Rinaldi B, Capuano A, Gritti G, Donniacuo M, Scotto Di Vettimo A, Sodano L, Rafaniello C, Rossi F, Matera M G
Centre of Excellence for Cardiovascular Diseases, Dept. of Experimental Medicine, Section of Pharmacology "L. Donatelli", Second University of Naples, Italy; Regional Centre for Pharmacovigilance and Pharmacoepidemiology, Dept. of Experimental Medicine, Section of Pharmacology "L. Donatelli", Second University of Naples, Italy.
Centre of Excellence for Cardiovascular Diseases, Dept. of Experimental Medicine, Section of Pharmacology "L. Donatelli", Second University of Naples, Italy.
Pulm Pharmacol Ther. 2014 Aug;28(2):109-13. doi: 10.1016/j.pupt.2014.04.005. Epub 2014 Apr 21.
Lung function abnormalities, both at rest and during exercise, are frequently observed in patients with chronic heart failure (HF), also in absence of respiratory disease. It has been documented that, in HF, chronic adrenergic stimulation down-regulates β-adrenoceptors (β-ARs) and modifies airway relaxant responses. This study was designed to investigate in an animal model of HF whether a treatment with a β-AR blocker, metoprolol, could modify the altered airway hyperresponsiveness. In rats, randomly assigned to 3 experimental groups sham-operated rats (SH), rats with HF induced by left anterior descending coronaric occlusion (HF n = 10), and rats treated with metoprolol 100 mg/kg/die (MET = 10), HF was evaluated after 10 weeks and resulted in increases in plasma norepinephrine and epinephrine and left ventricular end diastolic pressure. β2-ARs and G-protein-βAR2-kinase (GRK2) mRNA levels were determined by real time reverse transcriptase PCR. Carbachol-precontracted isolated tracheal rings were used to functionally assess airway smooth muscle relaxation. In pulmonary tissues, β2-AR mRNA level was significantly decreased in HF groups (-48.73 ± 5.18%, P < 0.01); in the same groups the GRK2 mRNA-levels were significantly enhanced (+222.50 ± 6.13%, P < 0.001); in lung deriving from MET groups the levels of mRNA were significantly increased (+339.86 ± 11.26%, P < 0.001), while the GRK2 mRNA-levels unchanged (-59.02 ± 3.97%, P < 0.001), when compared to SH groups. Relaxation of tracheal strips in response to salbutamol was significantly reduced in HF groups; in tracheal rings, deriving from MET groups, the relaxant effects of salbutamol were significantly enhanced (SH, Emax: 34.87 ± 2.98%, pD2: 7.45 ± 0.27; HF, Emax: 34.87 ± 2.98%, pD2: 7.45 ± 0.27; MET, Emax: 85.43 ± 6.80%, pD2: 6.95 ± 0.59, P < 0.001). In HF, the down-regulation of pulmonary β-ARs results in a significant attenuation of airway relaxation. These effects have been reversed by a treatment with metoprolol, suggesting a potential role of β-AR blockers in the treatment of patients suffering from HF and chronic obstructive airway diseases.
在慢性心力衰竭（HF）患者中，无论静息还是运动时，肺部功能异常都很常见，即便不存在呼吸系统疾病。有文献记载，在HF中，慢性肾上腺素能刺激会下调β-肾上腺素能受体（β-ARs）并改变气道舒张反应。本研究旨在通过HF动物模型研究β-AR阻滞剂美托洛尔治疗是否能改变气道高反应性的改变。将大鼠随机分为3组：假手术大鼠（SH）、左冠状动脉前降支闭塞诱导HF的大鼠（HF，n = 10）以及用美托洛尔100mg/kg/天治疗的大鼠（MET = 10），10周后评估HF情况，结果显示血浆去甲肾上腺素和肾上腺素以及左心室舒张末期压力升高。通过实时逆转录聚合酶链反应测定β2-ARs和G蛋白-βAR2激酶（GRK2）的mRNA水平。使用卡巴胆碱预收缩的离体气管环功能评估气道平滑肌舒张。在肺组织中，HF组β2-AR mRNA水平显著降低（-48.73±5.18%，P < 0.01）；在同一组中，GRK2 mRNA水平显著升高（+222.50±6.13%，P < 0.001）；与SH组相比，MET组肺组织中mRNA水平显著升高（+339.86±11.26%，P < 0.001），而GRK2 mRNA水平未改变（-59.02±3.97%，P < 0.001）。HF组对沙丁胺醇的气管条舒张反应显著降低；在MET组的气管环中，沙丁胺醇的舒张作用显著增强（SH，Emax：34.87±2.98%，pD2：7.45±0.27；HF，Emax：34.87±2.98%，pD2：7.45±0.27；MET，Emax：85.43±6.80%，pD2：6.95±0.59，P < 0.001）。在HF中，肺β-ARs的下调导致气道舒张显著减弱。美托洛尔治疗可逆转这些效应，提示β-AR阻滞剂在治疗HF和慢性阻塞性气道疾病患者中可能具有潜在作用。
