Mepivacaine attenuates vasodilation induced by ATP-sensitive potassium channels in rat aorta.

The goal of this in vitro study was to investigate the effect of mepivacaine on vasodilation induced by the ATP-sensitive potassium (KATP) channel opener levcromakalim in isolated endothelium-denuded rat aortas. The effects of mepivacaine and the KATP channel inhibitor glibenclamide, alone or in combination, on levcromakalim-induced vasodilation were assessed in the isolated aortas. The effects of mepivacaine or combined treatment with a protein kinase C (PKC) inhibitor, GF109203X, and mepivacaine on this vasodilation were also investigated. Levcromakalim concentration-response curves were generated for isolated aortas precontracted with phenylephrine or a PKC activator, phorbol 12,13-dibutyrate (PDBu). Further, the effects of mepivacaine and glibenclamide on levcromakalim-induced hyperpolarization were assessed in rat aortic vascular smooth muscle cells. Mepivacaine attenuated levcromakalim-induced vasodilation, whereas it had no effect on this vasodilation in isolated aortas pretreated with glibenclamide. Combined treatment with GF109203X and mepivacaine enhanced levcromakalim-induced vasodilation compared with pretreatment with mepivacaine alone. This vasodilation was attenuated in aortas precontracted with PDBu compared with those precontracted with phenylephrine. Mepivacaine and glibenclamide, alone or in combination, attenuated levcromakalim-induced membrane hyperpolarization. Taken together, these results suggest that mepivacaine attenuates vasodilation induced by KATP channels, which appears to be partly mediated by PKC.

Lipofundin® MCT/LCT 20% increase left ventricular systolic pressure in an ex vivo rat heart model via increase of intracellular calcium level.

BACKGROUND: Lipid emulsions have been used to treat various drug toxicities and for total parenteral nutrition therapy. Their usefulness has also been confirmed in patients with local anesthetic-induced cardiac toxicity. The purpose of this study was to measure the hemodynamic and composition effects of lipid emulsions and to elucidate the mechanism associated with changes in intracellular calcium levels in myocardiocytes. METHODS: We measured hemodynamic effects using a digital analysis system after Intralipid® and Lipofundin® MCT/LCT were infused into hearts hanging in a Langendorff perfusion system. We measured the effects of the lipid emulsions on intracellular calcium levels in H9c2 cells by confocal microscopy. RESULTS: Infusion of Lipofundin® MCT/LCT 20% (1 ml/kg) resulted in a significant increase in left ventricular systolic pressure compared to that after infusing modified Krebs-Henseleit solution (1 ml/kg) (P = 0.003, 95% confidence interval [CI], 2.4-12.5). Lipofundin® MCT/LCT 20% had a more positive inotropic effect than that of Intralipid® 20% (P = 0.009, 95% CI, 1.4-11.6). Both lipid emulsion treatments increased intracellular calcium levels. Lipofundin® MCT/LCT (0.01%) increased intracellular calcium level more than that of 0.01% Intralipid® (P < 0.05, 95% CI, 0.0-1.9). CONCLUSIONS: These two lipid emulsions had different inotropic effects depending on their triglyceride component. The inotropic effect of lipid emulsions could be related with intracellular calcium level.

Dexmedetomidine-Induced Contraction in the Isolated Endothelium-Denuded Rat Aorta Involves PKC-δ-mediated JNK Phosphorylation.

