Role of Ca2+-sensitive K+ channels in the remission phase of pulmonary hypertension in chronic obstructive pulmonary diseases

Objective: Clinically, the effect of chronic hypoxia (CH) in the pulmonary circulation alternates between phases of pulmonary artery hypertension (CH-PAHT) and normoxic normotensive remission (N-RE). Little information is available on the role of calcium-sensitive potassium channels (BKCa) in both CH-PAHT and N-RE phases. In the present study, we investigated the effects of both CH and N-RE on BKCa channels activity and their consequences on hypoxic pulmonary vasoconstriction (HPV). Methods: Using isolated ring preparation, the patch-clamp technique, RT-PCR and Western immunoblotting, we examined the role of the BKCa channel in normoxic, CH-PAHT and N-RE rat pulmonary artery smooth muscle cells (PASMCs). Results: In intrapulmonary arterial rings, acute hypoxia induced contraction in control vessels, relaxation in the N-RE rats, and had no effect in CH-PAHT. The hypoxia-induced relaxation in the N-RE rat pulmonary arteries was abolished by iberiotoxin (IbTx), a specific BKCa blocker. The IbTx-sensitive whole-cell K-Ca channel current was reduced in CH-PAHT and increased in N-RE rat PASMCs. The BKCa channel conductance and voltage sensitivity were not altered in CH and N-RE rat PASMCs, whereas its calcium sensitivity was decreased and increased in CH and N-RE rat PASMCs, respectively. Results of RT-PCR and Western blot analysis revealed a decrease in the mRNA and protein of the BKCa, alpha-subunit in CH, whereas no change at protein level was observed in the N-RE. Conclusion: In rat PASMCs, CH and N-RE are associated with a down- and up-regulation of BKCa activity, respectively, mainly due to modifications of its Ca2+ sensitivity. This could explain the acute hypoxic pulmonary constriction and relaxation observed in CH and N-RE rats, respectively. (C) 2003 European Society of Cardiology. Published by Elsevier B.V All rights reserved.