Contribution of BKCa channel to tone regulation by PDE3 and PDE4 depends on the mode of cAMP stimulation and is lost in heart failure - 26/03/18
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Résumé |
Introduction |
Regulation of vascular tone by 3’,5’-cyclic adenosine monophosphate (cAMP) involves many effectors, including large conductance, Ca2+-activated, K+ (BKCa) channels. In arteries, cAMP is mainly hydrolyzed by type 3 and 4 phosphodiesterases (PDE3 and PDE4).
Objective |
Here, we examined the specific contribution of BKCa channels to tone regulation by these PDEs in rat coronary arteries (CA), and how it may be altered in heart failure (HF).
Method |
CA were isolated from young adult rats or rats with HF sacrificed 22 weeks after surgical stenosis of the ascending aorta. Age-matched sham animals were used as controls. Tension measurements were conducted on CA contracted using the thromboxan analogue U46619. Myocytes were isolated from CA and used for patch clamp recordings or for proximity ligation assay (PLA).
Results |
Selective PDE3 (cilostamide, Cil) or PDE4 (Ro-20-1724, Ro) inhibition evoked vasorelaxation that was greatly reduced by iberiotoxin (IBTX), a BKCa channel blocker. Ro and Cil potentiated the relaxation induced by the β-adrenergic agonist isorenaline or the adenylyl cyclase activator L-858051. IBTX abolished the effect of PDE inhibitors on isoprenaline but did not on L-858051. Ro and Cil together increased single BKCa channel activity in myocytes. CA isolated from rats displaying robust signs of HF showed poor contractile capacity and relaxation to acetylcholine compared to sham rats. In contrast to sham, relaxations induced by PDE inhibitors in HF-CA were not sensitive to IBTX. Expression of the BKCa channel was 2-fold lower in HF-CA compared to sham-CA. Amount of a 70kDa-PDE4B was increased in HF. PLA demonstrated that PDE3 and PDE4 were localized in the vicinity of the channel. BKCa-PDE4B duplex was less abundant in HF.
Conclusion |
BKCa channels mediate the relaxation of rat CA induced by PDE3 and PDE4 inhibition. Their relative contribution, however, vary with the grade of cAMP stimulation and the physiopathological context of HF.
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Vol 10 - N° 2
P. 211-212 - avril 2018 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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