Prazosin Potentiates Mast Cell-Stabilizing Property of Adrenaline.

BACKGROUND/AIMS: Adrenaline quickly inhibits the release of histamine from mast cells. Besides ß2-adrenergic receptors, several in vitro studies also indicate the involvement of α-adrenergic receptors in the process of exocytosis. Since exocytosis in mast cells can be detected electrophysiologically by the changes in the membrane capacitance (Cm), its continuous monitoring in the presence of drugs would determine their mast cell-stabilizing properties. METHODS: Employing the whole-cell patch-clamp technique in rat peritoneal mast cells, we examined the effects of adrenaline on the degranulation of mast cells and the increase in the Cm during exocytosis. We also examined the degranulation of mast cells in the presence or absence of α-adrenergic receptor agonists or antagonists. RESULTS: Adrenaline dose-dependently suppressed the GTP-γ-S-induced increase in the Cm and inhibited the degranulation from mast cells, which was almost completely erased in the presence of butoxamine, a ß2-adrenergic receptor antagonist. Among α-adrenergic receptor agonists or antagonists, high dose prazosin, a selective α1-adrenergic receptor antagonist, significantly reduced the ratio of degranulating mast cells and suppressed the increase in the Cm. Additionally, prazosin augmented the inhibitory effects of adrenaline on the degranulation of mast cells. CONCLUSION: This study provided electrophysiological evidence for the first time that adrenaline dose-dependently inhibited the process of exocytosis, confirming its usefulness as a potent mast cell-stabilizer. The pharmacological blockade of α1-adrenergic receptor by prazosin synergistically potentiated such mast cell-stabilizing property of adrenaline, which is primarily mediated by ß2-adrenergic receptors.

Aortic valve replacement in a 41-year-old woman with uncorrected tetralogy of Fallot, pulmonary atresia, and major aortopulmonary collateral arteries: a case report.

BACKGROUND: Tetralogy of Fallot (TOF) is a complex cyanotic congenital heart disease. As most patients with TOF undergo palliative or radical surgical repair during childhood, cardiac surgery under cardiopulmonary bypass (CPB) for adult survivors with unrepaired TOF is exceedingly rare. CASE PRESENTATION: A 41-year-old woman with unrepaired TOF, pulmonary atresia (PA), and major aortopulmonary collateral arteries (MAPCAs) developed acute infectious endocarditis (IE). As vegetation gradually increased despite intravenous antibiotic administration, she was scheduled for urgent aortic valve replacement under CPB. Pulmonary blood flow was primarily provided by the MAPCAs originating from the descending aorta. Intra-aortic balloon occlusion for MAPCAs was performed to ensure a bloodless surgical field. Aortic valve replacement was successful. CONCLUSION: An adult with uncorrected TOF developed acute IE and subsequently had successful cardiac surgery under CPB. Understanding TOF physiology with PA and MAPCAs, particularly pulmonary blood flow through MAPCAs, is crucial.

Sonoclot® predicts operation time and blood loss after cardiopulmonary bypass in children.

Background: As the circulating blood volume is relatively small in pediatric patients, blood components are quickly lost when bleeding, which make it more difficult to stop the bleeding. Particularly in pediatric cardiac surgery, loss of clotting factors associated with cardiopulmonary bypass (CPB) would likely to be prominent. As a result, bleeding is further promoted and the operation time is extended. In order to search for the relation between clotting factors and the amount of bleeding, we used a viscoelastic point of care test. Objectives: We used Sonoclot® as viscoelastic point of care test to evaluate coagulation function before CPB and before weaning from CPB in pediatric cardiac surgery. Design: Retrospective. Setting: Single-institutional. Participants: We included 55 pediatric patients (median age 13 months [IQR 5-32]) who underwent cardiac surgery under CPB from December 2015 to November 2016. Interventions: None. Measurements and main results: Sonoclot® analysis was performed after induction of anesthesia (pre-data, or baseline data) and before any heparinized saline was given, and right after modified ultrafiltration after weaning from CPB (post-data). Post-data was compared with post-CPB operation time and post-CPB blood loss by multiple regression analysis. Furthermore, effects of fresh frozen plasma (FFP) added on CPB on coagulation function and post-platelet function (describe as PFSC) was assessed. Activated coagulation time (describe as ACTSC) and clot rate (describe as CRSC) showed no significant change between baseline data and post-data. Post-PFSC was worsened by prolonged CPB time (p < 0.05) and correlated to bleeding amount and operation time after CPB (p < 0.05). Total amount of platelet concentrate (PC) transfused was higher in patients with smaller PFSC (p < 0.05). Total amount of FFP and PC transfused correlated with bleeding amount and operation time after CPB (p < 0.05). In the subgroup analysis, PFSC declined in the FFP-included group, whereas there was no significant difference in coagulation function. Addition of FFP to CPB did not significantly affect CR, whereas PFSC deteriorated as CPB time was prolonged (CPB time = 1/(0.0021∗PFSC + 0.0055)). Conclusion: Sonoclot® is useful to evaluate coagulation function in pediatric patients who undergo CPB. Preventive administration of FFP or PC in CPB circuit could reduce bleeding after CPB.

