Susick R L, Dominick M A, Ulloa H M, Pegg D G
Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert, Ann Arbor, Michigan.
J Cardiovasc Pharmacol. 1994 Feb;23(2):275-82. doi: 10.1097/00005344-199402000-00015.
Angiotensin-converting enzyme (ACE) inhibitors have proven to be effective therapeutic agents for treatment of hypertension and congestive heart failure (CHF). Because of the role the renin-angiotensin system (RAS) plays in maintaining renal homeostasis, the effect these compounds have on renal function has been of interest. We assessed the effect of toxicologically significant doses of the new ACE inhibitor, quinapril, on renal function and morphology in dogs. Groups of 3 male beagle dogs were administered quinapril orally at daily doses of 0, 25, 125, or 250 mg/kg for 13 weeks. After treatment, animals were anesthetized and assessed for clinical pathologic and renal functional disturbances under normal conditions and after volume expansion and diuresis. Renal histopathology was conducted on perfusion-fixed kidney. No adverse effects on sensitive measures of renal function were detected; changes observed were consistent with the pharmacologic consequences of ACE inhibition. Decreased serum Na+ and Cl- (< 10%) and hematocrit at 125 and 250 mg/kg, twofold increases in serum creatinine and blood urea nitrogen (BUN) at 250 mg/kg, and decreased arterial blood pressure (BP) (20%) were observed at all doses. Under baseline conditions, urine flow increased 81-123% in quinapril-treated animals as compared with controls and urine specific gravities decreased 16% relative to controls at 125 and 250 mg/kg. Microscopically, juxtaglomerular hypertrophy was observed at all doses. At 250 mg/kg, minimal, widely scattered cortical tubular alterations were observed; glomerular lesions were not. No significant adverse effects of quinapril on renal morphology or function were observed at doses approximately 250 times the therapeutic dose.
血管紧张素转换酶（ACE）抑制剂已被证明是治疗高血压和充血性心力衰竭（CHF）的有效治疗药物。由于肾素-血管紧张素系统（RAS）在维持肾脏内环境稳定中所起的作用，这些化合物对肾功能的影响一直备受关注。我们评估了毒理学显著剂量的新型ACE抑制剂喹那普利对犬肾功能和形态的影响。将3只雄性比格犬分为一组，分别口服剂量为0、25、125或250 mg/kg的喹那普利，持续13周。治疗后，对动物进行麻醉，并在正常条件下以及扩容和利尿后评估临床病理和肾功能紊乱情况。对灌注固定的肾脏进行肾组织病理学检查。未检测到对肾功能敏感指标的不良反应；观察到的变化与ACE抑制的药理学后果一致。在125和250 mg/kg剂量下，血清Na+和Cl-降低（<10%）以及血细胞比容降低，在250 mg/kg剂量下，血清肌酐和血尿素氮（BUN）增加两倍，并且在所有剂量下均观察到动脉血压（BP）降低（20%）。在基线条件下，与对照组相比，喹那普利治疗的动物尿流量增加了81 - 123%，在125和250 mg/kg剂量下，尿比重相对于对照组降低了16%。在显微镜下，所有剂量下均观察到肾小球旁器肥大。在250 mg/kg剂量下，观察到最小程度的、广泛散在的皮质肾小管改变；未观察到肾小球病变。在约为治疗剂量250倍的剂量下，未观察到喹那普利对肾脏形态或功能有显著不良反应。
