Acute effect of calcium channel blockers on adriamycin exposed isolated adult cardiocytes

Summary When tested with isolated, calcium-resistant resting rat cardiocytes in an in vitro assay system, adriamycin exerted a dose-dependent cytotoxic effect which could easily be assessed by the ATP depletion of the heart cells and the loss of vitality as monitored by morphological changes (blebbing, spherical contraction). Apart from extremely high non pharmacological concentrations of verapamil and diltiazem, both calcium antagonists left the cardiocytes intact and without loss of internal ATP when given alone to the medium. Coincubation of adriamycin and verapamil or diltiazem did not increase adriamycin toxicity to the cardiocytes; instead a remarkable ATP preservation by verapamil could be demonstrated when both drugs (adriamycin and verapamil) were incubated simultaneously with the heart cells. This acute protective effect was limited in time and could no longer be detected after 9 hours. Diltiazem in coincubation experiments exerted neither a toxic nor an acute protective effect on adriamycin-exposed heart cells.Devoted to my distinguished academic teacher in cardiac physiology Prof. Dr. Ruthard Jacob on the occasion of his 60th birthdaySupported in part by DFG-grants MA 780/1-5     

1,6-二磷酸果糖对阿霉素所致大鼠心肌损伤的影响

目的研究1，6-二磷酸果糖(FDP)对阿霉素(ADM)导致大鼠心肌损伤的影响。方法采用wistar大鼠36只，随机分为ADM组、ADM FDP组及对照组。实验30d后进行心肌光镜病理形态学观察，测定血清及心肌超氧化物歧化酶(SOD)、肌酸激酶(CK)、乳酸脱氢酶(LDH)的活性及脂质过氧化物(LPO)的含量。结果光镜下ADM FDP组病理损害程度较ADM组轻；各组之间心肌及血清CK、LDH差异无统计学意义；和ADM组比较ADM FDP组血浆、心肌LPO含量显著降低，而SOD活性显著增加。结论FDP对ADM所致大鼠心肌损伤有保护作用。     

原代培养的心肌细胞中毒性心肌炎模型的建立

目的 为阿霉素(ADR)中毒性心肌炎机制的研究及药物治疗提供依据.方法 取0～2日龄sD乳鼠原代心肌细胞培养,观察ADR不同浓度(0.01、0.1、1、10、100μg/ml)及不同作用时间(1μg/ml ADR作用24,48,72h)对心肌细胞存活率及培养上清液乳酸脱氢酶(LDH)、谷草转氨酶(GOT)水平的影响,并检测细胞搏动频率.结果 不同浓度ADR均可降低细胞存活率,但10 ng/ml作用后存活率明显降低,呈浓度依赖性.不同浓度ADR均可升高LDH和GOT释放量,亦呈浓度依赖性;随ADR作用时间延长,心肌细胞存活率降低,LDH和COT升高,呈时间依赖性.结论 ADR对原代培养的心肌细胞可造成氧化损伤,损伤程度与ADR浓度及作用时间呈正比.     

Acute effects of doxorubicin (adriamycin) on left ventricular function in dogs

Although chronic doxorubicin (adriamycin) cardiotoxicity often is attributed to repeated episodes of acute myocardial injury, the acute effects of doxorubicin on in vivo left ventricular performance have not been studied in a carefully controlled setting. Accordingly, we recorded high-fidelity left ventricular pressures and segmental dimensions before and after either intravenous or intracoronary doxorubicin in twelve open-chest dogs. Propranolol was administered to prevent reflex sympathetic stimulation, and heart rate was held constant by atrial pacing. Intravenous doxorubicin (1.5 mg/kg) (n = 6) caused significant decreases in all measured indices of myocardial contractility, in association with a large decrease in left ventricular systolic pressure (125 ± 28 and 81 ± 23 mm Hg before and 5 min after doxorubicin, respectively, P < 0.01). Intracoronary doxorubicin (0.075 to 0.3 mg/kg) (n = 6) caused similar decreases in percent segment shortening (from 19 ± 7 to 16 ± 8, P < 0.05), mean normalized shortening rate (from 0.87 ± 0.34 to 0.71 ± 0.37 segment lengths/sec, P < 0.05), and peak positive left ventricular $\text{dP}\text{dt}$ (by 10 ± 11%, P < 0.07), although left ventricular systolic pressure was only modestly decreased (126 ± 20 and 113 ± 17 mm Hg before and after doxorubicin, respectively, P < 0.01). Intracoronary doxorubicin also slowed the rate of left ventricular relaxation, as evidenced by an increase in the time constant for isovolumic pressure fall from 32.0 ± 9.0 to 36.9 ± 7.5 msec, and significantly altered the relationship between left ventricular pressure and dimension at end-diastole.We conclude that a single dose of doxorubicin can acutely alter both systolic and diastolic left ventricular function in dogs. These effects are nearly immediate in onset, and are independent of potential functional alterations due to drug-induced systemic hypotension.     

