Rinaldi Barbara, Donniacuo Maria, Sodano Loredana, Gritti Giulia, Martuscelli Eugenio, Orlandi Augusto, Rafaniello Concetta, Rossi Francesco, Calzetta Luigino, Capuano Annalisa, Matera Maria Gabriella
Centre of Excellence for Cardiovascular Diseases, Second University of Naples, Naples, Italy.
Regional Centre for Pharmacovigilance and Pharmacoepidemiology, Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Second University of Naples, Naples, Italy.
Br J Pharmacol. 2015 Jul;172(14):3627-37. doi: 10.1111/bph.13148. Epub 2015 May 12.
The ability of a chronic treatment with indacaterol, a new ultra-long-acting β2 -adrenoceptor agonist, to reverse cardiac remodelling and its effects in combination with metoprolol, a selective β1 -adrenoceptor antagonist, were investigated on myocardial infarction in a rat model of heart failure (HF).
We investigated the effects of indacaterol and metoprolol, administered alone or in combination, on myocardial histology, β-adrenoceptor-mediated pathways, markers of remodelling and haemodynamic parameters in a rat model of HF. Five groups of rats were assessed: sham-operated rats; HF rats; HF + indacaterol 0.3 mg·kg(-1) ·day(-1) ; HF + metoprolol 100 mg·kg(-1) ·day(-1) ; HF + metoprolol + indacaterol. All pharmacological treatments continued for 15 weeks.
Treatment with either indacaterol or metoprolol significantly reduced the infarct size in HF rats. However, the combination of indacaterol and metoprolol reduced the infarct size even further, reduced both BP and heart rate, reversed the decrease in ejection fraction, normalized left ventricular systolic and diastolic internal diameters, normalized the decreased β1 adrenoceptor mRNA expression as well as cardiac cAMP levels and reduced cardiac GPCR kinase 2 expression, compared with the untreated HF group.
The results of our study demonstrated an additive interaction between indacaterol and metoprolol in normalizing and reversing cardiac remodelling in our experimental model of HF. The translation of these findings to clinical practice might be of interest, as this combination of drugs could be safer and more effective in patients suffering from HF and COPD.
研究新型超长效β2肾上腺素能受体激动剂茚达特罗长期治疗逆转心脏重塑的能力，以及其与选择性β1肾上腺素能受体拮抗剂美托洛尔联合应用对心力衰竭（HF）大鼠模型心肌梗死的影响。
我们研究了茚达特罗和美托洛尔单独或联合给药对HF大鼠模型心肌组织学、β肾上腺素能受体介导的信号通路、重塑标志物和血流动力学参数的影响。评估了五组大鼠：假手术大鼠；HF大鼠；HF + 茚达特罗0.3 mg·kg⁻¹·天⁻¹；HF + 美托洛尔100 mg·kg⁻¹·天⁻¹；HF + 美托洛尔 + 茚达特罗。所有药物治疗持续15周。
茚达特罗或美托洛尔治疗均显著减小了HF大鼠的梗死面积。然而，与未治疗的HF组相比，茚达特罗和美托洛尔联合使用进一步减小了梗死面积，降低了血压和心率，逆转了射血分数的降低，使左心室内径的收缩期和舒张期恢复正常，使降低的β1肾上腺素能受体mRNA表达以及心脏cAMP水平恢复正常，并降低了心脏GPCR激酶2的表达。
我们的研究结果表明，在我们的HF实验模型中，茚达特罗和美托洛尔在使心脏重塑正常化和逆转方面存在相加作用。将这些发现转化为临床实践可能会受到关注，因为这种药物组合在患有HF和慢性阻塞性肺疾病（COPD）的患者中可能更安全、更有效。
