Effects of Toborinone (OPC-18790), a New Positive Inotropic Agent, on Action Potential in Guinea Pig Sinoatrial Node: Compared with Milrinone and E-4031

Orito, Kensuke; Takase, Hiromichi; Fujiki, Hiroyuki; Mori, Toyoki

doi:10.1254/jjp.72.79

Cited by 7 publications

(5 citation statements)

References 9 publications

(11 reference statements)

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“…This is different from what we have observed in the mouse in which Mil and Rol each had similar stimulatory effects on AP frequency and where the stimulatory effect of EHNA, although smaller than Mil and Rol, was still robust. Other studies have also shown that PDE3 inhibitors increase SAN AP frequency in rabbits [35] and guinea pigs [36]; however, these studies did not compare these effects with inhibitors of other PDE families. Our data showing that PDE3 and PDE4 inhibitors can similarly increase AP frequency and I Ca,L in mouse SAN myocytes are consistent with studies showing these inhibitors also increase beating rate in mouse and rat atrial preparations [37].…”

Section: Discussionmentioning

confidence: 89%

Distinct Patterns of Constitutive Phosphodiesterase Activity in Mouse Sinoatrial Node and Atrial Myocardium

et al. 2012

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Phosphodiesterases (PDEs) are critical regulators of cyclic nucleotides in the heart. In ventricular myocytes, the L-type Ca2+ current (ICa,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 ICa,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 ICa,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 ICa,L in SAN, atrial and ventricular myocytes; however, important differences emerged in terms of which inhibitors could modulate ICa,L in each myocyte type. Consistent with our AP measurements, EHNA, Mil and Rol each increased ICa,L in SAN myocytes. Also, EHNA and Rol, but not Mil, increased atrial ICa,L. In complete contrast, no selective PDE inhibitors increased ICa,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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Section: Discussionmentioning

confidence: 89%

Distinct Patterns of Constitutive Phosphodiesterase Activity in Mouse Sinoatrial Node and Atrial Myocardium

et al. 2012

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“…An earlier observation by Tsien et al in Purkije fibers provided a clue that the level of cAMP in pacemaker cells was regulated by basal PDE activity, because various PDE inhibitors produced a marked increase in the DD slope and shortened AP plateau, mimicking effects of cAMP injection [25]. Later, several studies demonstrated that, similar to Purkinje fibers, suppression of PDE activity in isolated SA node [26-28] produced an increase in cAMP level [26] and an augmentation of the DD slope [27, 28] that resulted in a marked acceleration of the spontaneous beating rate. The extent of PDE-dependent control of the basal cAMP level, and of spontaneous firing of isolated rabbit SANC, has recently been demonstrated: inhibition of total PDE activity by a broad-spectrum PDE inhibitor, IBMX, produces a 9-fold increase in the cAMP level and ~50% increase in the SANC spontaneous beating rate (both effects being greater than those of the saturating concentration of β- AR agonist, isoproterenol [29].…”

Section: The Basal Camp Level Is Linked To Spontaneous Beating In mentioning

confidence: 99%

Regulation of basal and reserve cardiac pacemaker function by interactions of cAMP-mediated PKA-dependent Ca2+ cycling with surface membrane channels

Vinogradova¹,

Lakatta²

2009

Journal of Molecular and Cellular Cardiology

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Decades of intensive research of primary cardiac pacemaker, the sinoatrial node, have established potential roles of specific membrane channels in the generation of the diastolic depolarization, the major mechanism allowing sinoatrial node cells generate spontaneous beating. During the last three decades, multiple studies made either in the isolated sinoatrial node or sinoatrial node cells have demonstrated a pivotal role of Ca 2+ and, specifically Ca 2+ -release from sarcoplasmic reticulum, for spontaneous beating of cardiac pacemaker. Recently, spontaneous, rhythmic local subsarcolemmal Ca 2+ releases from ryanodine receptors during late half of the diastolic depolarization have been implicated as a vital factor in the generation of sinoatrial node cells spontaneous firing. Local Ca 2+ releases are driven by a unique combination of high basal cAMP production by adenylyl cyclases, high basal cAMP degradation by phosphodiesterases and a high level of cAMP-mediated PKAdependent phosphorylation. These local Ca 2+ releases activate an inward Na + -Ca 2+ exchange current which accelerates the terminal diastolic depolarization rate and, thus, controls the spontaneous pacemaker firing. Both the basal primary pacemaker beating rate and its modulation via β-adrenergic receptor stimulation appear to be critically dependent upon intact RyR function and local subsarcolemmal sarcoplasmic reticulum generated Ca 2+ releases. This review aspires to integrate the traditional viewpoint that has emphasized the supremacy of the ensemble of surface membrane ion channels in spontaneous firing of the primary cardiac pacemaker, and these novel perspectives of cAMP-mediated PKA-dependent Ca 2+ cycling in regulation of the heart pacemaker clock, both in the basal state and during β-adrenergic receptor stimulation.

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“…Inhibition of PDE3 causes sinoatrial tachycardia in guinea pigs, 7 rabbits, 5,8 dogs 9 and humans. 10 PDE4 is the dominant PDE isoform in the murine heart, 6 and inhibition of either PDE3 or PDE4 produces sinoatrial tachycardia in mice 11 and rats.…”

Section: Introductionmentioning

confidence: 99%

Basal Spontaneous Firing of Rabbit Sinoatrial Node Cells Is Regulated by Dual Activation of PDEs (Phosphodiesterases) 3 and 4

Vinogradova

Sirenko

Lukyanenko

et al. 2018

Circ: Arrhythmia and Electrophysiology

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Effects of Toborinone (OPC-18790), a New Positive Inotropic Agent, on Action Potential in Guinea Pig Sinoatrial Node: Compared with Milrinone and E-4031

Cited by 7 publications

References 9 publications

Distinct Patterns of Constitutive Phosphodiesterase Activity in Mouse Sinoatrial Node and Atrial Myocardium

Distinct Patterns of Constitutive Phosphodiesterase Activity in Mouse Sinoatrial Node and Atrial Myocardium

Regulation of basal and reserve cardiac pacemaker function by interactions of cAMP-mediated PKA-dependent Ca2+ cycling with surface membrane channels

Basal Spontaneous Firing of Rabbit Sinoatrial Node Cells Is Regulated by Dual Activation of PDEs (Phosphodiesterases) 3 and 4

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