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Delayed afterdepolarization in intact canine sinoatrial node as a novel mechanism for atrial arrhythmia.

ABSTRACT: Recent evidence indicates that spontaneous sarcoplasmic reticulum Ca release and Na-Ca exchanger current activation contribute to the sinoatrial node (SAN) automaticity. These findings suggest that SAN activity may share mechanisms that underlie both automaticity and triggered activity. The aim of this study is to test the hypothesis that spontaneous, nonvoltage gated, intracellular Ca (Ca(i)) elevation may induce delayed afterdepolarization (DAD) in intact SAN during isoproterenol infusion.We simultaneously mapped Ca(i) and membrane potential in 31 isolated Langendorff-perfused canine right atriums (RA). Isoproterenol increased heart rate and late diastolic Ca(i) elevation (LDCAE) of the superior SAN, leading to consistent SAN automaticity in all 31 RAs. However, DAD-like diastolic depolarizations (DD) were transiently observed in 4 RAs during isoproterenol infusion. These DAD-like DDs were preceded by LDCAE, but did not trigger a full action potential. The LDCAE preceding DAD-like DDs had smaller amplitude (0.41 ± 0.08 AU vs 0.48 ± 0.07 AU, P = 0.001) and less steep slopes (3.7 ± 1.3 AU/s vs 4.8 ± 1.4 AU/s, P = 0.001) than that of sinus beats. The coupling interval of DAD-like DDs was longer than that of the preceding normal beats (407 ± 48 ms vs 371 ± 44 ms, P = 0.002).The isoproterenol-induced LDCAE of superior SAN induced a full action potential in most cases. However, if the LDCAE was too small to trigger an action potential, then it induces only DAD-like DD. The failure of DAD-like DD to consistently trigger a sinus beat is a novel mechanism of atrial arrhythmogenesis.

SUBMITTER: Joung B

PROVIDER: S-EPMC3077449 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Delayed afterdepolarization in intact canine sinoatrial node as a novel mechanism for atrial arrhythmia.

Joung Boyoung B Zhang Hong H Shinohara Tetsuji T Maruyama Mitsunori M Han Seongwook S Kim Daehyeok D Choi Eue-Keun EK On Young-Keun YK Lin Shien-Fong SF Chen Peng-Sheng PS

Journal of cardiovascular electrophysiology 20101006 4

<h4>Introduction</h4>Recent evidence indicates that spontaneous sarcoplasmic reticulum Ca release and Na-Ca exchanger current activation contribute to the sinoatrial node (SAN) automaticity. These findings suggest that SAN activity may share mechanisms that underlie both automaticity and triggered activity. The aim of this study is to test the hypothesis that spontaneous, nonvoltage gated, intracellular Ca (Ca(i)) elevation may induce delayed afterdepolarization (DAD) in intact SAN during isopro ...[more]

PMID: 21040091

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Project description:Phosphodiesterases (PDEs) are critical regulators of cyclic nucleotides in the heart. In ventricular myocytes, the L-type Ca(2+) current (I(Ca,L)) is a major target of regulation by PDEs, particularly members of the PDE2, PDE3 and PDE4 families. Conversely, much less is known about the roles of PDE2, PDE3 and PDE4 in the regulation of action potential (AP) properties and I(Ca,L) in the sinoatrial node (SAN) and the atrial myocardium, especially in mice. Thus, the purpose of our study was to measure the effects of global PDE inhibition with Isobutyl-1-methylxanthine (IBMX) and selective inhibitors of PDE2, PDE3 and PDE4 on AP properties in isolated mouse SAN and right atrial myocytes. We also measured the effects of these inhibitors on I(Ca,L) in SAN and atrial myocytes in comparison to ventricular myocytes. Our data demonstrate that IBMX markedly increases spontaneous AP frequency in SAN myocytes and AP duration in atrial myocytes. Spontaneous AP firing in SAN myocytes was also increased by the PDE2 inhibitor erythro-9-[2-hydroxy-3-nonyl] adenine (EHNA), the PDE3 inhibitor milrinone (Mil) and the PDE4 inhibitor rolipram (Rol). In contrast, atrial AP duration was increased by EHNA and Rol, but not by Mil. IBMX also potently, and similarly, increased I(Ca,L) in SAN, atrial and ventricular myocytes; however, important differences emerged in terms of which inhibitors could modulate I(Ca,L) in each myocyte type. Consistent with our AP measurements, EHNA, Mil and Rol each increased I(Ca,L) in SAN myocytes. Also, EHNA and Rol, but not Mil, increased atrial I(Ca,L). In complete contrast, no selective PDE inhibitors increased I(Ca,L) in ventricular myocytes when given alone. Thus, our data show that the effects of selective PDE2, PDE3 and PDE4 inhibitors are distinct in the different regions of the myocardium indicating important differences in how each PDE family constitutively regulates ion channel function in the SAN, atrial and ventricular myocardium.

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Delayed afterdepolarization in intact canine sinoatrial node as a novel mechanism for atrial arrhythmia.

Publications

Delayed afterdepolarization in intact canine sinoatrial node as a novel mechanism for atrial arrhythmia.

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