MECHANISM OF POLOXAMER 407-INDUCED HYPERTRIGLYCERIDEMIA IN THE RAT

One 300 mg i.p. injection of the nonionic surfactant poloxamer 407 (Pl uronic(R) F-127)produces a significant increase above control of both circulating cholesterol and triglyceride (TG) concentrations. The pres ent study was conducted to determine the effect of poloxamer 407 (P-40 7) on the capacity to hydrolyze circulating TG by lipoprotein lipase ( LPL) in an attempt to determine the mechanism of action of P-407. The concentration of TG in the rat following a single 300 mg i.p. injectio n of P-407 was marked, increasing from 84 +/- 10 to 3175 +/- 322 mg/dL at 24 hr. The maximal rate of TG accumulation (5.74 mg/dL/min) in the plasma of P-407-injected rats occurred between 2 and 4 hr post-inject ion. In vitro incubation of LPL with P-407 significantly inhibited enz yme activity with an inhibitory concentration at which 50% of the enzy matic activity was lost of approximately 24 muM. Concentrations of P-4 07 exceeding 350 muM in vitro completely inhibited LPL activity. The e ffects of P-407 on the enzymatic activity of LPL in post-heparin plasm a obtained following a single 300 mg dose of P-407 to rats demonstrate d greater than 95% suppression of LPL activity 3 hr post-injection com pared with controls. Inhibition of LPL activity was greater than 90% a s long as 24 hr following a single i.p. injection of P-407. However, w hile the heparin-releasable fraction of capillary-bound LPL was inhibi ted in the plasma, LPL activity significantly increased in -cardiac an d skeletal muscle in poloxamer-injected animals compared with sham-inj ected controls. Although there was no significant change in LPL activi ty in adipose tissue, testes, and lung resulting from P-407 treatment, LPL activity increased by 37% in myocardium, 69% in soleus, and 66% i n gastrocnemius muscle in P-407-injected rats when compared with contr ols. Our studies would suggest that the predominant mechanism by which P-407 induced an increase in circulating TG was by a reduction in the rate at which TG was hydrolyzed due to inhibition of heparin-releasab le LPL by the surfactant