Expression of BKCa channels in human pulmonary arteries: Relationship with remodeling and hypoxic pulmonary vasoconstriction
Introduction
Pulmonary hypertension in chronic obstructive pulmonary disease (COPD) progresses over time and its severity correlates with the degree of airflow obstruction and the impairment of pulmonary gas exchange (Scharf et al., 2002, Weitzenblum et al., 1984). Unlike primary pulmonary hypertension, the rate of progression of pulmonary hypertension in COPD is slow and usually pulmonary artery pressure (PAP) is only moderately elevated, even in patients with advanced disease and severe hypoxemia (Scharf et al., 2002). A variety of factors may contribute to the development and maintenance of pulmonary hypertension in COPD, the most significant of which are the remodeling of pulmonary vessels and hypoxic pulmonary vasoconstriction (HPV).
The precise mechanism by which hypoxia causes pulmonary vasoconstriction still remains unsettled, but it is present in isolated pulmonary arteries irrespective of the presence of endothelium (Marshall and Marshall, 1992, Rodman et al., 1989). Although these results support the hypothesis that HPV is an intrinsic property of pulmonary artery smooth muscle cells (PASMC), an intact endothelial function plays a prominent role in modulating the magnitude of HPV (Peinado et al., 2002).
Potassium (K+) channels are important in pulmonary circulation because of their close relationship with HPV. The opening of potassium channels induces SMC to relax. Acute hypoxia, however, inhibits the PASMC outward K+ current, leading to membrane depolarization and constriction of small pulmonary arteries (Post et al., 1992). These hypoxic effects might be specific for PASMC because they were not observed in myocytes of systemic arteries (Madden et al., 1992, Vadula et al., 1993, Yuan et al., 1990). Currently, 9 classes of K+ channels expressed in SMC have been identified. Nevertheless, in pulmonary arteries only two types of K+ channels have been suggested to be targeted by hypoxia leading to HPV. These are the BKCa (Park et al., 1995, Post et al., 1992) and one or more members of the voltage-gated type (KV) (Archer et al., 1998, Hulme et al., 1999, Patel et al., 1997). BKCa channels in the membrane of vascular SMC are the predominant K+ channel specie in most arteries (Nelson and Quayle, 1995). Despite hypoxia can close BKCa channels (Peng et al., 1997), they can be opened by the membrane depolarization and high increases of intracellular Ca2+ such as occurring during HPV (Brayden and Nelson, 1992, Peng et al., 1996). Therefore, under conditions of hypoxia it is believed that BKCa can prevent excessive HPV rather than initiate it. BKCa channels can also be opened directly by endothelium-derived NO (Bolotina et al., 1994, Khan et al., 1993, Peng et al., 1996) and thus contribute synergistically with the cGMP-axis to reduce vascular tone. The other hypoxia-sensitive K+ currents expressed in most PASMC preparations are voltage-gated K+ (KV) delayed rectifier current types. PASMC express several types of KV channels, including KV1.2, KV1.5, KV2.1, KV3.1 and KV9.3 that are expressed in homomeric and/or heteromeric complexes (Archer et al., 1998, Hulme et al., 1999, Patel et al., 1997). The resting membrane potential (Em) in the PASMC is largely controlled by KV channels which inhibition by acute hypoxia can initiate HPV. It is known, however, that chronic hypoxia downregulates various KV channel genes in PASMC (Platoshyn et al., 2001, Smirnov et al., 1994, Wang et al., 1997).
Remodeling of pulmonary circulation of COPD patients is related in part to tobacco consumption. It is produced by the intimal proliferation of SMC phenotypically distinct from SMC of the media since they may change the pattern of filament expression (Santos et al., 2002). The physiological role of the intimal SMC proliferation in COPD is not known but its presence is usually associated with a greater variability of pulmonary vascular reactivity (Barbera et al., 1994, Peinado et al., 1998) suggesting changes in the expression of potassium channels. It is also documented that oxygen tension may modulate the expression profile of different K+ channels in pulmonary arteries playing an important role in regulating blood flow (Nelson and Quayle, 1995, Resnik et al., 2006). On the other hand, inhibition of K+ channels by hypoxia, a condition that is present in severe COPD, also diminishes the rate of apoptosis (Mandegar and Yuan, 2002, Platoshyn et al., 2006), which might in turn contribute to cell accumulation further amplifying vascular remodeling (Mandegar and Yuan, 2002, Remillard and Yuan, 2004).
The present study was designed to determine whether structural changes of pulmonary arteries observed in COPD patients may reflect changes in the mRNA expression of BKCa and KV channels and its potential relationship with HPV and endothelial function.
Section snippets
Methods
Pulmonary arteries dissected from 16 patients (14 men) were studied after lobectomy or pneumectomy for localized lung carcinoma.
Preoperative lung functional measurements were performed in all patients. Criteria for inclusion were patients with normal lung function (Control group; n = 5) or patients with mild to moderate altered ventilatory capacity defined by forced expiratory volume in one second (FEV1) < 80% predicted and FEV1-forced ventilatory capacity ratio (FEV1/FVC) < 0.70 (COPD group; n =
Results
Lung function measurements from individuals are shown in Table 2. All patients with COPD used in this study were heavy smokers. COPD subset had a lower PaO2 than controls, but the majority of them had values > 70 mm Hg. In the control group were included two nonsmokers and 3 smokers.
A representative response of an isolated pulmonary artery ring to hypoxic stimulus and relaxation to histamine is shown in Fig. 1. Maximal relaxation to histamine was attenuated when rings were incubated with
Discussion
The principal observations in this study indicate that the intimal thickening such as is shown in pulmonary arteries of patients with COPD is closely associated with changes in the expression of BKCa channels. Both mRNA and protein expression of BKCa channels was positively related to the intensity of response to hypoxia. Moreover, pulmonary arteries in the presence of a BKCa channel blocking agent showed lower response to endothelium-dependent vasodilators showing a role to reduce vascular
Acknowledgements
We thank Dr. Constancio González for helpful comments on the manuscript.
This work was supported by grants SEPAR-2000 from the Sociedad Española de Neumología y Cirugía Torácica and FIS 04/1424 from the Fondo de Investigación Sanitaria. The group is integrated into the cibeRes (ISCIII CB06/06).
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