Evaluation of contrast-enhanced ultrasonography with Sonazoid® in visualization of local anesthetic distribution in rectus sheath block: a prospective, clinical study.

PURPOSE: Clear visualization of ultrasound (US) images is crucial for successful US-guided nerve block. However, accurate determination of local anesthetic (LA) distribution from US images remains difficult. Sonazoid®, which comprises perflubutane microbubbles, is used to diagnose hepatic and breast tumors. This study aimed to investigate the visibility of Sonazoid® in perioperative US-guided nerve block. METHODS: We performed rectus sheath block (RSB) in patients scheduled for laparoscopic abdominal surgery (n = 10). 10 mL of a mixture containing equal amounts of 0.75% ropivacaine and iohexol with the addition of Sonazoid® diluted 100-fold was administered. We investigated the correlation and agreement between Sonazoid® and iohexol distributions. The brightness of the solution and tissues was calculated: a grayscale value between 0 (dark) and 255 (bright) was measured in all pixels of the region of interest. Adverse events were also investigated. RESULTS: Sonazoid® was clearly visualized and distinguished from the surrounding tissues both during and after RSB. The spread of Sonazoid® and iohexol was significantly correlated (spearman's ρ = 0.53, p = 0.0004). Bland-Altman analyses revealed significant mean difference between two methods (15.6 mm; 95% confidence interval [CI]: 10.6, 20.6; standard deviation (SD) 15.65; p < 0.0001). Limits of agreement were - 14.94 to 46.24 mm. Sonazoid® significantly increased the mean grayscale values at the posterior rectus sheath (93.7 vs. 201.9, p < 0.0001). There were no complications. CONCLUSION: Sonazoid diluted 100-fold® was clearly visualized real-time, and the enhancement was sustained and measurable after RSB. Sonazoid® could potentially be used for the contrast agent of US-guided nerve block.

Effects of oxytocin on responses to nociceptive and non-nociceptive stimulation in the upper central nervous system.

Oxytocin is known as a social bonding hormone, but it also functions as an anxiolytic or analgesic neurotransmitter. When oxytocin regulates pain or anxiousness centrally as a neurotransmitter, it is secreted by neurons and directly projected to targeted regions. Although the function of oxytocin at the spinal level is well studied, its effects at the supraspinal level are poorly understood. We aimed to investigate the effect of oxytocin at the supraspinal level in vivo using C57BL/6J (wild-type [WT]), oxytocin-deficient (Oxt-/-), oxytocin receptor-deficient (Oxtr-/-), and oxytocin receptor-Venus (OxtrVenus/+) mice lines. Response thresholds in Oxtr-/- mice in Hargreaves and von-Frey tests were significantly lower than those in WT mice, whereas open field and light/dark tests showed no significant differences. Moreover, response thresholds in Oxt-/- mice were raised to those in WT mice after oxytocin administration. Following the Hargreaves test, we observed the co-localisation of c-fos with Venus or the oxytocin receptor in the periaqueductal gray (PAG), medial amygdala (MeA), and nucleus accumbens (NAc) regions in OxtrVenus/+ mice. Furthermore, in the PAG, MeA, and NAc regions, the co-localisation of oxytocin with c-fos and gamma-aminobutyric acid was much stronger in Oxtr-/- mice than in WT mice. However, following von-Frey test, the same findings were observed only in the MeA and NAc regions. Our results suggest that oxytocin exerts its analgesic effect on painful stimulation via the PAG region and a self-protective effect on unpleasant stimulation via the MeA and NAc regions.

