Bocherens-Gadient S A, Quast U, Nussberger J, Brunner H R, Hof R P
Sandoz Pharma Ltd., Basel, Switzerland.
J Cardiovasc Pharmacol. 1992 May;19(5):770-8.
Treatment of male rabbits with adriamycin at a cardiotoxic dose (1 mg/kg intravenously, i.v., twice a week for 9 weeks) caused cardiovascular disturbances characteristic of chronic heart failure. The severity of symptoms varied, indicating differences in the individual sensitivity of the animals to adriamycin. Thus, cardiac output (CO) was decreased by greater than 40% in only 4 of the 7 animals in which it was measurable at 9 weeks. Elevated levels of atrial natriuretic factor (ANF) and plasma renin activity (PRA), as well as pulmonary congestion, hydrothorax, and ascites were also evident. The baroreflex response to sodium nitroprusside (NPS) was blunted. The response to the inotropic drug dobutamine was depressed by 50% as compared with the control animals. Right ventricular beta-adrenoceptor density was significantly reduced in these animals (22.9 +/- 3.1 as compared with 31.8 +/- 1.0 fmol/mg protein in control animals) owing to a selective downregulation of the beta 1-adrenoceptor population. The loss of beta-adrenoceptors was highly correlated with severity of heart failure symptoms: i.e., baroreflex dysfunction as indicated by the NPS slope (r = 0.91), decrease in CO during the previous weeks (r = 0.88), and plasma norepinephrine (NE) levels (r = 0.96). However, when all adriamycin-treated animals were compared collectively regardless of the severity of heart failure, with the controls, no difference in the beta-adrenoceptor density was detectable, a finding in agreement with previous observations in this model. Chronic treatment of rabbits with adriamycin thus causes low-output failure, reflecting some of the findings reported for the human disease; however, individual sensitivity to adriamycin varies considerably between rabbits.(ABSTRACT TRUNCATED AT 250 WORDS)
以心脏毒性剂量（静脉注射1毫克/千克，每周两次，共9周）给雄性兔子注射阿霉素，会引发慢性心力衰竭特有的心血管紊乱。症状的严重程度各不相同，表明动物对阿霉素的个体敏感性存在差异。因此，在9周时可测量心输出量（CO）的7只动物中，只有4只的心输出量降低了40%以上。心房利钠因子（ANF）和血浆肾素活性（PRA）水平升高，以及肺充血、胸腔积液和腹水也很明显。对硝普钠（NPS）的压力反射反应减弱。与对照动物相比，对强心药多巴酚丁胺的反应降低了50%。由于β1 - 肾上腺素能受体群体的选择性下调，这些动物的右心室β - 肾上腺素能受体密度显著降低（与对照动物的31.8±1.0飞摩尔/毫克蛋白质相比为22.9±3.1）。β - 肾上腺素能受体的丧失与心力衰竭症状的严重程度高度相关：即由NPS斜率表示的压力反射功能障碍（r = 0.91）、前几周CO的降低（r = 0.88）和血浆去甲肾上腺素（NE）水平（r = 0.96）。然而，当将所有接受阿霉素治疗的动物，无论心力衰竭的严重程度如何，与对照动物一起进行总体比较时，未检测到β - 肾上腺素能受体密度的差异，这一发现与该模型先前的观察结果一致。因此，用阿霉素对兔子进行慢性治疗会导致低输出量衰竭，反映了人类疾病报告中的一些发现；然而，兔子对阿霉素的个体敏感性差异很大。（摘要截断于250字）
