Local thrombus formation in the site of intravenous injection of chlorpromazine: possible colloid-osmotic lysis of the local endothelial cells.
Since amphiphilic drugs are known to interact with biomembranes, we investigated local vessel damage and thrombosis which might be brought about by intravenous dosing using chlorpromazine (CPZ) as a representative compound. CPZ-induced hemolysis was suppressed by an increase in sucrose concentration in the medium, characterizing this hemolysis to be colloid-osmotic lysis, which includes the enhancement of membrane phospholipid fluidity and consequent small pore formation in the membranes. This was supported by the observation that hemolysis by filipin, not featuring the stage of small pore formation, was not affected by sucrose. [14C]Glucose-entrapping liposomes were degraded by CPZ, and this degradation was enhanced by an increase in the intravesicle glucose concentration. These results indicated that the compound could induce colloid-osmotic lysis in erythrocytes and artificial membrane vesicles. CPZ also injured cultured porcine aortic endothelial cells (PAEC), as evidenced by lactate dehydrogenase (LDH) leakage. This injury was also suppressed by increase in sucrose concentration in the medium, suggesting that colloid-osmotic lysis again occurred. When rats were intravenously injected with CPZ, local endothelial cell (EC) injury and associated thrombus formation were observed, suggesting that CPZ's action was also evident in vivo. To our knowledge, this is the first finding which suggests that an intravenously dosed amphiphilic drug can injure local ECs based on a colloid-osmotic lysis mechanism leading to thrombosis.
Yabuki
M
M
Environmnental Health Science Laboratory, Sumitomo Chemical Co., Ltd., Osaka, Japan. yabukim1@sc.sumitomo-chem.co.jp
Tani
N
N
Yoshioka
T
T
Nishibe
H
H
Kanamaru
H
H
Kaneko
H
H
D000818:Animals; D002478:Cells, Cultured; D002746:Chlorpromazine / Q000008:administration & dosage* / Q000009:adverse effects; D003102:Colloids; D004730:Endothelium, Vascular / Q000293:injuries*; D006461:Hemolysis; D007275:Injections, Intravenous; D008297:Male; D009995:Osmosis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013552:Swine; D013927:Thrombosis / Q000473:pathology*
D003102:Colloids; D002746:Chlorpromazine