Search

Epicatechin, a flavonoid, is a well-known antioxidant linked to a variety of protective effects in both humans and animals. In particular, its role in protection against cardiovascular disease has been demonstrated by epidemiologic studies. Low-dose epicatechin, which does not have significant antioxidant activity, is also protective; however, the mechanism by which low-dose epicatechin induces this effect is unknown. Our laboratory tested the hypothesis that low-dose epicatechin mediates cardiac protection via opioid receptor activation. C57BL/6 mice were randomly assigned to 1 of 10 groups: control, epicatechin, naloxone (nonselective opioid receptor antagonist), epicatechin + naloxone, naltrindole (δ-specific opioid receptor antagonist), epicatechin + naltrindole, norbinaltorphimine (nor-BNI, κ-specific opioid receptor antagonist), epicatechin + nor-BNI, 5-hydroxydecanoic acid [5-HD, ATP-sensitive potassium channel antagonist], and epicatechin + 5-HD. Epicatechin (1 mg/kg) or other inhibitors (5 mg/kg) were administered by oral gavage or intraperitoneal injection, respectively, daily for 10 days. Mice were subjected to 30 min coronary artery occlusion followed by 2 h of reperfusion, and infarct size was determined via planimetry. Whole heart homogenates were assayed for downstream opioid receptor signaling targets. Infarct size was significantly reduced in epicatechin- and epicatechin + nor-BNI-treated mice compared with control mice. This protection was blocked by naloxone, naltrindole, and 5-HD. Epicatechin and epicatechin + nor-BNI increased the phosphorylation of Src, Akt, and IκBα, while simultaneously decreasing the expression of c-Jun NH2-terminal kinase and caspase-activated DNase. All signaling effects are consistent with opioid receptor stimulation and subsequent cardiac protection. Naloxone, naltrindole, and 5-HD attenuated these effects. In conclusion, epicatechin acts via opioid receptors and more specifically through the δ-opioid receptor to produce cardiac protection from ischemia-reperfusion injury.

Background Caveolae are small, flask-like invaginations of the plasma membrane. Caveolins are structural proteins found in caveolae that have scaffolding properties to allow organization of signaling. The authors tested the hypothesis that delayed cardiac protection induced by volatile anesthetics is caveolae or caveolin dependent. Methods An in vivo mouse model of ischemia-reperfusion injury with delayed anesthetic preconditioning (APC) was tested in wild-type, caveolin-1 knockout, and caveolin-3 knockout mice. Mice were exposed to 30 min of oxygen or isoflurane and allowed to recover for 24 h. After 24 h recovery, mice underwent 30-min coronary artery occlusion followed by 2 h of reperfusion at which time infarct size was determined. Biochemical assays were also performed in excised hearts. Results Infarct size as a percent of the area at risk was reduced by isoflurane in wild-type (24.0 +/- 8.8% vs. 45.1 +/- 10.1%) and caveolin-1 knockout mice (27.2 +/- 12.5%). Caveolin-3 knockout mice did not show delayed APC (41.5 +/- 5.0%). Microscopically distinct caveolae were observed in wild-type and caveolin-1 knockout mice but not in caveolin-3 knockout mice. Delayed APC increased the amount of caveolin-3 protein but not caveolin-1 protein in discontinuous sucrose-gradient buoyant fractions. In addition, glucose transporter-4 was increased in buoyant fractions, and caveolin-3/glucose transporter-4 colocalization was observed in wild-type and caveolin-1 knockout mice after APC. Conclusions These results show that delayed APC involves translocation of caveolin-3 and glucose transporter-4 to caveolae, resulting in delayed protection in the myocardium.

Caveolin-3 (Cav-3) plays a critical role in organizing signaling molecules and ion channels involved in cardiac conduction and metabolism. Mutations in Cav-3 are implicated in cardiac conduction abnormalities and myopathies. Additionally, cardiac-specific overexpression of Cav-3 (Cav-3 OE) is protective against ischemic and hypertensive injury, suggesting a potential role for Cav-3 in basal cardiac electrophysiology and metabolism involved in stress adaptation. We hypothesized that overexpression of Cav-3 may alter baseline cardiac conduction and metabolism. We examined: (1) ECG telemetry recordings at baseline and during pharmacological interventions, (2) ion channels involved in cardiac conduction with immunoblotting and computational modeling, and (3) baseline metabolism in Cav-3 OE and transgene-negative littermate control mice. Cav-3 OE mice had decreased heart rates, prolonged PR intervals, and shortened QTc intervals with no difference in activity compared to control mice. Dobutamine or propranolol did not cause significant changes between experimental groups in maximal (dobutamine) or minimal (propranolol) heart rate. Cav-3 OE mice had an overall lower chronotropic response to atropine. The expression of Kv1.4 and Kv4.3 channels, Nav1.5 channels, and connexin 43 were increased in Cav-3 OE mice. A computational model integrating the immunoblotting results indicated shortened action potential duration in Cav-3 OE mice linking the change in channel expression to the observed electrophysiology phenotype. Metabolic profiling showed no gross differences in VO2, VCO2, respiratory exchange ratio, heat generation, and feeding or drinking. In conclusion, Cav-3 OE mice have changes in ECG intervals, heart rates, and cardiac ion channel expression. These findings give novel mechanistic insights into previously reported Cav-3 dependent cardioprotection.

