Westendorp Bart, Hamming Inge, Szymanski Mariusz K, Navis Gerjan, van Goor Harry, Buikema Hendrik, van Gilst Wiek H, Schoemaker Regien G
Department of Experimental Cardiology, University Medical Center Groningen, Groningen, The Netherlands.
Eur J Pharmacol. 2009 Jan 14;602(2-3):373-9. doi: 10.1016/j.ejphar.2008.11.055. Epub 2008 Dec 3.
Diuretics, when added to angiotensin-converting enzyme inhibitors (ACE inhibitors) treatment, can augment the response to ACE inhibitors, but may have adverse effects on renal function, which negatively affect prognosis. While in heart failure rats combined therapy initially improved cardiac function and prognosis, this benefit was completely lost at later stages. We now studied renal effects of adding hydrochlorothiazide to ACE inhibitor after myocardial infarction in rats. Rats were randomized to ACE inhibitor quinapril monotherapy or quinapril with add-on hydrochlorothiazide. Survival was monitored for 14 months. Plasma creatinine, measured at 4 months, was increased by 40% in quinapril with add-on hydrochlorothiazide compared to quinapril. Although overall 14-months mortality was similar in quinapril with add-on hydrochlorothiazide and quinapril, stratification based on plasma creatinine showed increased mortality in the tertile with highest plasma creatinine (P=0.03, Log rank). With add-on hydrochlorotiazide, renal morphology displayed severe renal interstitial lesions; tubular dilatation and fibrosis. Interstitial myofibroblast transformation (alpha-smooth muscle actine staining) was increased at 8 and 14 months, and coincided with collagen deposition and interstitial inflammation (macrophage influx). In rats with quinapril monotherapy or untreated rats, renal structure was normal. Thus, adding hydrochlorotiazide to ACE inhibitor detrimentally affected not only renal function, but also renal structure in rats with myocardial infarction. Altered pharmacokinetics, resulting from a vicious circle of reduced renal function and increased circulating drug levels, may provide an explanation for the adverse renal effects and may exert unfavorable effects on long-term prognosis after myocardial infarction.
利尿剂与血管紧张素转换酶抑制剂（ACE抑制剂）联合使用时，可增强对ACE抑制剂的反应，但可能对肾功能产生不良影响，进而对预后产生负面影响。虽然在心力衰竭大鼠中，联合治疗最初可改善心脏功能和预后，但在后期这种益处完全丧失。我们现在研究了在大鼠心肌梗死后，将氢氯噻嗪添加到ACE抑制剂中对肾脏的影响。将大鼠随机分为接受ACE抑制剂喹那普利单药治疗或喹那普利加用氢氯噻嗪治疗。监测其14个月的生存率。在4个月时测量的血浆肌酐水平显示，与喹那普利单药治疗组相比，喹那普利加用氢氯噻嗪治疗组的血浆肌酐水平升高了40%。虽然喹那普利加用氢氯噻嗪治疗组和喹那普利单药治疗组的总体14个月死亡率相似，但根据血浆肌酐进行分层分析显示，血浆肌酐水平最高的三分位数组死亡率增加（P=0.03，对数秩检验）。加用氢氯噻嗪后，肾脏形态显示出严重的肾间质病变；肾小管扩张和纤维化。在8个月和14个月时，间质肌成纤维细胞转化（α-平滑肌肌动蛋白染色）增加，同时伴有胶原蛋白沉积和间质炎症（巨噬细胞浸润）。在接受喹那普利单药治疗的大鼠或未治疗的大鼠中，肾脏结构正常。因此，在大鼠心肌梗死后，将氢氯噻嗪添加到ACE抑制剂中不仅对肾功能有不利影响，而且对肾脏结构也有不利影响。肾功能降低和循环药物水平升高的恶性循环导致的药代动力学改变，可能为肾脏不良影响提供解释，并可能对心肌梗死后的长期预后产生不利影响。