Vasoconstriction mediated by the highly selective alpha-2 adrenoceptor agonist dexmedetomidine leads to transiently increased blood pressure and severe hypertension. The dexmedetomidine-induced contraction involves the protein kinase C (PKC)-mediated pathway. However, the main PKC isoform involved in the dexmedetomidine-induced contraction remains unknown. The goal of this in vitro study was to examine the specific PKC isoform that contributes to the dexmedetomidine-induced contraction in the isolated rat aorta. The endothelium-denuded rat aorta was suspended for isometric tension recording. Dexmedetomidine dose-response curves were generated in the presence or absence of the following inhibitors: the pan-PKC inhibitor, chelerythrine; the PKC-α and -ß inhibitor, Go6976; the PKC-α inhibitor, safingol; the PKC-ß inhibitor, ruboxistaurin; the PKC-δ inhibitor, rottlerin; the c-Jun NH2-terminal kinase (JNK) inhibitor, SP600125; and the myosin light chain kinase inhibitor, ML-7 hydrochloride. Western blot analysis was used to examine the effect of rottlerin on dexmedetomidine-induced PKC-δ expression and JNK phosphorylation in rat aortic vascular smooth muscle cells (VSMCs) and to investigate the effect of dexmedetomidine on PKC-δ expression in VSMCs transfected with PKC-δ small interfering RNA (siRNA) or control siRNA. Chelerythrine as well as SP600125 and ML-7 hydrochloride attenuated the dexmedetomidine-induced contraction. Go6976, safingol, and ruboxistaurin had no effect on the dexmedetomidine-induced contraction, whereas rottlerin inhibited the dexmedetomidine-induced contraction. Dexmedetomidine induced PKC-δ expression, whereas rottlerin and PKC-δ siRNA transfection inhibited dexmedetomidine-induced PKC-δ expression. Dexmedetomidine also induced JNK phosphorylation, which was inhibited by rottlerin. Taken together, these results suggest that the dexmedetomidine-induced contraction involves PKC-δ-dependent JNK phosphorylation in the isolated rat aorta.

Lipid Emulsion Attenuates Acetylcholine-Induced Relaxation in Isolated Rat Aorta.

We investigated the effect of Lipofundin MCT/LCT and Intralipid on acetylcholine-induced nitric oxide- (NO-) mediated relaxation in rat aorta to determine which lipid emulsion (LE) is more potent in terms of inhibition of NO-induced relaxation. Dose-response curves of responses induced by acetylcholine, the calcium ionophore A23187, and sodium nitroprusside were generated using isolated rat aorta with or without LE. The effect of Lipofundin MCT/LCT on acetylcholine-induced endothelial nitric oxide synthase (eNOS) phosphorylation in human umbilical vein endothelial cells (HUVECs) was investigated using western blotting. Lipofundin MCT/LCT (0.1 and 0.2%) attenuated acetylcholine-induced relaxation in endothelium-intact aorta with or without tiron, whereas 0.2% Intralipid only inhibited relaxation. Lipofundin MCT/LCT inhibited relaxation induced by the calcium ionophore A23187 and sodium nitroprusside in endothelium-intact aorta, but Lipofundin MCT/LCT had no effect on sodium nitroprusside-induced relaxation in the endothelium-denuded aorta. Combined pretreatment with l-arginine plus Lipofundin MCT/LCT increased acetylcholine-induced maximal relaxation in endothelium-intact aorta compared with Lipofundin MCT/LCT alone. L-Arginine attenuated Lipofundin MCT/LCT-mediated inhibition of acetylcholine-induced eNOS phosphorylation in HUVECs. Taken together, Lipofundin MCT/LCT attenuated acetylcholine-induced NO-mediated relaxation via an inhibitory effect on the endothelium including eNOS, which is proximal to activation of guanylyl cyclase.

Anesthetic management for percutaneous computed tomography-guided radiofrequency ablation of reninoma: a case report.

A reninoma is an uncommon, benign, renin-secreting juxtaglomerular cell tumor that causes secondary hypertension in young patients. This hypertension is treated by tumor resection. Except for increased levels of plasma renin and angiotensin I and II, the other physical and laboratory examinations and electrocardiographs were within normal limits upon admission of a 19-year-old woman with a reninoma. For percutaneous computed tomography-guided radiofrequency ablation, general anesthesia was induced by thiopental sodium and rocuronium bromide and maintained with servoflurane (2-4 vol%) and oxygen. The operation ended uneventfully in hemodynamic stability. However, the patient complained of dizziness while sitting 5 hours after the operation, and hypotension was diagnosed. After aggressive normal saline (1 L) infusion over 30 min, the hypotension was corrected and the patient recovered without any other surgical complications. Here, we report the anesthetic management of a patient who underwent percutaneous computed tomography-guided radiofrequency ablation for reninoma destruction, particularly focusing on postoperative hypotension.