Successive perioperative management of laparoscopic liver resection in the reverse Trendelenburg position for a patient with Fontan physiology: a case report.

BACKGROUND: Laparoscopic surgery for a patient with Fontan physiology is challenging because pneumoperitoneum and positive pressure ventilation could decrease venous return and the accumulated partial pressure of arterial carbon dioxide (PaCO2) could increase pulmonary vascular resistance, which might lead to disruption of the hemodynamics. CASE PRESENTATION: A 25-year-old man with Fontan physiology was scheduled to undergo laparoscopic liver resection for Fontan-associated liver disease (FALD) with noninvasive monitoring of cardiac output (CO) by transpulmonary thermodilution in addition to transesophageal echocardiography. The abdominal air pressure was maintained low, and we planned to switch to open abdominal surgery promptly if hemodynamic instability became apparent because of the accumulated PaCO2 or postural change. Consequently, the pneumoperitoneum had limited influence on circulatory dynamics, but central venous pressure significantly decreased with postural change to the reverse Trendelenburg position. Laparoscopic liver resection for FALD was performed successfully with no significant changes in CO and central venous saturation. CONCLUSIONS: With strict circulation management, laparoscopic surgery for a patient with Fontan physiology can be performed safely. Comprehensive hemodynamic assessment by noninvasive transpulmonary thermodilution can provide valuable information to determine the time for shift to open abdominal surgery.

Management of cesarean section in a patient with Fontan circulation: a case report of dramatic reduction of maternal oxygen consumption after delivery.

BACKGROUND: The anesthetic management of cesarean sections in Fontan-palliated parturients requires strict hemodynamic control. However, patient management with central venous oxygen saturation (ScvO2) and oxygen consumption (VO2) has never been reported. CASE PRESENTATION: A 30-year-old woman, who had received a total cavopulmonary connection for tricuspid atresia, was planned to undergo cesarean section at 38 weeks' gestation. During combined spinal-epidural anesthesia, ScvO2 in addition to arterial pressure-based cardiac output (APCO) and central venous pressure (CVP) was monitored, and the change of VO2 was evaluated. After delivery, her APCO was almost unchanged. However, her ScvO2 increased dramatically from 42.1 to 67.3% and her CVP increased from 9 to 11 mm Hg. The calculated mean maternal VO2 changed from 443 to 295 mL/min. CONCLUSIONS: In a cesarean section for a Fontan-palliated parturient, ScvO2 dramatically increased and maternal VO2 decreased by more than 25% after delivery.

α 1-Adrenergic Receptor Blockade by Prazosin Synergistically Stabilizes Rat Peritoneal Mast Cells.

BACKGROUND: Adrenaline quickly inhibits the release of histamine from mast cells. Besides ß 2-adrenergic receptors, several in vitro studies also indicate the involvement of α-adrenergic receptors in the process of exocytosis. Since exocytosis in mast cells can be detected electrophysiologically by the changes in the membrane capacitance (Cm), its continuous monitoring in the presence of drugs would determine their mast cell-stabilizing properties. METHODS: Employing the whole-cell patch-clamp technique in rat peritoneal mast cells, we examined the effects of adrenaline on the degranulation of mast cells and the increase in the Cm during exocytosis. We also examined the degranulation of mast cells in the presence or absence of α-adrenergic receptor agonists or antagonists. RESULTS: Adrenaline dose-dependently suppressed the GTP-γ-S-induced increase in the Cm and inhibited the degranulation from mast cells, which was almost completely erased in the presence of butoxamine, a ß 2-adrenergic receptor antagonist. Among α-adrenergic receptor agonists or antagonists, high-dose prazosin, a selective α 1-adrenergic receptor antagonist, significantly reduced the ratio of degranulating mast cells and suppressed the increase in the Cm. Additionally, prazosin augmented the inhibitory effects of adrenaline on the degranulation of mast cells. CONCLUSIONS: This study provided electrophysiological evidence for the first time that adrenaline dose-dependently inhibited the process of exocytosis, confirming its usefulness as a potent mast cell stabilizer. The pharmacological blockade of α 1-adrenergic receptor by prazosin synergistically potentiated such mast cell-stabilizing property of adrenaline, which is primarily mediated by ß 2-adrenergic receptors.

