Mepivacaine-induced contraction is attenuated by endothelial nitric oxide release in isolated rat aorta

Abstract

Mepivacaine is an aminoamide-linked local anesthetic with an intermediate duration that intrinsically produces vasoconstriction both in vivo and in vitro. The aims of this in-vitro study were to examine the direct effect of mepivacaine in isolated rat aortic rings and to determine the associated cellular mechanism with a particular focus on endothelium-derived vasodilators, which modulate vascular tone. In the aortic rings with or without endothelium, cumulative mepivacaine concentration-response curves were generated in the presence or absence of the following antagonists: N(ω)-nitro-L-arginine methyl ester [L-NAME], indomethacin, fluconazole, methylene blue, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one [ODQ], verapamil, and calcium-free Krebs solution. Mepivacaine produced vasoconstriction at low concentrations (1 × 10(-3) and 3 × 10(-3) mol/L) followed by vasodilation at a high concentration (1 × 10(-2) mol/L). The mepivacaine-induced contraction was higher in endothelium-denuded aortae than in endothelium-intact aortae. Pretreatment with L-NAME, ODQ, and methylene blue enhanced mepivacaine-induced contraction in the endothelium-intact rings, whereas fluconazole had no effect. Indomethacin slightly attenuated mepivacaine-induced contraction, whereas verapamil and calcium-free Krebs solution more strongly attenuated this contraction. The vasoconstriction induced by mepivacaine is attenuated mainly by the endothelial nitric oxide - cyclic guanosine monophosphate pathway. In addition, mepivacaine-induced contraction involves cyclooxygenase pathway activation and extracellular calcium influx via voltage-operated calcium channels.

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

“…Second, lipid emulsion inhibits acetylcholine-induced nitric oxide-mediated relaxation in isolated endothelium-intact aortae [25]. In addition, the vasoconstriction induced by local anesthetics, including levobupivacaine, mepivacaine and ropivacaine, has been reported to be attenuated by endothelial nitric oxide [26,27,28]. Furthermore, it has been reported that the lipid emulsion-mediated inhibition of levobupivacaine-induced endothelial nitric oxide synthase phosphorylation partially contributes to the lipid emulsion-mediated reversal of toxic-dose levobupivacaine-induced vasodilation [3,29].…”

“…Taking into consideration previous reports, we hypothesized that the magnitude of the lipid emulsion-mediated reversal of toxic-dose bupivacaine-induced vasodilation during sodium orthovanadate-induced contraction may be greatly enhanced in endothelium-intact aortae compared with endothelium-denuded aortae [3,9,25,26,27,28,29,30,31]. However, we used l -NAME-pretreated endothelium-denuded rat aortae to focus on the vascular smooth muscle and to avoid confounding factors, such as vasodilation induced by endothelial nitric oxide released by local anesthetics and sodium orthovanadate [9,26,27,28,30,31]. Third, vascular tone is regulated by extrinsic factors in vivo, including the sympathetic nervous system and circulating hormones [4].…”

Ropivacaine-Induced Contraction Is Attenuated by Both Endothelial Nitric Oxide and Voltage-Dependent Potassium Channels in Isolated Rat Aortae

“…The aforementioned inhibitors were directly added to the organ bath 20 min before the addition of ropivacaine. Inhibitor concentrations were chosen on the basis of the concentrations used in previous experiments similar to this experiment [6, 10, 13–18]. …”

“…Ropivacaine is an aminoamide local anesthetic of the n -alkyl-substituted pipecolyl xylidine family, which includes levobupivacaine and mepivacaine [5]. Vasoconstriction induced by levobupivacaine and mepivacaine is attenuated by endothelial nitric oxide (NO) [6–8]. In endothelium-denuded aortae, ropivacaine-induced contraction is mediated mainly by the lipoxygenase pathway and partly by the cyclooxygenase pathway [4].…”

The Mechanisms Underlying Lipid Resuscitation Therapy

“…At lower concentrations, local anesthetics will increase vascular tone, whereas at higher concentrations they induce vasorelaxation by interacting with a number of protein kinases and second messengers (protein kinase C [PKC], mitogen activated protein kinase [MAPK], extracellular signal-regulated kinase [ERK], c-Jun N-terminal kinase [JNK], Ca 2+ , endothelial nitric oxide synthase). [102][103][104][105][106] In addition, local anesthetics block pharmacological agent-induced vasoreactivity of a number of compounds (phenylephrine, acetylcholine, KCl). [107][108][109] This dualistic concentration effect creates ambiguities for experimental models using lipid emulsion.…”