Dexmedetomidine-induced contraction involves phosphorylation of caldesmon by JNK in endothelium-denuded rat aortas.

Caldesmon, an inhibitory actin binding protein, binds to actin and inhibits actin-myosin interactions, whereas caldesmon phosphorylation reverses the inhibitory effect of caldesmon on actin-myosin interactions, potentially leading to enhanced contraction. The goal of this study was to investigate the cellular signaling pathway responsible for caldesmon phosphorylation, which is involved in the regulation of the contraction induced by dexmedetomidine (DMT), an alpha-2 adrenoceptor agonist, in endothelium-denuded rat aortas. SP600125 (a c-Jun NH2-terminal kinase [JNK] inhibitor) dose-response curves were generated in aortas that were pre-contracted with DMT or phorbol 12,13-dibutyrate (PDBu), a protein kinase C (PKC) activator. Dose-response curves to the PKC inhibitor chelerythrine were generated in rat aortas pre-contracted with DMT. The effects of SP600125 and rauwolscine (an alpha-2 adrenoceptor inhibitor) on DMT-induced caldesmon phosphorylation in rat aortic vascular smooth muscle cells (VSMCs) were investigated by western blot analysis. PDBu-induced caldesmon and DMT-induced PKC phosphorylation in rat aortic VSMCs was investigated by western blot analysis. The effects of GF109203X (a PKC inhibitor) on DMT- or PDBu-induced JNK phosphorylation in VSMCs were assessed. SP600125 resulted in the relaxation of aortas that were pre-contracted with DMT or PDBu, whereas rauwolscine attenuated DMT-induced contraction. Chelerythrine resulted in the vasodilation of aortas pre-contracted with DMT. SP600125 and rauwolscine inhibited DMT-induced caldesmon phosphorylation. Additionally, PDBu induced caldesmon phosphorylation, and GF109203X attenuated the JNK phosphorylation induced by DMT or PDBu. DMT induced PKC phosphorylation in rat aortic VSMCs. These results suggest that alpha-2 adrenoceptor-mediated, DMT-induced contraction involves caldesmon phosphorylation that is mediated by JNK phosphorylation by PKC.

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

BACKGROUND: A 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. METHODS: Isolated 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 ([Ca(2+)]i) and tension in aortas precontracted with phenylephrine were measured simultaneously with the acetoxymethyl ester of a fura-2-loaded aortic strip. RESULTS: Pretreatment 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 [Ca(2+)]i decrease in the aortas precontracted with phenylephrine. CONCLUSIONS: Taken 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.

Systemic blockage of nitric oxide synthase by L-NAME increases left ventricular systolic pressure, which is not augmented further by Intralipid®.

Intravenous lipid emulsions (LEs) are effective in the treatment of toxicity associated with various drugs such as local anesthetics and other lipid soluble agents. The goals of this study were to examine the effect of LE on left ventricular hemodynamic variables and systemic blood pressure in an in vivo rat model, and to determine the associated cellular mechanism with a particular focus on nitric oxide. Two LEs (Intralipid(®) 20% and Lipofundin(®) MCT/LCT 20%) or normal saline were administered intravenously in an in vivo rat model following induction of anesthesia by intramuscular injection of tiletamine/zolazepam and xylazine. Left ventricular systolic pressure (LVSP), blood pressure, heart rate, maximum rate of intraventricular pressure increase, and maximum rate of intraventricular pressure decrease were measured before and after intravenous administration of various doses of LEs or normal saline to an in vivo rat with or without pretreatment with the non-specific nitric oxide synthase inhibitor N(ω)-nitro-L-arginine-methyl ester (L-NAME). Administration of Intralipid(®) (3 and 10 ml/kg) increased LVSP and decreased heart rate. Pretreatment with L-NAME (10 mg/kg) increased LSVP and decreased heart rate, whereas subsequent treatment with Intralipid(®) did not significantly alter LVSP. Intralipid(®) (10 ml/kg) increased mean blood pressure and decreased heart rate. The increase in LVSP induced by Lipofundin(®) MCT/LCT was greater than that induced by Intralipid(®). Intralipid(®) (1%) did not significantly alter nitric oxide donor sodium nitroprusside-induced relaxation in endothelium-denuded rat aorta. Taken together, systemic blockage of nitric oxide synthase by L-NAME increases LVSP, which is not augmented further by intralipid(®).