Delayed Rectifier K+-Channel Is a Novel Therapeutic Target for Interstitial Renal Fibrosis in Rats with Unilateral Ureteral Obstruction.

BACKGROUND: Delayed rectifier K+-channel, Kv1.3, is most predominantly expressed in T-lymphocytes and macrophages. In such leukocytes, Kv1.3-channels play pivotal roles in the activation and proliferation of cells, promoting cellular immunity. Since leukocyte-derived cytokines stimulate fibroblasts to produce collagen fibers in inflamed kidneys, Kv1.3-channels expressed in leukocytes would contribute to the progression of tubulointerstitial renal fibrosis. METHODS: Male Sprague-Dawley rats that underwent unilateral ureteral obstruction (UUO) were used at 1, 2, or 3 weeks after the operation. We examined the histological features of the kidneys and the leukocyte expression of Kv1.3-channels. We also examined the therapeutic effects of a selective channel inhibitor, margatoxin, on the progression of renal fibrosis and the proliferation of leukocytes within the cortical interstitium. RESULTS: In rat kidneys with UUO, progression of renal fibrosis and the infiltration of leukocytes became most prominent at 3 weeks after the operation, when Kv1.3-channels were overexpressed in proliferating leukocytes. In the cortical interstitium of margatoxin-treated UUO rat kidneys, immunohistochemistry revealed reduced expression of fibrosis markers. Additionally, margatoxin significantly decreased the numbers of leukocytes and suppressed their proliferation. CONCLUSIONS: This study clearly demonstrated that the numbers of T-lymphocytes and macrophages were markedly increased in UUO rat kidneys with longer postobstructive days. The overexpression of Kv1.3-channels in leukocytes was thought to be responsible for the proliferation of these cells and the progression of renal fibrosis. This study strongly suggested the therapeutic usefulness of targeting lymphocyte Kv1.3-channels in the treatment of renal fibrosis.

Increase in circulating ACE-positive endothelial microparticles during acute lung injury.

Circulating endothelial microparticles (EMPs) are considered to be markers of endothelial injury, and lung microvascular endothelial cells express higher levels of angiotensin-converting enzyme (ACE). The aim of this study is to examine whether the number of ACE+ microvascular EMPs could be a prognostic marker for the development of acute respiratory distress syndrome (ARDS) in septic patients.The numbers of EMPs and ACE+ EMPs in the culture supernatant from human microvascular endothelial cells, as well as in the blood of mouse lung injury models and septic patients (n=82), were examined using flow cytometry.ACE+ EMPs in the culture supernatant from pulmonary microvascular endothelial cells increased after exposure to an inflammatory stimulus. In the mouse lung injury models, the circulating ACE+ EMPs and ACE+ EMP/EMP ratio were higher than in the controls (p<0.001). The ACE+ EMP/EMP ratio was correlated with the wet/dry lung ratio (rs=0.775, p<0.001). The circulating ACE+ EMPs and ACE+ EMP/EMP ratio on admission were significantly increased in septic patients who developed ARDS compared with septic patients who did not (p<0.001).Therefore, circulating ACE+ EMPs may be a prognostic marker for the development of ARDS in the septic patients.

Second-Generation Histamine H1 Receptor Antagonists Suppress Delayed Rectifier K+-Channel Currents in Murine Thymocytes.

