Abstract
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.
Highlights
Phosphodiesterases (PDEs) are phosphohydrolase enzymes that are responsible for the degradation of the cyclic nucleotides adenosine and guanosine 39,59 cyclic monophosphate [1,2]
These specific PDE isoforms were selected because our electrophysiological experiments are focused on the PDE2, 3 and 4 families and prior studies [7,11] have shown that the isoforms we measured are expressed in whole ventricular tissue and ventricular myocytes
Amongst the PDE2, 3 and 4 families, prior studies have shown that the PDE2A, PDE3A, PDE3B, PDE4A, PDE4B and PDE4D subtypes are expressed in whole ventricular myocardium and/or isolated ventricular myocytes in rodents [7,11]
Summary
Phosphodiesterases (PDEs) are phosphohydrolase enzymes that are responsible for the degradation of the cyclic nucleotides adenosine and guanosine 39,59 cyclic monophosphate (cAMP and cGMP) [1,2]. PDEs exist in 11 families (PDE1-11) with several isoforms in each and are regulated by diverse mechanisms including phosphorylation, binding of cyclic nucleotides, calcium binding and protein-protein interactions [1] With such a large number of families and isoforms PDE signaling is clearly complex and in this context it is thought that PDEs are importantly involved in the compartmentation of cyclic nucleotide signaling whereby the subcellular localization of different PDE isoforms can lead to distinct spatial and temporal pools of cAMP and/or cGMP [3,4,5,6]. The effects of PDE2, 3 and 4 inhibition on ICa,L have been well characterized in ventricular myocytes much less is known about the role of these PDE families in the sinoatrial node (SAN) and atria, in mice, a very common model organism due to its use in studies incorporating genetic manipulations
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