Mepivacaine-induced contraction involves increased calcium sensitization mediated via Rho kinase and protein kinase C in endothelium-denuded rat aorta.

Mepivacaine is an aminoamide local anesthetic that produces vasoconstriction in vivo and in vitro. The goals of this in vitro study were to determine whether mepivacaine-induced contraction involves calcium sensitization in isolated endothelium-denuded aortas, and to investigate the specific protein kinases involved. The effects of mepivacaine and potassium chloride on intracellular calcium concentrations ([Ca(2+)]i) and tension in the presence or absence of Y-27632 or GF 109203X were measured simultaneously using the acetoxymethyl ester of fura-2-loaded aortic strips. Cumulative mepivacaine concentration-response curves were generated in the presence or absence of the following inhibitors: Rho kinase inhibitor Y-27632, protein kinase C (PKC) inhibitor GF 109203X, extracellular signal-regulated kinase (ERK) inhibitor PD 98059, c-Jun NH2-terminal kinase (JNK) inhibitor SP600125, and p38 mitogen-activated protein kinase (MAPK) inhibitor SB 203580. Phosphorylation of PKC and MAPK, and membrane translocation of Rho kinase were detected in vascular smooth muscle cells by Western blotting. The slope of the mepivacaine-induced [Ca(2+)]i-tension curve was higher than that of the KCl-induced [Ca(2+)]i-tension curve. Pretreatment with Y-27632 or GF 109203X shifted the mepivacaine-induced [Ca(2+)]i-tension curve to the lower right. Pretreatment with Y-27632, GF 109203X, PD 98059, or SP600125 attenuated mepivacaine-induced contraction in a concentration-dependent manner. Y-27632 and GF 109203X attenuated mepivacaine-induced Rho kinase membrane translocation and PKC phosphorylation, respectively. PD 98059 and SP600125 attenuated mepivacaine-induced ERK and JNK phosphorylation, respectively. Taken together, these results indicate that mepivacaine-induced contraction involves increased calcium sensitization mediated by Rho kinase and PKC. Such contraction mainly involves activation of ERK- and JNK-mediated pathways.

Mepivacaine-induced contraction involves phosphorylation of extracellular signal-regulated kinase through activation of the lipoxygenase pathway in isolated rat aortic smooth muscle.

Mepivacaine is an aminoamide local anesthetic with an intermediate duration that intrinsically produces vasoconstriction both in vivo and in vitro. This study investigated the arachidonic acid metabolic pathways involved in mepivacaine-induced contraction, and elucidated the associated cellular mechanism with a particular focus on extracellular signal-regulated kinase (ERK) in endothelium-denuded rat aorta. Isolated rat thoracic aortic rings were suspended for isometric tension recording. Cumulative mepivacaine concentration-response curves were generated in the presence or absence of the following inhibitors: quinacrine dihydrochloride, nordihydroguaiaretic acid, phenidone, AA-861, indomethacin, NS-398, SC-560, fluconazole, PD 98059, and verapamil. Mepivacaine-induced ERK phosphorylation, 5-lipoxygenase (5-LOX) expression, and cyclooxygenase (COX)-2 expression in rat aortic smooth muscle cells were detected by Western blot analysis in the presence or absence of inhibitors. Mepivacaine produced tonic contraction in isolated endothelium-denuded rat aorta. Quinacrine dihydrochloride, nordihydroguaiaretic acid, phenidone, AA-861, NS-398, PD 98059, and verapamil attenuated mepivacaine-induced contraction in a concentration-dependent manner. However, fluconazole had no effect on mepivacaine-induced contraction. PD 98059, quinacrine dihydrochloride, nordihydroguaiaretic acid, AA-861, phenidone, and indomethacin attenuated mepivacaine-induced ERK phosphorylation. Mepivacaine upregulated 5-LOX and COX-2 expression. These results suggest that mepivacaine-induced contraction involves ERK activation, which is primarily mediated by the 5-LOX pathway and in part by the COX-2 pathway.

