Direct protective effects of dexmedetomidine against myocardial ischemia-reperfusion injury in anesthetized pigs.

Systemic administration of α2-adrenergic agonists has been shown to protect ischemic myocardium, but the direct effects on ischemia-reperfused myocardium have not yet been clarified. This study was carried out to determine the effects of intracoronary dexmedetomidine (DEX) on the myocardial ischemia-reperfusion injury in anesthetized pigs. In open-chest pigs, the left anterior descending coronary artery was perfused through an extracorporeal circuit from the carotid artery. They received intracoronary infusion of DEX at a rate of 1 ng · mL(-1) (group LD, n = 9), 10 ng · mL(-1) (group MD, n = 9), or 100 ng · mL(-1) (group HD, n = 9) of coronary blood flow or vehicle (group C, n = 12) for 30 min before ischemia. Myocardial stunning was produced by 12-min ischemia of the perfused area of left anterior descending coronary artery and 90-min reperfusion. The effect on reperfusion-induced arrhythmias was evaluated using the incidence of ventricular tachycardia or fibrillation after reperfusion. Regional myocardial contractility was evaluated with segment shortening (%SS). Dexmedetomidine significantly reduced the incidence of reperfusion-induced ventricular arrhythmias. Dexmedetomidine significantly improved the recovery of percentage segment shortening at 90 min after reperfusion (32.6% ± 3.1% in group C, 58.2% ± 2.1% in group LD, 61.1% ± 1.8% in group MD, and 72.0% ± 2.0% in group HD). Dexmedetomidine suppressed the increase in plasma norepinephrine concentration after reperfusion. The results indicate that DEX would exert the protective effect against ischemia-reperfusion injury by the direct action on the myocardium, which is not mediated through the central nervous system.

High-dose fasudil preserves postconditioning against myocardial infarction under hyperglycemia in rats: role of mitochondrial KATP channels.

BACKGROUND: The current study was carried out to determine whether fasudil hydrochloride (fasudil), a Rho-kinase inhibitor, has myocardial postconditioning (PostC) activity under hyperglycemia as well as normoglycemia, and if so, whether the effects could be mediated by mitochondrial ATP-sensitive potassium (m-KATP) channels. METHODS: Male Sprague-Dawley rats were anesthetized with sodium pentobarbital. After opening the chest, all rats underwent 30-min coronary artery occlusion followed by 2-h reperfusion. The rats received low-dose (0.15 mg/kg) or high-dose (0.5 mg/kg) fasudil or diazoxide, an m-KATP channel opener, at 10 mg/kg, just before reperfusion under normoglycemic or hyperglycemic conditions. In another group, rats received 5-hydroxydecanoic acid (5HD), an m-KATP channel blocker, at 10 mg/kg, before high-dose fasudil. Myocardial infarct size was expressed as a percentage of area at risk (AAR). RESULTS: Under normoglycemia, low-dose and high-dose fasudil and diazoxide reduced myocardial infarct size (23 ± 8%, 21 ± 9% and 21 ± 10% of AAR, respectively) compared with that in the control (42 ± 7%). Under hyperglycemia, low-dose fasudil (40 ± 11%) and diazoxide (44 ± 14%) could not exert this beneficial effect, but high-dose fasudil reduced myocardial infarct size in the same manner as under normoglycemia (21 ± 13%). 5HD prevented fasudil-induced reduction of myocardial infarct size (42 ± 13%). CONCLUSION: Fasudil induces PostC against myocardial infarction via activation of m-KATP channels in the rat. Although hyperglycemia attenuates the PostC, high-dose fasudil can restore cardioprotection.

Postischemic infusion of sivelestat sodium hydrate, a selective neutrophil elastase inhibitor, protects against myocardial stunning in swine.

PURPOSE: It seems controversial whether or not neutrophil elastase inhibitors are effective in attenuating myocardial ischemia/reperfusion injury. We thus investigated possible protective effects of sivelestat, a neutrophil elastase inhibitor, against myocardial stunning i.e., prolonged myocardial dysfunction following a brief episode of ischemia. METHODS: Swine were divided into control group (group C), low-dose sivelestat group (group L), and high-dose sivelestat group (group H) (n = 7 for each group). All the swine were subjected to myocardial ischemia through ligation of the left anterior descending (LAD) coronary artery for 12-min, followed by 90-min reperfusion. Sivelestat was infused intracoronally at concentrations of 6 and 60 mg/ml throughout the reperfusion period in groups L and H, respectively, while saline was infused in the group C. Heart rate (HR), left ventricular developed pressure (LVdP), maximum rate of LVdP (LVdP/dt (max)), LV end-diastolic pressure (LVEDP), percentage of segment shortening (%SS, an index of regional myocardial contractility), and coronary venous interleukin-6 concentration in the LAD perfusion area were measured before ischemic induction and during reperfusion. RESULTS: The ischemia/reperfusion insult did not cause any significant changes in HR, LVdP, LVdP/dt (max), and LVEDP in all groups. However, it significantly reduced %SS in the LAD perfusion area and increased the interleukin-6 concentration in group C. Those changes in %SS and the interleukin-6 concentration were both greatly attenuated, but not prevented, in groups L and H. CONCLUSION: Sivelestat presumably attenuates myocardial contractile dysfunction due to myocardial stunning by inhibiting neutrophil-derived elastase, thereby suppressing the production of interleukin-6 in activated neutrophils.