CASE Toshi, a 14-year-old Japanese boy, had uncontrolled asthma after relocating from Japan with his family 1 year ago. In Japan, he was diagnosed with moderate, persistent asthma, which was controlled with salmeterol and albuterol on an as needed basis. Since moving to the United States, Toshi complained of frequent dyspnea.Initially, he was seen by a Japanese physician who prescribed 200 mg of fluticasone 3 times a day and albuterol nebulization as needed. When Toshi came to the Pediatric Primary Care Clinic, he reported using his nebulizer up to 25 times daily. A physical examination revealed a thin, anxious, jittery, hypertensive, and tachycardic adolescent with hyperreflexia and dysmetria. Toshi complained of difficulty breathing, in the absence of wheezing or respiratory distress; peak flow recordings in the office were normal. Furthermore, he had a history of "panic attacks," being a "worrier," and stopped attending school, playing sports, and socializing over the past 6 months due to his "breathing difficulties."Citalopram was prescribed for anxiety, but the family's apprehension about mental health disorders led to resistance to treatment recommendations. With motivational interviewing and negotiation, Toshi and his family agreed to a trial of citalopram. Three months later, he no longer took fluticasone or albuterol. The tachycardia, hypertension, and neurological symptoms improved. As he gained weight and improved his strength, he attended classes and participated in sports.A few months later, with improvement of his health, Toshi and his parents decided to discontinue citalopram. He then developed behaviors consistent with generalized anxiety and obsessive-compulsive disorder. Currently, his symptoms associated with anxiety have worsened, but he and his family are resistant to medication or initiating cognitive behavioral therapy due to their cultural beliefs regarding mental health disorders.

Brugada syndrome is characterized by an electrocardiograph pattern of right bundle-branch block and has an increased risk for cardiac arrest due to malignant arrhythmia. We describe the successful anesthetic management for electroconvulsive therapy in a patient with Brugada electrocardiograph pattern. Patients with Brugada ECG pattern are not recommended to use neostigmine which augments ST elevation. Sugammadex was administered as a neuromuscular reversal agent in this case. Sugammadex provides rapid reversal of profound rocuronium-induced neuromuscular blockade under propofol anesthesia.

Background Volatile anesthetics have a dual effect on cell survival dependent on caveolin expression. The effect of volatile anesthetics on cancer cell survival and death after anesthetic exposure has not been well investigated. The authors examined the effects of isoflurane exposure on apoptosis and its regulation by caveolin-1 (Cav-1). Methods The authors exposed human colon cancer cell lines to isoflurane and proapoptotic stimuli and assessed what role Cav-1 plays in cell protection. They evaluated apoptosis using assays for nucleosomal fragmentation, cleaved caspase 3 expression, and caspase activity assays. To test the mechanism, they used pharmacologic inhibitors (i.e., pertussis toxin) and assessed changes in glycolysis. Results Apoptosis as measured by nucleosomal fragmentation was enhanced by isoflurane (1.2% in air) in HT29 (by 64% relative to control, P < 0.001) and decreased in HCT116 (by 23% relative to control, P < 0.001) cells. Knockdown of Cav-1 in HCT116 cells increased the sensitivity to apoptotic stimuli but not with scrambled small interfering RNA (siRNA) treatment (19.7 ± 0.4 vs. 20.0 ± 0.6, P = 0.7786 and 19.7 ± 0.5 vs. 16.3 ± 0.4, P = 0.0012, isoflurane vs. control in Cav-1 small interfering RNA vs. scrambled small interfering RNA treated cells, respectively). The protective effect of isoflurane with various exposure times on apoptosis was enhanced in HT29 cells overexpressing Cav-1 (P < 0.001 by two-way ANOVA). Pertussis toxin effectively blocked the antiapoptotic effect of isoflurane exhibited by Cav-1 in all cell lines. Cav-1 cells had increased glycolysis with isoflurane exposure; however, in the presence of tumor necrosis factor-related apoptosis-inducing ligand, this increase in glycolysis was maintained in HT29-Cav-1 but not control cells. Conclusion Brief isoflurane exposure leads to resistance against apoptosis via a Cav-1-dependent mechanism.