BACKGROUND/AIMS: Voltage-dependent potassium channels (Kv1.3) are predominantly expressed in lymphocyte plasma membranes. These channels are critical for the activation and proliferation of lymphocytes. Since second-generation antihistamines are lipophilic and exert immunomodulatory effects, they are thought to affect the lymphocyte Kv1.3-channel currents. METHODS: Using the patch-clamp whole-cell recording technique in murine thymocytes, we tested the effects of second-generation antihistamines, such as cetirizine, fexofenadine, azelastine, and terfenadine, on the channel currents and the membrane capacitance. RESULTS: These drugs suppressed the peak and the pulse-end currents of the channels, although the effects of azelastine and terfenadine on the peak currents were more marked than those of cetirizine and fexofenadine. Both azelastine and terfenadine significantly lowered the membrane capacitance. Since these drugs did not affect the process of endocytosis in lymphocytes, they were thought to have interacted directly with the plasma membranes. CONCLUSIONS: Our study revealed for the first time that second-generation antihistamines, including cetirizine, fexofenadine, azelastine, and terfenadine, exert suppressive effects on lymphocyte Kv1.3-channels. The efficacy of these drugs may be related to their immunomodulatory mechanisms that reduce the synthesis of inflammatory cytokine.

Implantation of ventricular assist device for systemic right ventricular failure in a patient with transposition of the great arteries and post-Mustard procedure: a case report.

BACKGROUND: Ventricular assist device (VAD) is usually attached by an inflow cannula to the apex of the systemic left ventricle (LV), but very few cases with implantation of the VAD in the morphologic right ventricle (RV) have been described. CASE PRESENTATION: We describe the case of a 41-year-old male who developed severe systemic RV failure related to a Mustard procedure he had as an infant for treatment of TGA. His heart failure was refractory and irreversible, and therefore, he underwent VAD implantation for systemic RV support. Although the patient developed pulmonary congestion on postoperative day (POD) 5, he was discharged on POD 60. He is now looking forward to receiving heart transplantation. CONCLUSIONS: Placement of a VAD for systemic RV failure could be a life-saving treatment in adult patients with heart failure due to congenital heart disease.

Less contribution of mast cells to the progression of renal fibrosis in Rat kidneys with chronic renal failure.

AIM: Chronic renal failure (CRF) is histopathologically characterized by tubulointerstitial fibrosis in addition to glomerulosclerosis. Although mast cells are known to infiltrate into the kidneys with chronic inflammation, we know little about their contribution to the pathogenesis of renal fibrosis associated with CRF. The aim of this study was to reveal the involvement of mast cells in the progression of renal fibrosis in CRF. METHODS: Using a rat model with CRF resulting from 5/6 nephrectomy, we examined the histopathological features of the kidneys and the infiltration of mast cells into the renal interstitium. By treating the rats with a potent mast cell stabilizer, tranilast, we also examined the involvement of mast cells in the progression of renal fibrosis associated with CRF. RESULTS: The CRF rat kidneys were characterized by the wide staining of collagen III and increased number of myofibroblasts, indicating the progression of renal fibrosis. Compared to T-lymphocytes or macrophages, the number of tryptase-positive mast cells was much smaller within the fibrotic kidneys and they did not proliferate in situ. The mRNA expression of mast cell-derived fibroblast-activating factors was not increased in the renal cortex isolated from CRF rat kidneys. Treatment with tranilast did not suppress the progression of renal fibrosis, nor did it ameliorate the progression of glomerulosclerosis and the interstitial proliferation of inflammatory leukocytes. CONCLUSIONS: This study demonstrated for the first time that mast cells are neither increased nor activated in the fibrotic kidneys of CRF rats. Compared to T-lymphocytes or macrophages that proliferate in situ within the fibrotic kidneys, mast cells were less likely to contribute to the progression of renal fibrosis associated with CRF.

Hydrocortisone and dexamethasone dose-dependently stabilize mast cells derived from rat peritoneum.

