β-Adrenergic agonists differentially regulate highly selective and nonselective epithelial sodium channels to promote alveolar fluid clearance in vivo
β-Adrenergic agonists differentially regulate highly selective and nonselective epithelial sodium channels to promote alveolar fluid clearance in vivo
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DOI：
10.1152/ajplung.00038.2012
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发表时间：
2012-06-01
影响因子：
4.9
通讯作者：
Helms, My N.
中科院分区：
文献类型：
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作者：
Downs, Charles A.;Kriener, Lisa H.;Helms, My N.
唐斯CA，Kriener LH，Yu L，Eaton DC，Jain L，Helms MN.β-肾上腺素能激动剂差异调节高选择性和非选择性上皮钠通道以促进体内肺泡液体清除。美国生理学杂志肺细胞分子生理学302：L1167-L1178，2012年。首次发表于2012年4月13日; doi：10.1152/ajplung.00038.2012.-β-肾上腺素能受体（β-AR）增加上皮钠通道（ENaC）活性以促进肺流体清除。然而，选择性β-AR激动剂对肺泡1型（T1）和2型（T2）细胞中的高选择性阳离子（HSC）通道或非选择性阳离子（NSC）通道的影响尚不清楚。我们假设用β（1）-AR激动剂（地诺帕明）或β（2）-AR激动剂（特布他林）刺激会增加肺泡上皮细胞中HSC和/或NSC通道活性。我们从大鼠肺切片获得的T1和T2细胞进行单通道测量。特布他林（20 μ M）增加T1（从0.96 +/- 0.61至1.25 +/- 0.71，n = 5，P < 0.05）和T2细胞（从0.28 +/- 0.14至1.0 +/- 0.30，n = 8，P = 0.02）中HSC ENaC活性（开放概率，NPo）。地诺帕明（20 μ M）增加T1细胞（从0.34 +/- 0.09至0.63 +/- 0.14，n = 7，P = 0.02）和T2细胞（从0.47 +/- 0.09至0.68 +/- 0.10，P = 0.004）中的NSC NPo。肺液清除的体内X射线成像和β（2）-AR的ICI 118，551选择性抑制证实了膜片钳发现。地诺帕明或特布他林治疗后cAMP浓度升高（n = 3，P < 0.002）。评估了全身（腹膜内，IP）和局部（腹膜内，IT）给药模式对肺液体清除的影响。IT交付的地诺帕胺促进肺泡洪水，而IP交付促进延迟液体清除。总之，β-AR激动剂差异调节T1和T2细胞中的HSC和NSC以促进体内肺液清除，并且药物递送模式对于最大化β-AR激动剂功效至关重要。
Downs CA, Kriener LH, Yu L, Eaton DC, Jain L, Helms MN. beta-Adrenergic agonists differentially regulate highly selective and nonselective epithelial sodium channels to promote alveolar fluid clearance in vivo. Am J Physiol Lung Cell Mol Physiol 302: L1167-L1178, 2012. First published April 13, 2012; doi: 10.1152/ajplung.00038.2012.-beta-Adrenergic receptors (beta-AR) increase epithelial sodium channel (ENaC) activity to promote lung fluid clearance. However, the effect of selective beta-AR agonist on highly selective cation (HSC) channels or nonselective cation (NSC) channels in alveolar type 1 (T1) and type 2 (T2) cells is unknown. We hypothesized that stimulation with beta(1)-AR agonist (denopamine) or beta(2)-AR agonist (terbutaline) would increase HSC and/or NSC channel activity in alveolar epithelial cells. We performed single-channel measurements from T1 and T2 cells accessed from rat lung slices. Terbutaline (20 mu M) increased HSC ENaC activity (open probability, NPo) in T1 (from 0.96 +/- 0.61 to 1.25 +/- 0.71, n = 5, P < 0.05) and T2 cells (from 0.28 +/- 0.14 to 1.0 +/- 0.30, n = 8, P = 0.02). Denopamine (20 mu M) increased NSC NPo in T1 cells (from 0.34 +/- 0.09 to 0.63 +/- 0.14, n = 7, P = 0.02) and in T2 cells (from 0.47 +/- 0.09 to 0.68 +/- 0.10, P = 0.004). In vivo X-ray imaging of lung fluid clearance and ICI 118,551 selective inhibition of beta(2)-ARs confirmed patch-clamp findings. cAMP concentrations increased following treatment with denopamine or terbutaline (n = 3, P < 0.002). The effects of systemic (intraperitoneal, IP) and local (intratracheal, IT) modes of delivery on lung fluid clearance were assessed. IT delivery of denopamine promoted alveolar flooding, whereas IP delivery promoted delayed fluid clearance. In summary, beta-AR agonists differentially regulate HSC and NSC in T1 and T2 cells to promote lung fluid clearance in vivo, and the mode of drug delivery is critical for maximizing beta-AR agonist efficacy.