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

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

doi:10.1111/bph.14034

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

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

Physiology of circulation, kidney and lung

5 Citations (Scopus)

Abstract

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 language	English
Journal	British Journal of Pharmacology
Volume	174
Issue number	22
Pages (from-to)	4186-4198
Number of pages	13
ISSN	0007-1188
DOIs	https://doi.org/10.1111/bph.14034
Publication status	Published - Nov 2017

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@article{dc822a53c2dd45538cb75e7402fbe3fe,

title = "Phosphodiesterase 1a inhibition elicits cGMP-dependent relaxation of rat mesenteric arteries",

abstract = "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.",

author = "Khammy, {Makhala Michell} and Thomas Dalsgaard and Larsen, {Peter Hj{\o}rringgaard} and Christoffersen, {Claus Tornby} and Dorte Clausen and Rasmussen, {Lars Kyhn} and Lasse Folkersen and Morten Grunnet and Jan Kehler and Christian Aalkjaer and Jacob Nielsen",

year = "2017",

month = nov,

doi = "10.1111/bph.14034",

language = "English",

volume = "174",

pages = "4186--4198",

journal = "British Journal of Pharmacology",

issn = "0007-1188",

publisher = "Wiley",

number = "22",

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TY - JOUR

T1 - Phosphodiesterase 1a inhibition elicits cGMP-dependent relaxation of rat mesenteric arteries

AU - Khammy, Makhala Michell

AU - Dalsgaard, Thomas

AU - Larsen, Peter Hjørringgaard

AU - Christoffersen, Claus Tornby

AU - Clausen, Dorte

AU - Rasmussen, Lars Kyhn

AU - Folkersen, Lasse

AU - Grunnet, Morten

AU - Kehler, Jan

AU - Aalkjaer, Christian

AU - Nielsen, Jacob

PY - 2017/11

Y1 - 2017/11

N2 - 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.

AB - 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.

U2 - 10.1111/bph.14034

DO - 10.1111/bph.14034

M3 - Journal article

C2 - 28910498

SN - 0007-1188

VL - 174

SP - 4186

EP - 4198

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

IS - 22

ER -

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

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