Lipid emulsion alleviates the vasodilation and mean blood pressure decrease induced by a toxic dose of verapamil in isolated rat aortae and an in vivo rat model

Abstract

This study aimed to examine the effects of lipid emulsion on the vasodilation and cardiovascular depression induced by toxic doses of calcium channel blockers. The effects of lipid emulsion on the vasodilation induced by bepridil, verapamil, nifedipine, and diltiazem were investigated in isolated endothelium-denuded rat aortae. The effect of lipid emulsion on the comparable hemodynamic depression induced by the continuous infusion of a toxic dose of either verapamil or diltiazem was examined in an in vivo rat model. The results showed the following decreasing order for the magnitude of lipid emulsion-mediated inhibition of vasodilation: bepridil, verapamil, nifedipine, and diltiazem. Lipid emulsion (0.5-2%) reversed the vasodilation induced by a toxic dose of verapamil, whereas only a higher concentration (2%) reversed the vasodilation induced by a toxic dose of diltiazem. Pretreatment with lipid emulsion alleviated the systolic and mean blood pressure decreases induced by a toxic dose of verapamil, whereas it had no effect on the decrease induced by diltiazem. Taken together, these results suggest that lipid emulsion alleviates the severe vasodilation and systolic blood pressure decrease induced by a toxic dose of verapamil, and this alleviation appears to be associated with the relatively high lipid solubility of verapamil.

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

“…Lipid emulsion attenuates the inhibition of cardiomyocyte contractility induced by verapamil and reduces the verapamil concentration (Kryshtal et al 2016). Furthermore, the treatment with a lipid emulsion alleviates vasodilation evoked by calcium channel blockers, which appears to be positively correlated with the lipid solubility (oil/Ringer partition coefficient) of calcium channel blockers and the order of uptake of calcium channel blockers into rat aortic vascular smooth muscle cells (Pang and Sperelakis 1984;Ok et al 2018b). The centrifuged aqueous extract (CAE) lacking the upper lipid phase (layer) obtained after the ultracentrifugation of a mixture of the highly lipid-soluble local anaesthetic bupivacaine and lipid emulsion produces a smaller reduction in mean arterial pressure than bupivacaine alone, but a significant difference in the mean arterial pressure was not observed between subjects administered the CAE and subjects given the bupivacaine and lipid emulsion mixture (Hori et al 2015).…”

“…However, the detailed mechanism contributing to the inhibitory effect of lipid emulsion on the vasodilation evoked by toxic doses of calcium channel block-ers remains unknown. Based on previous reports, we tested the hypothesis that lipid emulsion inhibits the vasodilation induced by a toxic dose of calcium channel blockers through the partitioning of calcium channel blockers into the lipid phase of lipid emulsions (Pang and Sperelakis 1984;Wagner et al 2014;Hori et al 2015;Ok et al 2018aOk et al , 2018b. First, the objective of this study was to examine whether a lipid emulsion (Intralipid ® ) inhibits vasodilation induced by toxic doses of calcium channel blockers through the partitioning of the calcium channel blocker into the lipid phase of lipid emulsions using ultracentrifugation to separate a mixture of lipid emulsion and calcium channel blockers into an upper lipid phase and lower CAE.…”

“…Isolated rat thoracic aorta was prepared for tension measurement as described previously (Ok et al 2018b). Male Sprague-Dawley rats (body weight: 250 to 300 g; n = 35) were anaesthetized with 100% carbon dioxide.…”

“…The recommended plasma lipid emulsion concentration for the partitioning effect in cases of oral overdose-induced intoxication is 1% triglyceride (1000 mg/dl) (Fettiplace et al 2015). In addition, a previous study suggested that 1% lipid emulsion attenuates vasodilation induced by a toxic dose of a calcium channel blocker (Ok et al 2018b). Therefore, a 0.998% lipid emulsion concentration, which corresponds to an approximately 1% plasma lipid emulsion concentration, was chosen in this experiment using 20% Intralipid® as the lipid emulsion (Fettiplace et al 2015;Ok et al 2018b).…”

“…Furthermore, the inhibitory effect of lipid emulsion on diltiazem-induced vasodilation was not significant (10 ± 13%), whereas lipid emulsion (1%) decreased the diltiazem concentration by 8 ± 5%. This difference between the lipid emulsion-mediated inhibition of vasodilation and the lipid emulsion-mediated reduction in the concentration of each calcium channel blocker may be due to the following putative causes: First, the potency of calcium channel blockers to produce vasodilation in isolated endothelium-denuded rat aortas precontracted with phenylephrine is as follows: nifedipine > verapamil > diltiazem (Ok et al 2018b). Second, lipid emulsion reduced the diltiazem concentration but potentially not to a level to increase calcium influx.…”