Lipid emulsion-mediated reversal of toxic-dose aminoamide local anesthetic-induced vasodilation in isolated rat aorta.

BACKGROUND: Intravenous lipid emulsion has been used to treat systemic toxicity of local anesthetics. The goals of this in vitro study were to determine the ability of two lipid emulsions (Intralipid® and Lipofundin® MCT/LCT) to reverse toxic dose local anesthetic-induced vasodilation in isolated rat aortas. METHODS: Isolated endothelium-denuded aortas were suspended for isometric tension recording. Vasodilation was induced by bupivacaine (3 × 10(-4) M), ropivacaine (10(-3) M), lidocaine (3 × 10(-3) M), or mepivacaine (7 × 10(-3) M) after precontraction with 60 mM KCl. Intralipid® and Lipofundin® MCT/LCT were then added to generate concentration-response curves. We also assessed vasoconstriction induced by 60 mM KCl, 60 mM KCl with 3 × 10(-4) M bupivacaine, and 60 mM KCl with 3 × 10(-4) M bupivacaine plus 1.39% lipid emulsion (Intralipid® or Lipofundin® MCT/LCT). RESULTS: The two lipid emulsions reversed vasodilation induced by bupivacaine, ropivacaine, and lidocaine but had no effect on vasodilation induced by mepivacaine. Lipofundin® MCT/LCT was more effective than Intralipid® in reversing bupivacaine-induced vasodilation. The magnitude of lipid emulsion-mediated reversal of vasodilation induced by high-dose local anesthetics was as follows (from highest to lowest): 3 × 10(-4) M bupivacaine-induced vasodilation, 10(-3) M ropivacaine-induced vasodilation, and 3 × 10(-3) M lidocaine-induced vasodilation. CONCLUSIONS: Lipofundin® MCT/LCT-mediated reversal of bupivacaine-induced vasodilation was greater than that of Intralipid®; however, the two lipid emulsions equally reversed vasodilation induced by ropivacaine and lidocaine. The magnitude of lipid emulsion-mediated reversal of vasodilation appears to be correlated with the lipid solubility of the local anesthetic.

Vasoconstriction potency induced by aminoamide local anesthetics correlates with lipid solubility.

Aminoamide local anesthetics induce vasoconstriction in vivo and in vitro. The goals of this in vitro study were to investigate the potency of local anesthetic-induced vasoconstriction and to identify the physicochemical property (octanol/buffer partition coefficient, pKa, molecular weight, or potency) of local anesthetics that determines their potency in inducing isolated rat aortic ring contraction. Cumulative concentration-response curves to local anesthetics (levobupivacaine, ropivacaine, lidocaine, and mepivacaine) were obtained from isolated rat aorta. Regression analyses were performed to determine the relationship between the reported physicochemical properties of local anesthetics and the local anesthetic concentration that produced 50% (ED(50)) of the local anesthetic-induced maximum vasoconstriction. We determined the order of potency (ED(50)) of vasoconstriction among local anesthetics to be levobupivacaine > ropivacaine > lidocaine > mepivacaine. The relative importance of the independent variables that affect the vasoconstriction potency is octanol/buffer partition coefficient > potency > pKa > molecular weight. The ED(50) in endothelium-denuded aorta negatively correlated with the octanol/buffer partition coefficient of local anesthetics (r(2) = 0.9563; P < 0.001). The potency of the vasoconstriction in the endothelium-denuded aorta induced by local anesthetics is determined primarily by lipid solubility and, in part, by other physicochemical properties including potency and pKa.

A Patient with Kikuchi's Disease: What Should Pain Clinicians Do?

Kikuchi's disease (KD) is an idiopathic and self-limiting necrotizing lymphadenitis that predominantly occurs in young females. It is common in Asia, and the cervical lymph nodes are commonly involved. Generally, KD has symptoms and signs of lymph node tenderness, fever, and leukocytopenia, but there are no reports on treatment for the associated myofacial pain. We herein report a young female patient who visited a pain clinic and received a trigger point injection 2 weeks before the diagnosis of KD. When young female patients with myofascial pain visit a pain clinic, doctors should be concerned about the possibility of KD, which is rare but can cause severe complications.

