Bupivacaine-induced Vasodilation Is Mediated by Decreased Calcium Sensitization in Isolated Endothelium-denuded Rat Aortas Precontracted with Phenylephrine

Abstract

BackgroundA toxic dose of bupivacaine produces vasodilation in isolated aortas. The goal of this in vitro study was to investigate the cellular mechanism associated with bupivacaine-induced vasodilation in isolated endotheliumdenuded rat aortas precontracted with phenylephrine.MethodsIsolated endothelium-denuded rat aortas were suspended for isometric tension recordings. The effects of nifedipine, verapamil, iberiotoxin, 4-aminopyridine, barium chloride, and glibenclamide on bupivacaine concentration-response curves were assessed in endothelium-denuded aortas precontracted with phenylephrine. The effect of phenylephrine and KCl used for precontraction on bupivacaine-induced concentration-response curves was assessed. The effects of verapamil on phenylephrine concentration-response curves were assessed. The effects of bupivacaine on the intracellular calcium concentration ([Ca2+]i) and tension in aortas precontracted with phenylephrine were measured simultaneously with the acetoxymethyl ester of a fura-2-loaded aortic strip.ResultsPretreatment with potassium channel inhibitors had no effect on bupivacaine-induced relaxation in the endothelium-denuded aortas precontracted with phenylephrine, whereas verapamil or nifedipine attenuated bupivacaine-induced relaxation. The magnitude of the bupivacaine-induced relaxation was enhanced in the 100 mM KCl-induced precontracted aortas compared with the phenylephrine-induced precontracted aortas. Verapamil attenuated the phenylephrine-induced contraction. The magnitude of the bupivacaine-induced relaxation was higher than that of the bupivacaine-induced [Ca2+]i decrease in the aortas precontracted with phenylephrine.ConclusionsTaken together, these results suggest that toxic-dose bupivacaine-induced vasodilation appears to be mediated by decreased calcium sensitization in endothelium-denuded aortas precontracted with phenylephrine. In addition, potassium channel inhibitors had no effect on bupivacaine-induced relaxation. Toxic-dose bupivacaine- induced vasodilation may be partially associated with the inhibitory effect of voltage-operated calcium channels.

A Lipid Emulsion Reverses Toxic-Dose Bupivacaine-Induced Vasodilation during Tyrosine Phosphorylation-Evoked Contraction in Isolated Rat Aortae

“…However, in the current study, a toxic dose of bupivacaine inhibited sodium orthovanadate-induced MYPT1 phosphorylation. It has been reported that bupivacaine inhibits calcium sensitization in aortae precontracted with PDBu, NaF and phenylephrine [12,13,14]. In agreement with previous reports and the present Western blot results, bupivacaine decreased more tension than [Ca 2+ ] i during sodium orthovanadate-induced contraction, suggesting that the bupivacaine-induced reduction in calcium sensitization is mediated by the inhibition of sodium orthovanadate-induced MYPT1 phosphorylation [12,13,14].…”

Past, Present, and Future of Lipid Resuscitation Therapy

“…However, orders of magnitude below their sodium channel blocking threshold, 36 , 37 they can interfere with intracellular signaling, 38 and above their sodium channel blocking threshold, they interfere with mitochondrial metabolism, thereby altering oxidative phosphorylation 39 . These multiple effects lead to a combination of systematic issues with both vasodilation 40 and cardiac collapse 41 . It is still unclear which effect is responsible for the lethality of LAST 9 .…”

Lipid Emulsion Inhibits Vasodilation Induced by a Toxic Dose of Bupivacaine via Attenuated Dephosphorylation of Myosin Phosphatase Target Subunit 1 in Isolated Rat Aorta

“…Low doses of levobupivacaine produce vasoconstriction at the resting tension, whereas high doses of levobupivacaine cause vasodilation, which appears to be associated with vascular collapse evoked by such high doses of levobupivacaine 6 - 8 . In addition, a toxic dose of bupivacaine induces vasodilation that appears to be partially associated with decreased calcium sensitization in isolated endothelium-denuded rat aorta precontracted with phenylephrine 9 . Agonists, including phenylephrine, activate Rho kinase and protein kinase C (PKC), which leads to contraction via increased calcium sensitization 10 .…”

“…Rho kinase and PKC phosphorylate myosin phosphatase target subunit 1 (MYPT1) and phosphorylation-dependent inhibitory protein of myosin phosphatase, respectively, leading to increased calcium sensitization via the inhibition of myosin light chain phosphatase (MLCP) 10 . Because the phosphorylation of MYPT1, which is a signaling molecule downstream of Rho kinase that participates in vascular smooth muscle contraction, is involved in calcium sensitization, whereas bupivacaine-induced vasodilation causes decreased calcium sensitization, we tested the hypothesis that lipid emulsion attenuated bupivacaine-induced vasodilation via the modulation of MYPT1 phosphorylation 3 - 5 , 9 , 10 . The goal of this in vitro study was to investigate the cellular mechanism responsible for the lipid emulsion-mediated attenuation of severe vasodilation induced by a toxic dose of bupivacaine, focusing on MYPT1 phosphorylation.…”