Characterization of nicardipine hydrochloride-induced cell injury in human vascular endothelial cells

Abstract

-Nicardipine hydrochloride (NIC), a dihydropyridine calcium-channel blocking agent, has been widely used for the treatment of hypertension. Especially, nicardipine hydrochloride injection is used as first-line therapy for emergency treatment of abnormally high blood pressure. Although NIC has an attractive pharmacological profile, one of the dose-limiting factors of NIC is severe peripheral vascular injury after intravenous injection. The goal of this study was to better understand and thereby reduce NIC-mediated vascular injury. Here, we investigated the mechanism of NIC-induced vascular injury using human dermal microvascular endothelial cells (HMVECs). NIC decreased cell viability and increased percent of dead cells in a dose-dependent manner (10-30 μg/mL). Although cell membrane injury was not significant over 9 hr exposure, significant changes of cell morphology and increases in vacuoles in HMVECs were observed within 30 min of NIC exposure (30 μg/mL). Autophagosome labeling with monodansylcadaverine revealed increased autophagosomes in the NIC-treated cells, whereas caspase 3/7 activity was not increased in the NIC-treated cells (30 μg/mL). Additionally, NIC-induced reduction of cell viability was inhibited by 3-methyladenine, an inhibitor of autophagosome formation. These findings suggest that NIC causes severe peripheral venous irritation via induction of autophagic cell death and that inhibition of autophagy could contribute to the reduction of NIC-induced vascular injury.

Autophagy in vascular endothelial cells

“…For example, treatment of human endothelial cells with the endogenous angiogenic inhibitor endostatin induces autophagy as well as cell death, which is insensitive to caspase inhibitors, but is suppressed by the autophagy inhibitor 3-methyladenine 58. Similarly, inhibition of autophagy either by pharmacological inhibitors or by genetic silencing of autophagy-specific genes effectively prevents endothelial cell death triggered by different stressors, including fatty acid overload, 59 simulated ischemia/reperfusion, 52 and the dihydropyridine anti-hypertensive drug nicardipine hydrochloride 60. More interestingly, Chen et al61 have provided evidence showing that in endothelial cells challenged with hypoxia, there is a transition from autophagy-mediated cell survival to autophagy-mediated cell death in a time-dependent manner.…”

Protective effect of <i>N</i>-acetylcysteine against nicardipine hydrochloride-induced autophagic cell death of human vascular endothelial cells

“…3-MA is a specifi c inhibitor of autophagosome formation via the inhibition of type III phosphatidylinositol 3-kinases (Seglen and Gordon, 1982;Blommaart et al, 1997). These fi ndings demonstrated that autophagy is the main pathway of NIC-induced cell injury, and that inhibition of autophagy could reduce NIC-induced cell death (Ochi et al, 2015). Thus, inhibition of autophagy at the site of injection might reduce NIC-induced vascular injury.…”

“…Morphological changes and autophagosome stainings of NIC-exposed HMVEC Previously, we determined the NIC-induced increase of autophagosomes with MDC staining (Ochi et al, 2015). To confirm the cytoprotective mechanism of NAC against NIC-induced autophagic cell death, MDC staining was conducted in NIC-treated HMVECs with or without NAC (Fig.…”

“…We also demonstrated the cytoprotective effect of 3-methyladenine (3-MA), an autophagosome formation inhibitor that is active against NIC-induced cell toxicity (Ochi et al, 2015). However, the safety of 3-MA in the human body has never been confirmed.…”

Paeonol Inhibits Oxidized Low-Density Lipoprotein-Induced Vascular Endothelial Cells Autophagy by Upregulating the Expression of miRNA-30a

“…However, in some instances, excessive autophagy leads to dysregulation of major proteins in VECs, thereby might contribute to the VECs injury and death ( Chau et al, 2003 ; Green and Levine, 2014 ; Gatica et al, 2015 ). More interestingly, VECs challenged with hypoxia, there is a transition from autophagy-mediated cell survival to autophagy-mediated cell death in a time-dependent manner ( Ochi et al, 2015 ). The beneficial effects of autophagy in VECs are likely to be context-dependent, since autophagy may also contribute to cell death under certain circumstances.…”