Volatile anesthetics protect the heart from ischemia/reperfusion injury but the mechanisms for this protection are poorly understood. Caveolae, sarcolemmal invaginations, and caveolins, scaffolding proteins in caveolae, localize molecules involved in cardiac protection. We tested the hypothesis that caveolae and caveolins are essential for volatile anesthetic-induced cardiac protection using cardiac myocytes (CMs) from adult rats and in vivo studies in caveolin-3 knockout mice (Cav-3(-/-)). We incubated CM with methyl-beta-cyclodextrin (MbetaCD) or colchicine to disrupt caveolae formation, and then exposed the myocytes to the volatile anesthetic isoflurane (30 min, 1.4%), followed by simulated ischemia/reperfusion (SI/R). Isoflurane protected CM from SI/R [23.2+/-1.6% vs. 71.0+/-5.8% cell death (assessed by trypan blue exclusion), P0.001] but this protection was abolished by MbetaCD or colchicine (84.9+/-5.5% and 64.5+/-6.1% cell death, P0.001). Membrane fractionation by sucrose density gradient centrifugation of CM treated with MbetaCD or colchicine revealed that buoyant (caveolae-enriched) fractions had decreased phosphocaveolin-1 and caveolin-3 compared to control CM. Cardiac protection in vivo was assessed by measurement of infarct size relative to the area at risk and cardiac troponin levels. Isoflurane-induced a reduction in infarct size and cardiac troponin relative to control (infarct size: 26.5%+/-2.6% vs. 45.3%+/-5.4%, P0.01; troponin: 27.7+/-4.4 vs. 77.7+/-11.8 ng/ml, P0.05). Isoflurane-induced cardiac protection was abolished in Cav-3(-/-) mice (infarct size: 53.4%+/-6.1% vs. 53.2%+/-3.5%, P0.01; troponin: 102.1+/-22.3 vs. 105.9+/-8.2 ng/ml, P0.01). Isoflurane-induced cardiac protection is thus dependent on the presence of caveolae and the expression of caveolin-3. We conclude that caveolae and caveolin-3 are critical for volatile anesthetic-induced protection of the heart from ischemia/reperfusion injury.

Reactive oxygen species (ROS) generated by ischemic and pharmacological preconditioning are known to act as triggers of cardiac protection; however, the involvement of ROS in ischemic and pharmacological postconditioning (PostC) in vivo and in vitro is unknown. We tested the hypothesis that ROS are involved in PostC in the mouse heart in vivo and in the isolated adult cardiac myocyte (ACM). Mice were subjected to 30 min coronary artery occlusion followed by 2 h of reperfusion with or without ischemic or pharmacologic PostC (three cycles of 20 s reperfusion/ischemia; 1.4% isoflurane; 10 mg/kg SNC-121). Additional groups were treated with 2-mercaptopropionyl glycine (MPG), a ROS scavenger, 10 min before or after the PostC stimuli. Ischemia-, isoflurane-, and SNC-121- induced PostC reduced infarct size (24.1+/-3.2, 15.7+/-2.6, 24.9+/-2.6%, p0.05, respectively) compared to the control group (43.4+/-3.3%). These cardiac protective effects were abolished by MPG when administered before (40.0+/-3.6, 39.3+/-3.1, 38.5+/-1.6%, respectively), but not after the PostC stimuli (26.6+/-2.3, 17.0+/-2.2, 23.9+/-1.7%, respectively). Additionally, ACM were subjected to a simulated ischemia/reperfusion protocol with isoflurane and SNC PostC. Isoflurane- and SNC-induced PostC in vitro were abolished by prior treatment with MPG. These data indicate that ROS signaling is an essential trigger of ischemic and pharmacological PostC and this is occurring at the level of the cardiac myocyte.

Purpose : Post-operative nausea and vomiting (PONV) remains the most fre- quently reported patient complaint after anesthesia. Aprepitant is the first neurokinin- 1(NK1) receptor antagonism available for use as an antiemetic. We investigated whether aprepitant can effectively decrease PONV in patients undergoing laparoscopic gyneco- logical surgery. Methods : Sixty four patients receiving general anesthesia for laparoscopic gynecological surgery were randomly assigned to either receive a preoperative dose of 80 mg aprepitant or no drug. Efficacy was assessed in 2 and 24 hours after surgery. Primary and secondary endpoints were analyzed for the time intervals 0-2 hours (acute phase) and 2-24 hours (delayed phase). Vomiting, nausea, use of rescue anti-emetic, and visual analog scale (VAS) were assessed. Nausea was assessed on a 4-point scale, from 0 to 3. Results : Sixty patients participated in the study. At acute phase, PONV was present in both control and NK1 group and were 63% nd 43% respectively. The severity of nausea was much less in the NK1 group. PONV prevalence at delayed phase was present in control but absent in NK1 group 27% s. 0% respectively. The amount of pain medication used by patients in the NK1 group was significantly less for diclofenac and pentazocine sug- gesting increase pain tolerance. Conclusions : Neurokinin-1 receptor antagonism effec- tively lowered PONV increased pain tolerance, and expedited recovery in patients under- going laparoscopic gynecological surgery. J. Med. Invest. 58 : 246-251, August, 2011