Newsholme S J, Thudium D T, Gossett K A, Watson E S, Schwartz L W
Safety Assessment, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA.
Toxicol Pathol. 2000 Sep-Oct;28(5):688-93. doi: 10.1177/019262330002800508.
Plasma von Willebrand factor (vWF) was evaluated as a potential biomarker of acute arterial damage in rats after a vasotoxic dose of the dopaminergic vasodilator, fenoldopam (FP). Male Sprague-Dawley rats were given FP or isotonic saline by subcutaneous injection, and plasma vWF was measured at 2, 6, and 24 hours after challenge. Mean plasma vWF values increased in FP-treated rats compared to controls at 2 hours (167 vs 122%; p < 0.05) and 6 hours postdose (172 vs 130%; p < 0.01) but were comparable to control values after 24 hours. Mesenteric arterial lesions were observed microscopically in all FP-treated rats 24 hours postdose but were not present in rats at 1, 2, 4, 6, or 8 hours after FP challenge. Further, plasma vWF concentrations increased in saline-treated rats after only the minimal perturbation of repeated venipuncture. These results indicate an early, minimal, and transient release of vWF that precedes the onset of morphologically evident vascular damage. The minimal increases in plasma vWF concentrations were of limited predictive value, may be more reflective of an acute-phase reactant response, and were not considered a reliable biomarker of acute FP-induced arterial damage in the rat.
在给予多巴胺能血管扩张剂非诺多泮(FP)的血管毒性剂量后,评估血浆血管性血友病因子(vWF)作为大鼠急性动脉损伤潜在生物标志物的作用。对雄性Sprague-Dawley大鼠皮下注射FP或等渗盐水,并在激发后2小时、6小时和24小时测量血浆vWF。与对照组相比,FP处理组大鼠在给药后2小时(167%对122%;p<0.05)和6小时(172%对130%;p<0.01)时血浆vWF平均水平升高,但在24小时后与对照组值相当。给药后24小时,在所有FP处理的大鼠中均观察到肠系膜动脉病变,但在FP激发后1小时、2小时、4小时、6小时或8小时的大鼠中未出现。此外,仅在反复静脉穿刺的轻微干扰后,盐水处理组大鼠的血浆vWF浓度就升高了。这些结果表明,在形态学上明显的血管损伤发生之前,vWF会有早期、轻微和短暂的释放。血浆vWF浓度的最小升高具有有限的预测价值,可能更反映急性期反应物反应,并且不被认为是大鼠急性FP诱导动脉损伤的可靠生物标志物。