BACKGROUND: Besides their anti-inflammatory properties, corticosteroid drugs exert anti-allergic effects. Exocytosis of mast cells is electrophysiologically detected as the increase in the whole-cell membrane capacitance (Cm). Therefore, the lack of such increase after exposure to the drugs suggests their mast cell-stabilizing effects. METHODS: We examined the effects of 1, 10, 100 and 200µM hydrocortisone or dexamethasone on the degranulation from rat peritoneal mast cells. Employing the whole-cell patch-clamp recording technique, we also tested their effects on the Cm during exocytosis. RESULTS: At relatively lower concentrations (1, 10µM), both hydrocortisone and dexamethasone did not significantly affect the degranulation from mast cells and the increase in the Cm induced by GTP-γ-S. Nevertheless, at higher doses (100, 200µM), these drugs inhibited the degranulation from mast cells and markedly suppressed the GTP-γ-S-induced increase in the Cm. CONCLUSIONS: Our results provided electrophysiological evidence for the first time that corticosteroid drugs, such as hydrocortisone and dexamethasone, inhibited the exocytotic process of mast cells in a dose-dependent manner. The mast cell-stabilizing effects of these drugs may be attributable to their "non-genomic" action, by which they exert rapid anti-allergic effects.

Preoperative Assessment of the Impact of Positive Pressure Ventilation With Noninvasive Positive Pressure Ventilation in a Patient With Eisenmenger Syndrome: A Case Study.

In Eisenmenger syndrome (ES), positive pressure ventilation (PPV) during general anesthesia may lead to an increase in pulmonary vascular resistance and potentially to hypoxemia. In an attempt to predict the patient's hemodynamic response to intraoperative ventilation, we tested preoperatively the hemodynamic effects of noninvasive PPV with continuous positive pressure in a woman with ES scheduled for oophorectomy. The surgery was performed without complications, and the patient was discharged on postoperative day 8.

Clarithromycin Dose-Dependently Stabilizes Rat Peritoneal Mast Cells.

BACKGROUND: Macrolides, such as clarithromycin, have antiallergic properties. Since exocytosis in mast cells is detected electrophysiologically via changes in membrane capacitance (Cm), the absence of such changes due to the drug indicates its mast cell-stabilizing effect. METHODS: Employing the whole-cell patch clamp technique in rat peritoneal mast cells, we examined the effects of clarithromycin on Cm during exocytosis. Using a water-soluble fluorescent dye, we also examined its effect on deformation of the plasma membrane. RESULTS: Clarithromycin (10 and 100 µM) significantly inhibited degranulation from mast cells and almost totally suppressed the GTP-x03B3;-S-induced increase in Cm. It washed out the trapping of the dye on the surface of mast cells. CONCLUSIONS: This study provides for the first time electrophysiological evidence that clarithromycin dose-dependently inhibits the process of exocytosis. The mast cell-stabilizing action of clarithromycin may be attributable to its counteractive effect on plasma membrane deformation induced by exocytosis.

Management of three cardiogenic pulmonary edemas occurring in a patient scheduled for left ventricular assist device implantation: indicators for determining left ventricular assist device pump speed.

A male patient with Marfan syndrome underwent aortic root replacement and developed left ventricular (LV) failure. Four years later, he underwent aortic arch and aortic valve replacement. Thereafter, his LV failure progressed, and cardiogenic pulmonary edema (CPE) appeared, which we treated with extracorporeal LV assist device (LVAD) placement. Three months later, the patient developed aspiration pneumonia, which caused hyperdynamic right ventricle (RV) and CPE. We treated by changing his pneumatic LVAD to a high-flow centrifugal pump. A month later, he underwent thoracoabdominal aortic replacement. After four weeks, he developed septic thrombosis and LVAD failure, which caused CPE. We treated with LVAD circuit replacement and an additional membrane oxygenator. Four months later, he underwent DuraHeart(®) implantation. During this course, pulmonary artery wedge pressure (PAWP) varied markedly. Additionally, systolic pulmonary artery pressure (sPAP), left atrial diameter (LAD), RV end-diastolic diameter (RVEDD) and estimated RV systolic pressure (esRVP) changed with PAWP changes. In this patient, LV failure and hyperdynamic RV caused the CPEs, which we treated by adjusting the LVAD output to the RV output. Determining LVAD output, RV function and LV end-diastolic diameter are typically referred, and PAWP, LAD, RVEDD, and sPAP could be also referred.