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

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.

Calcium sensitization involved in dexmedetomidine-induced contraction of isolated rat aorta.

Dexmedetomidine, a full agonist of the α2B-adrenoceptor that is mainly involved in vascular smooth muscle contraction, is primarily used for analgesia and sedation in intensive care units. High-dose dexmedetomidine produces hypertension in children and adults. The goal of this in vitro study was to investigate the role of the calcium (Ca(2+)) sensitization mechanism involving Rho-kinase, protein kinase C (PKC), and phosphoinositide 3-kinase (PI3-K) in mediating contraction of isolated rat aortic smooth muscle in response to dexmedetomidine. The effect of dexmedetomidine on the intracellular Ca(2+) level ([Ca(2+)]i) and tension was measured simultaneously. Dexmedetomidine concentration-response curves were generated in the presence or absence of the following antagonists: rauwolscine, Y 27632, LY 294002, GF 109203X, and verapamil. Dexmedetomidine-induced phosphorylation of PKC and membrane translocation of Rho-kinase were detected with Western blotting. Rauwolscine, Y 27632, GF 109203X, LY 294002, and verapamil attenuated dexmedetomidine-induced contraction. The slope of the [Ca(2+)]i-tension curve for dexmedetomidine was higher than that for KCl. Dexmedetomidine induced phosphorylation of PKC and membrane translocation of Rho-kinase. These results suggest that dexmedetomidine-induced contraction involves a Ca(2+) sensitization mechanism mediated by Rho-kinase, PKC, and PI3-K that is secondary to α2-adrenoceptor stimulation in rat aortic smooth muscle.

Lipid emulsion reverses Levobupivacaine-induced responses in isolated rat aortic vessels.

BACKGROUND: The goal of this in vitro study was to investigate the effects of lipid emulsion (LE) on local anesthetic levobupivacaine-induced responses in isolated rat aorta and to determine whether the effect of LE is related to the lipid solubility of local anesthetics. METHODS: Isolated rat aortic rings were suspended for isometric tension recording. The effects of LE were determined during levobupivacaine-, ropivacaine-, and mepivacaine-induced responses. Endothelial nitric oxide synthase and caveolin-1 phosphorylation was measured in human umbilical vein endothelial cells treated with levobupivacaine alone and with the addition of LE. RESULTS: Levobupivacaine produced vasoconstriction at lower, and vasodilation at higher, concentrations, and both were significantly reversed by treatment with LE. Levobupivacaine and ropivacaine inhibited the high potassium chloride-mediated contraction, which was restored by LE. The magnitude of LE-mediated reversal was greater with levobupivacaine treatment than with ropivacaine, whereas this reversal was not observed in mepivacaine-induced responses. In LE-pretreated rings, low-dose levobupivacaine- and ropivacaine-induced contraction was attenuated, whereas low-dose mepivacaine-induced contraction was not significantly altered. Treatment with LE also inhibited the phosphorylation of endothelial nitric oxide synthase induced by levobupivacaine in human umbilical vein endothelial cells. CONCLUSIONS: These results indicate that reversal of levobupivacaine-induced vasodilation by LE is mediated mainly through the attenuation of levobupivacaine-mediated inhibition of L-type calcium channel-dependent contraction and, in part, by inhibition of levobupivacaine-induced nitric oxide release. LE-mediated reversal of responses induced by local anesthetics may be related to their lipid solubility.

Myocardial protective effect by ulinastatin via an anti-inflammatory response after regional ischemia/reperfusion injury in an in vivo rat heart model.

