Lipid emulsion attenuates the vasodilation induced by a toxic dose of a calcium channel blocker through its partitioning into the lipid phase

Abstract

The present in vitro study examined whether lipid emulsion attenuates the vasodilation evoked by toxic doses of calcium channel blockers (bepridil, verapamil, nifedipine and diltiazem) via their partitioning into the lipid phase. The effects of the calcium channel blockers alone, the lipid emulsion and calcium channel blocker mixture, and the centrifuged aqueous extract (CAE) obtained from ultracentrifugation of the lipid emulsion and calcium channel blocker mixture on isolated endothelium-denuded rat aortas precontracted with phenylephrine were observed. The effects of lipid emulsion on calcium channel blocker concentration in the Krebs solution were examined using ultraperformance liquid chromatography. A mixture of lipid emulsion with either bepridil or verapamil and the corresponding CAE more effectively attenuated vasodilation than either bepridil or verapamil alone, whereas the vasodilation induced by the mixture of lipid emulsion and either bepridil or verapamil was not significantly different from that induced by the corresponding CAE. The magnitude of the lipid emulsion-mediated reduction in vasodilation and calcium channel blocker concentration was as follows: bepridil > verapamil > nifedipine or diltiazem. These results suggest that lipid emulsion attenuates vasodilation induced by a toxic dose of bepridil and verapamil, seemingly through partitioning of the calcium channel blocker into the lipid phase.Abbreviations: HPLC, high-performance liquid chromatography; L-NAME, N W -nitro-L-arginine methyl ester; UPLC-Q-TOF MS, ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry; CAE, centrifuged aqueous extract.

Lipid emulsion inhibits the vasodilation induced by a toxic dose of amlodipine in isolated rat aortae

“…These previous studies suggest that when a lower CAE layer and an upper lipid layer from the mixture of lipid emulsion with lipid-soluble drugs are separated by ultracentrifugation (Fig. 1B), a large portion of relatively lipid-soluble drugs (bepridil, verapamil and bupivacaine) is sequestered into the upper lipid layer, leading to reduced concentrations of relatively lipid-soluble drugs in the lower CAE layer and supporting the lipid sink theory 1,10,12,13,16. Similar to a previous report involving verapamil (log [octanol/water partition coefficient]: 3.79), lipid emulsion (0.25, 0.3 and 1%) attenuated the vasodilation caused by a toxic dose of amlodipine (Fig.…”

“…2A and B), and lipid emulsion (0.25 and 1%) decreased amlodipine (3 × 10 -7 M) concentrations to 83 ± 6 and 82 ± 5% of their original concentrations, respectively (Fig. 6) 16,31. These findings suggest that this lipid emulsion-mediated attenuation of the vasodilation induced by a toxic dose of amlodipine is associated with the reduction in amlodipine concentration caused by lipid emulsion.…”

Lipid emulsion attenuates extrinsic apoptosis induced by amlodipine toxicity in rat cardiomyoblasts

“…Amlodipine (10 −5 M) was emulsified with lipid emulsion (Intralipid: 0%, 0.125%, and 0.25%) in Krebs solution, using a rotator for 30 min, as described previously. 7,8 To determine the concentration of amlodipine released from the samples, the emulsified samples were centrifuged at 75,000 × g for 40 min. The concentration of amlodipine in the aqueous phase (equivalent to centrifuged aqueous extract) was measured by ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF MS; Waters, Milford, MA, USA), using an Acquity UPLC BEH C18 column (100 mm × 2.1 mm, 1.7 μm; Waters).…”

“…6 In vitro studies have suggested that lipid emulsion inhibits severe vasodilation induced by calcium channel blockers, including amlodipine, bepridil, and verapamil, at toxic doses. 7,8 However, some case reports have suggested that lipid emulsion may have no effect on cardiovascular collapse induced by amlodipine toxicity. 9,10 Overall, the conclusions on lipid emulsion treatment for amlodipine toxicity are conflicting.…”

Calcium dosage in the lipid emulsion used to treat verapamil toxicity

“…We have read the interesting report titled "Effect of intralipid administration on calcium therapy in verapamil toxicity," recently published in Bratislava Medical Journal (1). Lipid emulsions can effectively attenuate severe vasodilation induced by toxic doses of the highly lipid soluble calcium channel blocker, verapamil (2). The following comments should be considered when assessing this report.…”