[Anesthesia for cesarean hysterectomy in a parturient with placenta accreta].

A 35-year-old parturient highly suspicious of the placenta accreta/increta was scheduled for cesarean hysterectomy. She had received two cesarean sections and two intrauterine curettages. Prior to cesarean hysterectomy, 900 g of autologous blood was stored for the predictable massive bleeding. Epidural catheter was introduced at T12-L1 the day before surgery. Bilateral internal iliac artery occlusion balloons were placed in the angiography suite under local anesthesia. Bilateral double J ureteral catheters were inserted under epidural anesthesia in the operating room. Then, the general anesthesia was induced followed by immediate delivery of the baby uneventfully by cesarean section. The occlusion balloons of bilateral internal iliac arteries were inflated immediately after the umbilical cord was clamped so as to minimize the risk of fetal ischemia. Hysterectomy was performed uneventfully. Intraoperative blood loss was 1,170 g, and 300 g of autologous blood was transfused. The postoperative course was uneventful and the patient was discharged 14 days after operation. Histopathological diagnosis was placenta accreta. We successfully managed the anesthesia for cesarean hysterectomy in a parturient with placenta accreta under a combination of general anesthesia and epidural anesthesia.

Effects of traditional "Juci" (contralateral acupuncture) on orofacial nociceptive behavior in the rat.

PURPOSE: "Juci", one of the traditional acupuncture techniques, means contralateral acupuncture; i.e., implanting a needle into an acupoint to treat a given disease or disorder, but on the side of the body opposite to the diseased side. The aim of this study was: (1) to assess acupuncture effects on formalin-induced nociceptive behavior in the orofacial region in the rat, and (2) to evaluate the efficacy of Juci in the orofacial formalin test. METHODS: Forty-four adult male Wistar rats were used in the present study. A 1.0% formalin solution (25 microl s.c., diluted in saline) was injected into the right upper lip. The rats were randomly assigned to five groups. (1) The control group (n = 9), which received formalin injection without acupuncture pretreatment; (2) the ipsilateral Ho-ku (see note below) acupuncture group (n = 10); (3) the contralateral Ho-ku acupuncture group (n = 11); (4) the acupuncture plus naloxone group (n = 9), where intraperitoneal naloxone (1.0 mgxkg(-1)) was injected immediately before acupuncture pretreatment; and (5) the sham acupuncture group (n = 5). "Ho-ku" is the term used for the "Large Intestine 4" acupoint, located between the first and second metacarpal bones. RESULTS: The injection of formalin produced the characteristic biphasic behavioral response. Acupuncture significantly inhibited the response in the early and late phases. Naloxone significantly reversed these effects. There were no statistically significant differences between the ipsilateral and Juci acupuncture groups. Sham acupuncture did not exert any significant effect on the formalin-induced behavior. CONCLUSION: Our results showed that the degree of effectiveness of Juci was similar to that of the ipsilateral acupuncture technique. Therefore, the Juci technique is also useful for the treatment of orofacial pain.

Cardioprotective effects of KB-R7943, a novel inhibitor of Na+/Ca2+ exchanger, on stunned myocardium in anesthetized dogs.

PURPOSE: The present study was carried out to determine the cardioprotective effects of KB-R7943 (KBR), a selective inhibitor of the reverse mode of Na+/Ca2+ exchanger (NCX), on stunned myocardium in anesthetized dogs. METHODS: The dogs were allocated to one of three groups (n = 7 for each group), and received drug vehicle (group C), low-dose KBR (5 mg x kg(-1) i.v.) (group L) or high-dose KBR (10 mg x kg(-1) i.v.) (group H) at 15 min before left anterior descending coronary artery (LAD) occlusion. Stunned myocardium was produced by 15-min occlusion of LAD and 90-min reperfusion in all dogs. Regional myocardial contractility was evaluated with segment shortening (%SS). RESULTS: Recovery of %SS at 90 min after reperfusion was significantly improved in group H (70.8% +/- 3.9% of baseline), whereas the recovery was poor in groups C and L (34.3% +/- 2.8% and 36.4% +/- 5.4% of baseline, respectively). Regional myocardial blood flow showed no significant difference among groups. KBR had no effect on coronary or systemic hemodynamics. CONCLUSION: The results show that preischemic administration of high-dose KBR markedly improves myocardial contractile dysfunction after ischemia-reperfusion in anesthetized dogs, indicating that KBR protects myocardium against the ischemia-reperfusion injury in vivo.

Mini-dose (0.05 mg) intrathecal morphine provides effective analgesia after transurethral resection of the prostate.

