Ferrari R, Curello S, Ceconi C, Cargnoni A, Pasini E, Visioli O
Cattedra di Cardiologia, Università di Brescia, Italy.
Eur Heart J. 1993 Sep;14(9):1258-72. doi: 10.1093/eurheartj/14.9.1258.
Nisoldipine was administered at 10(-9) M, a dose lacking negative inotropism, to isolated and perfused rabbit hearts submitted to 60 min ischaemia (1 ml.min-1) followed by 30 min reperfusion. The drug was delivered either 30 min before ischaemia, at the onset and after 30 min of ischaemia and during reperfusion only. Cardiac protection was evaluated in terms of recovery of left ventricular pressure during reperfusion, release of creatine phosphokinase (CPK), mitochondrial function, tissue content of adenosine triphosphate (ATP) and creatine phosphate (CP), calcium homeostasis and the occurrence of oxidative stress, established measuring content and release of reduced and oxidized glutathione. The cytoprotective action of nisoldipine occurs in the absence of negative inotropism and is closely related to the time of administration. Optimal myocardial preservation is achieved when nisoldipine is given before or at the onset of ischaemia. Prophylactic administration of nisoldipine improved the recovery of the developed pressure from 15.9 +/- 1.0 (SE) mmHg to 47.8 +/- 1.9 mmHg, P < 0.01 and reduced the release of CPK from 830 +/- 29 to 229 +/- 27 mU.min-1 g-1 wet wt, P < 0.01. The accumulation of tissue and mitochondrial calcium was reduced from 58 +/- 11 and 49 +/- 9 to 14 +/- 6 and 10 +/- 4 mmol.kg-1 dry wt respectively, P < 0.01. This resulted in a significant (P < 0.01) preservation of all indices of mitochondrial function, allowing a higher recovery of ATP and CP after reperfusion (from 4.1 +/- 0.7 and 10.0 +/- 0.6 to 16.1 +/- 1.0 and 29.9 +/- 0.2 mumol.g-1 dry wt respectively, P < 0.001). Reperfusion-induced myocardial accumulation and release of oxidized glutathione were reduced from 0.493 +/- 0.07 nmol.mg-1 protein and 0.768 +/- 0.063 nmol.min-1 g-1 wet wt to 0.225 +/- 0.07 and 0.157 +/- 0.038 respectively, P < 0.01. Similar data were obtained when nisoldipine was given at the time of ischaemia, while administration 30 min after the onset of ischaemia showed only a trend towards protection. Nisoldipine lost its protective effect when given on reperfusion. A multifactorial analysis of the data suggest that the cardioprotective effect of nisoldipine is related to the maintenance of membrane integrity, possibly since nisoldipine is highly lipophilic.
将尼索地平以10(-9) M的剂量给予离体灌注兔心脏，该剂量无负性肌力作用，使心脏经历60分钟缺血（1毫升/分钟），随后再灌注30分钟。药物分别在缺血前30分钟、缺血开始时、缺血30分钟后以及仅在再灌注期间给药。通过再灌注期间左心室压力的恢复、肌酸磷酸激酶（CPK）的释放、线粒体功能、三磷酸腺苷（ATP）和磷酸肌酸（CP）的组织含量、钙稳态以及氧化应激的发生情况（通过测定还原型和氧化型谷胱甘肽的含量及释放来确定）来评估心脏保护作用。尼索地平的细胞保护作用在无负性肌力作用的情况下发生，且与给药时间密切相关。当尼索地平在缺血前或缺血开始时给药时，可实现最佳的心肌保护。预防性给予尼索地平可使发展压力从15.9±1.0（标准误）毫米汞柱提高到47.8±1.9毫米汞柱，P<0.01，并使CPK的释放从830±29降低到229±27毫单位·分钟-1·克-1湿重，P<0.01。组织和线粒体钙的积累分别从58±11和49±9降低到14±6和10±4毫摩尔·千克-1干重，P<0.01。这导致线粒体功能所有指标的显著（P<0.01）保留，使再灌注后ATP和CP有更高的恢复（分别从4.1±0.7和10.0±0.6提高到16.1±1.0和29.9±0.2微摩尔·克-1干重，P<0.001）。再灌注诱导的心肌氧化型谷胱甘肽的积累和释放分别从0.493±0.07纳摩尔·毫克-1蛋白质和0.768±0.063纳摩尔·分钟-1·克-1湿重降低到0.225±0.07和0.157±0.038，P<0.01。当在缺血时给予尼索地平也获得了类似的数据，而在缺血开始后30分钟给药仅显示出一种保护趋势。尼索地平在再灌注时给药则失去其保护作用。对数据的多因素分析表明，尼索地平的心脏保护作用与维持膜完整性有关，可能是因为尼索地平具有高度脂溶性。