Effect of timing of antihypertensive therapy on glomerular injury: comparison between captopril and diltiazem

Recent studies have suggested that the progression of experimentalchronic renal disease may be prevented by early use of antihypertensivedrugs. It is unclear, however, whether such therapies may alsoaffect established and progressive renal disease. In the presentstudy we compared the effects of captopril (CEI) and diltiazem(CCB), started either at week 10 or at week 24 on the evolutionof adriamycin nephropathy (AN). Rats were studied at weeks 7,16, 24, 32, and 38 of the disease. None of the treatments influencedthe development of nephrotic range proteinuria. The use of CCBfrom week 10 was even associated with increased proteinuria.The moderate hypertension of ADR rats was reduced to the samedegree with both drugs. Inulin clearance (GFR) was significantlyreduced in all ADR rats. However, in ADR rats treated with CEIfrom week 10 and in those treated with CCB from week 24, theGFR was relatively higher. Glomerular injury, evaluated by semiquantitativemethods, was not ameliorated by CEI treatment. Earlier CCB treatment(week 10) worsened glomerular lesions, whilst CCB treatmentinitiated at week 24 reduced significantly the degree of mesangialexpansion and focal glomerular sclerosis. We conclude that,in addition to their common antihypertensive action, the specificeffect of drug therapy seems to be crucially time dependent.     

脂质体阿霉素对小鼠移植性肿瘤的治疗作用

目的　对比研究阿霉素和脂质体阿霉素对实体型和腹水型荷瘤小鼠的治疗作用。方法　将小鼠分为几个不同剂量的对应组 ,观察两种剂型的阿霉素经静脉注射给药后对小鼠实体型肿瘤的抑瘤率、腹腔给药后对荷瘤小鼠的生命延长率。结果　在 4、6mg·kg-1两对应组中 ,脂质体阿霉素对实体瘤的抑瘤作用较游离型阿霉素明显提高 ;9mg·kg-1组中两药物抑瘤率相仿 ;在 5、7.5、10mg·kg-1各组中 ,与游离药物相比脂质体载药可显著提高荷瘤动物的生命延长率。结论　脂质体载药后可保留或提高药物的抗肿瘤作用     

Reduced 11beta-hydroxysteroid dehydrogenase activity in experimental nephrotic syndrome.

BACKGROUND: The disease state of the nephrotic syndrome is characterized by abnormal renal sodium retention that cannot be completely explained by a secondary hyperaldosteronism for the following reasons. Firstly, in rats an enhanced sodium retention is observed before proteinuria with intravascular volume depletion occurs. Secondly, in patients with the nephrotic syndrome, volume expansion with hypertension has been reported despite suppression of the renin-aldosterone system. Therefore, another mechanism for sodium retention must be postulated for this disease state. We hypothesize that this mechanism is a reduced 11beta-hydroxysteroid dehydrogenase 2 (11beta-HSD2) activity, a phenomenon known to cause enhanced access of cortisol or corticosterone to the mineralocorticoid receptor. METHODS: We assessed the 11beta-HSD activity by measuring the urinary ratio of tetrahydrocorticosterone (THB) plus 5alpha-tetrahydrocorticosterone (5alpha-THB) to 11-dehydro-tetrahydrocorticosterone (THA) by gas chromatography-mass spectrometry in rats with puromycin aminonucleoside (PAN)-induced proteinuria and with adriamycin nephrosis. Furthermore, the plasma ratios of corticosterone to 11-dehydrocorticosterone were measured. RESULTS: The urinary ratio of (THB+5alpha-THB)/THA increased in all animals following injection of PAN or adriamycin, indicating a reduced activity of 11beta-HSD. The reduced activity of 11beta-HSD was confirmed by an increased plasma ratio of corticosterone to 11-dehydrocorticosterone. The changes in the glucocorticoid metabolite ratios were already present before significant proteinuria appeared. CONCLUSION: PAN- or adriamycin-treated rats develop proteinuria with a reduced activity of 11beta-HSD, a mechanism contributing to the abnormal sodium retention in nephrotic syndrome.     

阿霉素不同给药方法对静脉血管损伤的实验研究

目的 探讨阿霉素不同给药方法对静脉血管的损伤情况。方法 采用自身对照法对20只家免进行微量泵（实验组）和手工（对照组）静脉注射阿霉素，48h后活检穿刺局部组织，光镜下观察穿刺部位血管厦周围组织的变化。结果 实验组静脉血管炎性反应发生率为30．0％，对照组为100．0％．两组比较χ^2=21．54．P〈0．01．差异有显著性意义。结论 微量录静脉注射给药可减少静脉血管炎性反应发生率。     

Attenuating effect of castration or oestrogen administration on glomerular injury in adriamycin-induced nephropathy of rats

Summary: To clarify the role of sex-related factors in the development of focal segmental glomerulosclerosis (FSGS) we investigated the effect of castration or oestrogen administration in adriamycin (ADR)-induced nephropathy of Sprague-Dawley rats. At 6 weeks of age, group 1 (control group) and group 3 were shamoperated and group 2 was castrated. Adriamycin 2 mg/kg was administered intravenously to all rats at 8 weeks of age twice at a 20-day interval. Group 3 was administered 0.2 mg oestrogen subcutaneously once a month. Bodyweight (BW) and urinary protein were measured every 4 weeks (mm 15 to 23 weeks of age. Blood pressure and serum constituents were measured at 15 and 23 weeks of age. Each group was studied morphologically at 23 weeks of age. Adriamycin induced massive proteinuria in group 1, whereas castration or oestrogen significantly attenuated proteinuria, accompanied by a significant reduction of urinary sex-related low molecular weight (LMW) protein. the glomerulosclerosis index was significantly higher in the control group than in the castrated group or oestrogen-treated group. Attenuation in glomerular injury was more associated with reduction of urinary sex-related LMW protein than the reduction of serum testosterone. These observations suggest that sex-related factors, such as a sex-related LMW protein, influenced by castration or oestrogen administration may play a contributory role in the development of glomerulosclerosis in ADR-induced nephropathy.