PURPOSE: To determine the optimal dose of intrathecal morphine that produces satisfactory analgesia with minimum side effects in elderly patients undergoing transurethral resection of the prostate (TURP). METHODS: In this double-blind prospective study, 42 patients undergoing TURP with spinal anesthesia were allocated to one of three groups. Group A (n = 14) received tetracaine, 10 mg, alone. Group B (n = 13) and Group C (n = 15) received morphine 0.05 mg and 0.10 mg, respectively, in combination with tetracaine. Postoperative pain, nausea and pruritus were evaluated using visual analogue scales (VAS). SpO(2) and respiratory rate were also assessed. RESULTS: At three, five, seven and 24 hr after spinal anesthesia, the VAS scores for pain in Groups B and C were significantly less than in Group A. Group C experienced significantly greater VAS scores for pruritus as compared to Groups A and B. There was no significant difference in the intensity of nausea among the three groups. No patient experienced hypoxemia (SpO(2) < 90%) and respiratory depression (respiratory rate < 10 beats*min(-1)) in any group. CONCLUSION: A dose of 0.05 mg in intrathecal morphine with spinal anesthesia would be optimal for elderly patients undergoing TURP.

Site of action of the general anesthetic propofol in muscarinic M1 receptor-mediated signal transduction.

Although a potential target site of general anesthetics is primarily the GABA A receptor, a chloride ion channel, a previous study suggested that the intravenous general anesthetic propofol attenuates the M1 muscarinic acetylcholine receptor (M1 receptor)-mediated signal transduction. In the present study, we examined the target site of propofol in M1 receptor-mediated signal transduction. Two-electrode voltage-clamp method was used in Xenopus oocytes expressing both M1 receptors and associated G protein alpha subunits (Gqalpha). Propofol inhibited M1 receptor-mediated signal transduction in a dose-dependent manner (IC50 = 50 nM). Injection of guanosine 5'-3-O-(thio)triphosphate (GTPgammaS) into oocytes overexpressing Gqalpha was used to investigate direct effects of propofol on G protein coupled with the M1 receptor. Propofol did not affect activation of Gqalpha-mediated signal transduction with the intracellular injection of GTPgammaS. We also studied effects of propofol on l-[N-methyl-3H]scopolamine methyl chloride ([3H]NMS) binding and M1 receptor-mediated signal transduction in mammalian cells expressing M1 receptor. Propofol inhibited the M1 receptor-mediated signal transduction but did not inhibit binding of [3H]NMS. Effects of propofol on Gs- and Gi/o-coupled signal transduction were investigated, using oocytes expressing the beta2 adrenoceptor (beta2 receptor)/cystic fibrosis transmembrane conductance regulator or oocytes expressing the M2 muscarinic acetylcholine receptor (M2 receptor)/Kir3.1 (a member of G protein-gated inwardly rectifying K(+) channels). Neither beta2 receptor-mediated nor M2 receptor-mediated signal transduction was inhibited by a relatively high concentration of propofol (50 microM). These results indicate that propofol inhibits M1 receptor-mediated signal transduction by selectively disrupting interaction between the receptor and associated G protein.

Reactive oxygen species accelerate production of vascular endothelial growth factor by advanced glycation end products in RAW264.7 mouse macrophages.

Advanced glycation end products (AGEs) are believed to play an important role in the development of angiopathy in diabetes mellitus. Previous reports suggested a correlation between accumulation of AGEs and production of vascular endothelial growth factor (VEGF) in human diabetic retina. However, the mechanisms involved were not revealed. In this study, we investigated the transcriptional regulation of the expression of vascular endothelial growth factor (VEGF) by AGEs, and possible involvement of reactive oxygen species (ROS) in the induction. We employed an AGE of bovine serum albumin (BSA) prepared by an incubation of BSA with D-glucose for 40 weeks and N(epsilon)-(carboxymethyl)lysine (CML), a major AGE. The expression of VEGF was induced by CML-BSA in RAW264.7 mouse macrophage-like cells. CML-BSA stimulated the DNA-binding activity of activator protein-1 (AP-1). Promoter assay showed that the induction of VEGF was dependent on AP-1. The activity of Ras/Raf-1/MEK/ERK1/2 was involved in the CML-BSA-stimulated signaling pathways to activate the AP-1 transcription with a peak at 1 h. AGE-BSA also induced VEGF mediated by AP-1, however, there was a difference of effect between AGE-BSA and CML-BSA in the activation of AP-1. AGE-BSA-stimulated AP-1 activity showed a peak at 5 h, which paralleled the formation of ROS. Reduction of AGE-BSA with NaBH(4) or addition of vitamin E attenuated the AGE-BSA-stimulated signaling pathways leading to the same pattern as for CML-BSA-stimulated signals. These results suggest an important role for AGEs in stimulation of the development of angiogenesis observed in diabetic complications, and that ROS accelerates the AGE-stimulated VEGF expression.