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Original Article

Korean J Physiol Pharmacol 2021; 25(3): 227-237

Published online May 1, 2021

Copyright © Korean J Physiol Pharmacol.

Carbon monoxide activates large-conductance calcium-activated potassium channels of human cardiac fibroblasts through various mechanisms

Hyemi Bae1, Taeho Kim2, and Inja Lim1,*

1Department of Physiology, College of Medicine, Chung-Ang University, Seoul 06974, 2Department of Internal Medicine, College of Medicine, Chung-Ang University Hospital, Seoul 06973, Korea

Correspondence to:Inja Lim

Received: November 17, 2020; Revised: February 8, 2021; Accepted: February 9, 2021

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.


Carbon monoxide (CO) is a cardioprotectant and potential cardiovascular therapeutic agent. Human cardiac fibroblasts (HCFs) are important determinants of myocardial structure and function. Large-conductance Ca2+-activated K+ (BK) channel is a potential therapeutic target for cardiovascular disease. We investigated whether CO modulates BK channels and the signaling pathways in HCFs using whole-cell mode patch-clamp recordings. CO-releasing molecules (CORMs; CORM-2 and CORM-3) significantly increased the amplitudes of BK currents (IBK). The CO-induced stimulating effects on IBK were blocked by pre-treatment with specific nitric oxide synthase (NOS) blockers (L-NG-monomethyl arginine citrate and L-NG-nitroarginine methyl ester). 8-bromo-cyclic GMP increased IBK. KT5823 (inhibits PKG) or ODQ (inhibits soluble guanylate cyclase) blocked the CO-stimulating effect on IBK. Moreover, 8-bromo-cyclic AMP also increased IBK, and pre-treatment with KT5720 (inhibits PKA) or SQ22536 (inhibits adenylate cyclase) blocked the CO effect. Pre-treatment with Nethylmaleimide (a thiol-alkylating reagent) also blocked the CO effect on IBK, and DLdithiothreitol (a reducing agent) reversed the CO effect. These data suggest that CO activates IBK through NO via the NOS and through the PKG, PKA, and S-nitrosylation pathways.

Keywords: Calcium-activated potassium channel, Carbon monoxide, Nitric oxide, Protein kinases