BACKGROUND: Ulinastatin has anti-inflammatory properties and protects organs from ischemia/reperfusion-induced injury. The aim of this study was to investigate whether ulinastatin provides a protective effect on a regional myocardial ischemia/reperfusion injury in an in vivo rat heart model and to determine whether the anti-inflammatory response is related to its myocardial protective effect. METHODS: Rats were randomized to two groups. One group is received ulinastatin (50,000 U/kg or 100,000 U/kg) diluted in normal saline and the other group is received normal saline, which was administered intraperitoneally 30 min before the ischemic insult. Reperfusion after 30 min of ischemia of the left coronary artery territory was applied. Hemodynamic measurements were recorded serially during 6 h after reperfusion. After the 6 h reperfusion, myocardial infarct size, cardiac enzymes, myeloperoxidase activity, and inflammatory cytokine levels were compared between the ulinastatin treated and untreated groups. RESULTS: Ulinastatin improved cardiac function and reduced infarct size after regional ischemia/reperfusion injury. Ulinastatin significantly attenuated tumor necrosis factor-α expression and reduced myeloperoxidase activity. CONCLUSIONS: Ulinastatin showed a myocardial protective effect after regional ischemia/reperfusion injury in an in vivo rat heart model. This protective effect of ulinastatin might be related in part to ulinastatin's ability to inhibit myeloperoxidase activity and decrease expression of tumor necrosis factor-α.

Ethyl pyruvate has anti-inflammatory and delayed myocardial protective effects after regional ischemia/reperfusion injury.

PURPOSE: Ethyl pyruvate has anti-inflammatory properties and protects organs from ischemia/reperfusion (I/R)-induced tissue injury. The aim of this study was to determine whether ethyl pyruvate decreases the inflammatory response after regional I/R injury and whether ethyl pyruvate protects against delayed regional I/R injury in an in vivo rat heart model after a 24 hours reperfusion. MATERIALS AND METHODS: Rats were randomized to receive lactated Ringer's solution or ethyl pyruvate dissolved in Ringer's solution, which was given by intraperitoneal injection 1 hour prior to ischemia. Rats were subjected to 30 min of ischemia followed by reperfusion of the left coronary artery territory. After a 2 hours reperfusion, nuclear factor κB, myocardial myeloperoxidase activity, and inflammatory cytokine levels were determined. After the 24 hours reperfusion, the hemodynamic function and myocardial infarct size were evaluated. RESULTS: At 2 hours after I/R injury, ethyl pyruvate attenuated I/R-induced nuclear factor κB translocation and reduced myeloperoxidase activity in myocardium. The plasma circulating levels of inflammatory cytokines decreased significantly in the ethyl pyruvate-treated group. At 24 hours after I/R injury, ethyl pyruvate significantly improved cardiac function and reduced infarct size after regional I/R injury. CONCLUSION: Ethyl pyruvate has the ability to inhibit neutrophil activation, inflammatory cytokine release, and nuclear factor κB translocation. Ethyl pyruvate is associated with a delayed myocardial protective effect after regional I/R injury in an in vivo rat heart model.

Propofol has delayed myocardial protective effects after a regional ischemia/reperfusion injury in an in vivo rat heart model.

BACKGROUND: It is well known that propofol protects myocardium against myocardial ischemia/reperfusion injury in the rat heart model. The aim of this study was to investigate whether propofol provides a protective effect against a regional myocardial ischemia/reperfusion injury in an in vivo rat heart model after 48 h of reperfusion. METHODS: Rats were subjected to 25 min of left coronary artery occlusion followed by 48 h of reperfusion. The sham group received profopol without ischemic injury. The control group received normal saline with ischemia/reperfusion injury. The propofol group received profopol with ischemia/reperfusion injury. The intralipid group received intralipid with ischemia/reperfusion injury. A microcatheter was advanced into the left ventricle and the hemodynamic function was evaluated. The infarct size was determined by triphenyltetrazolium staining. The serum level of cardiac troponin-I (cTn-I) was determined by ELISA (enzyme-linked immunosorbent assay). RESULTS: Propofol demonstrated protective effects on hemodynamic function and infarct size reduction. In the propofol group, the +dP/d(tmax) (P = 0.002) was significantly improved compared to the control group. The infarct size was 49.8% of the area at risk in the control group, and was reduced markedly by administration of propofol to 32.6% in the propofol group (P = 0.014). The ischemia/reperfusion-induced serum level of cTn-I was reduced by propofol infusion during the peri-ischemic period (P = 0.0001). CONCLUSIONS: Propofol, which infused at clinically relevant concentration during the peri-ischemic period, has delayed myocardial protective effect after regional myocardial ischemia/reperfusion injury in an in vivo rat heart model after 48 h of reperfusion.