Self-Association of Endothelin-1 with Sterically Stabilized Phospholipid Nanomicelles Amplifies Its Hemodynamic Effects in Rats

Endothelin-1 (ET-1) is a potent amphipathic vasoactive mammalian peptide. However, its hemodynamic effects in vivo are relatively short-lived most likely due to proteolytic degradation and inactivation. Accordingly, the purpose of this study was to determine whether self-association of ET-1 with long-circulating, biocompatible and biodegradable sterically stabilized phospholipid nanomicelles (SSM) composed distearoylphosphatidylethanolamine (DSPE-PEG₂₀₀₀) conjugated with poly(ethylene glycol) (molecular mass, 2,000) amplifies its systemic and regional hemodynamic effects in anesthetized rats. Solutions were infused at 0.1 ml/minute for 30 minutes. Infusion of SSM alone (0.1 ml/min for 30 min) had no significant effects of mean arterial pressure (MAP), heart rate, cardiac output (CO), total peripheral vascular resistance (TPR), and regional blood circulation. By contrast, infusion of ET-1 in SSM (50 ng/kg/min for 30 min) elicited a significant and prolonged increase in MAP and TPR, and a significant decrease in CO relative to infusion of ET-1 alone (P < 0.05). Likewise, ET-1 in SSM elicited a significant and prolonged decrease in blood flow coupled with a significant and prolonged increase in vascular resistance in the kidney and gastrointestinal tract relative to ET-1 alone (P < 0.05). By contrast, brain ET-1 in SSM-induced increase in vascular resistance in the brain which was significantly greater than that evoked by ET-1 in SSM (P < 0.05). Taken together, these data indicate that self-association of ET-1 with long-circulating, biocompatible and biodegradable SSM amplifies its hemodynamic effects in vivo and that these nanomicelles do not readily cross the intact blood-brain barrier. We suggest this new formulation of ET-1 could be used as a vasoconstrictor drug to treat hypovolemic shock and selectively reduce blood flow to cancer.