Phosphodiesterase 1a inhibition elicits cGMP-dependent relaxation of rat mesenteric arteries

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Makhala Michell Khammy, Thomas Dalsgaard, Peter Hjørringgaard Larsen, Claus Tornby Christoffersen, Dorte Clausen, Lars Kyhn Rasmussen, Lasse Folkersen, Morten Grunnet, Jan Kehler, Christian Aalkjaer, Jacob Nielsen

BACKGROUND AND PURPOSE: Phosphodiesterase 1 (PDE1), a subfamily of cyclic nucleotide phosphodiesterases consisting of three isoforms, PDE1A, PDE1B, and PDE1C, has been implicated in regulation of vascular tone. The PDE1 isoform(s) responsible for tone regulation is unknown. This study used isoform-preferring PDE1 inhibitors, Lu AF58027, Lu AF64196, Lu AF66896, and Lu AF67897, to investigate the relative contribution of PDE1 isoforms to regulation of vascular tone.

EXPERIMENTAL APPROACH: In rat mesenteric arteries, expression and localisation of Pde1 isoforms were determined by qPCR and in situ hybridisation, and physiological impact of PDE1 inhibition were evaluated by isometric tension recordings.

KEY RESULTS: In rat mesenteric arteries, Pde1a mRNA expression was higher than Pde1b and Pde1c. In situ hybridisation revealed localisation of Pde1a to vascular smooth muscle cells (VSMC) and only minor appearance of Pde1b and Pde1c. The potency of the PDE1 inhibitors in eliciting relaxation showed excellent correlation with their potency of PDE1A inhibition. Thus, Lu AF58027 exhibited highest potency at inhibiting PDE1A (IC50 = 4 nM) and was also most potent at eliciting relaxation in mesenteric arteries (EC50 = 32 nM). Inhibition of NOS with L-NAME, soluble GC with ODQ, or PKG with Rp-8-Br-PET-cGMP all attenuated PDE1 inhibition-induced relaxation, whereas PKA inhibition with H89 had no effect.

CONCLUSION AND IMPLICATIONS: Pde1a was the dominant PDE1 isoform present in VSMC and relaxation mediated by PDE1A-inhibition was predominantly driven by enhanced cGMP signalling. These results imply that isoform-selective PDE1 inhibitors are powerful investigative tools allowing examination of physiological and pathological roles of PDE1 isoforms.

Original languageEnglish
JournalBritish Journal of Pharmacology
Volume174
Issue number22
Pages (from-to)4186-4198
Number of pages13
ISSN0007-1188
DOIs
Publication statusPublished - Nov 2017

ID: 183469390