP-induced negative chronotropy. A negative inotropic action of ATP (100 µM) in paced right ventricular (RV) strips was only evidence after blockage of P2X4R or NCX with 5-BDBD (10 µM; −6±2% vs −19±5%, p<0.05) and KB-R7943 (3 µM; −5±2% vs −19±5%, p<0.05), respectively. Co-localization of P2X4R and NCX1 was observed in SAN and RV cardiomyocytes by immunofluorescence confocal microscopy. </p> <p>In conclusion, activation of P2X4R exerts a dual role in decreasing HR and increasing ventricular inotropy. This dual mechanism is operated by NCX inhibition, in a digitalis-like manner. Therefore, the P2X4R represents a novel therapeutic target for HR control in patients with acutely deteriorated HF, ischemic disease and possibly atrial fibrillation. </p>
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