Dipfluzine hydrochloride, diphenylpiperazine calcium channel blocker, is a promising candidate to treat ischemic stroke. The purpose of the study is to evaluate the acute toxicity and toxicokinetics of dipfluzine hydrochloride after single intravenous doses in rats. Acute toxicity study was performed in rats at doses of 5, 6, 10, 15, 25, 30, 35, and 40 mg/kg. Concentrations of dipfluzine in plasma and tissues were determined with a reverse-phase HPLC method after single doses of 5, 15 and 30 mg/kg. The results demonstrated that no-observed-adverse-effect level (NOAEL), lowestobserved-adverse-effect level (LOAEL), maximal tolerance dose (MTD), and minimal lethal dose (MLD) were respectively 5, 6, 30, 35 mg/kg for i.v. administration of dipfluzine hydrochloride. The toxicokinetic study revealed that the severity of toxicity was linear with the level of systemic exposure. The highest tissue exposure was detected in lung tissue and it may primarily contribute to the pulmonary congestion in dead rats. Longer elimination half-lives of dipfluzine in kidney, brain, liver, and pancreas imply a possible accumulation of dipfluzine in these tissues for long-term exposure. In addition, a temporary impairment in liver and heart was observed for clinical chemistry in 30 mg/kg dose group. The findings will help to design further studies to characterize the repeat-dose toxicity of dipfluzine hydrochloride.

为了观察正常和心衰时心内膜下和心外膜下心肌细胞L-型钙电流（ICa-L）的差别，我们采用主动脉弓狭窄的方法建立小鼠压力超负荷性心衰模型，采用全细胞膜片钳技术记录了正常、主动脉狭窄（band）及假手术对照（sham）组动物左心室游离壁内、外膜下心肌细胞的动作电位时程（actionpotentialduration，APD）和ICa-L。结果显示：（1）与sham组同龄的正常小鼠左心室心内膜下细胞动作电位复极达90%的时程（APD90）为（38.2±6.44）ms，较心外膜下细胞的APD90（15.67±5.31）ms明显延长，二者的比值约为2.5：1；内膜下细胞和外膜下细胞ICa-L密度没有差异，峰电流密度分别为（?2.7±0.49）pA/pF和（?2.54±0.53）pA/pF；（2）Band组内、外膜下细胞的动作电位复极达50%的时程（APD50）、APD90均较sham组显著延长，尤以内膜下细胞延长突出，分别较sham组延长了400%和360%，内、外膜下细胞APD90的比值约为4.2：1；（3）与sham组相比，band组内膜下细胞ICa-L密度显著减小，在+10mV+40mV的4个电压下分别降低了20.2%、21.4%、21.6%和25.7%（P<0.01），但其激活电位、峰电位和翻转电位没有改变；band组外膜下细胞的ICa-L密度与同期sham组相比无明显变化；band组钙通道激活、失活及复活的动力学特征与sham组相比没有改变。以上结果提示，生理状态下小鼠左心室内、外膜下细胞ICa-L密度不存在明显差别，提示ICa-L与APD跨壁异质性的产生无关；心衰时左心室内、外膜下细胞APD明显延长，以内膜下细胞延长尤为突出，内膜下细胞ICa-L密度明显减少，而外膜下细胞ICa-L密度无明显改变，这种ICa-L的非同步变化在心衰时可能起到对抗APD延长、减少复极离散度的有益作用。