Contribution of BKCa channels to vascular tone regulation by PDE3 and PDE4 is lost in heart failure

Autor: Boris Manoury, Sarah Idres, Rodolphe Fischmeister, A. Varin, Valérie Domergue, Germain Perrin, Véronique Leblais, Susana Gomez, Florence Lefebvre
Přispěvatelé: Signalisation et physiopathologie cardiovasculaire (UMRS1180), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Paris Saclay d’Innovation Thérapeutique (IPSIT), Université Paris-Sud - Paris 11 (UP11)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Manoury, Boris
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
Male
medicine.medical_specialty
coronary artery
[SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO]
Physiology
BKCa channel
Vasodilator Agents
Phosphodiesterase 3
heart failure
030204 cardiovascular system & hematology
Phosphodiesterase 3 Inhibitors
Adenylyl cyclase
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
[SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
Physiology (medical)
Internal medicine
cAMP
medicine
[SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO]
Animals
Cyclic adenosine monophosphate
Large-Conductance Calcium-Activated Potassium Channels
Rats
Wistar

Cilostamide
Voltage-dependent calcium channel
Electrical impedance myography
Phosphodiesterase
Iberiotoxin
Coronary Vessels
Cyclic Nucleotide Phosphodiesterases
Type 3

[SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
Cyclic Nucleotide Phosphodiesterases
Type 4

Vasodilation
Disease Models
Animal

030104 developmental biology
Endocrinology
chemistry
[SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology
[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology
Phosphodiesterase 4 Inhibitors
Cardiology and Cardiovascular Medicine
Ion Channel Gating
phosphodiesterase
Signal Transduction
Zdroj: Cardiovascular Research
Cardiovascular Research, Oxford University Press (OUP), 2019, 115 (1), pp.130-144. ⟨10.1093/cvr/cvy161⟩
Cardiovascular Research, 2019, 115 (1), pp.130-144. ⟨10.1093/cvr/cvy161⟩
ISSN: 0008-6363
DOI: 10.1093/cvr/cvy161⟩
Popis: Aims Regulation of vascular tone by 3′,5′-cyclic adenosine monophosphate (cAMP) involves many effectors including the large conductance, Ca2+-activated, K+ (BKCa) channels. In arteries, cAMP is mainly hydrolyzed by type 3 and 4 phosphodiesterases (PDE3, PDE4). Here, we examined the specific contribution of BKCa channels to tone regulation by these PDEs in rat coronary arteries, and how this is altered in heart failure (HF). Methods and results Concomitant application of PDE3 (cilostamide) and PDE4 (Ro-20-1724) inhibitors increased BKCa unitary channel activity in isolated myocytes from rat coronary arteries. Myography was conducted in isolated, U46619-contracted coronary arteries. Cilostamide (Cil) or Ro-20-1724 induced a vasorelaxation that was greatly reduced by iberiotoxin (IBTX), a BKCa channel blocker. Ro-20-1724 and Cil potentiated the relaxation induced by the β-adrenergic agonist isoprenaline (ISO) or the adenylyl cyclase activator L-858051 (L85). IBTX abolished the effect of PDE inhibitors on ISO but did not on L85. In coronary arteries from rats with HF induced by aortic stenosis, contractility and response to acetylcholine were dramatically reduced compared with arteries from sham rats, but relaxation to PDE inhibitors was retained. Interestingly, however, IBTX had no effect on Ro-20-1724- and Cil-induced vasorelaxations in HF. Expression of the BKCa channel α-subunit, of a 98 kDa PDE3A and of a 80 kDa PDE4D were lower in HF compared with sham coronary arteries, while that of a 70 kDa PDE4B was increased. Proximity ligation assays demonstrated that PDE3 and PDE4 were localized in the vicinity of the channel. Conclusion BKCa channels mediate the relaxation of coronary artery induced by PDE3 and PDE4 inhibition. This is achieved by co-localization of both PDEs with BKCa channels, enabling tight control of cAMP available for channel opening. Contribution of the channel is prominent at rest and on β-adrenergic stimulation. This coupling is lost in HF.
Databáze: OpenAIRE