CP-25 inhibits the hyperactivation of rheumatic synoviocytes by suppressing the switch in Gαs-Gαi coupling to the ß2-adrenergic receptor.

In essence, the ß2 adrenergic receptor (ß2AR) plays an antiproliferative role by increasing the intracellular cyclic 3',5'-adenosine monophosphate (cAMP) concentration through Gαs coupling, but interestingly, ß2AR antagonists are able to effectively inhibit fibroblast-like synoviocytes (FLSs) proliferation, thus ameliorating experimental RA, indicating that the ß2AR signalling pathway is impaired in RA FLSs via unknown mechanisms. The local epinephrine (Epi) level was found to be much higher in inflammatory joints than in normal joints, and high-level stimulation with Epi or isoproterenol (ISO) directly promoted FLSs proliferation and migration due to impaired ß2AR signalling and cAMP production. By applying inhibitor of receptor internalization, and small interfering RNA (siRNA) of Gαs and Gαi, and by using fluorescence resonance energy transfer and coimmunoprecipitation assays, a switch in Gαs-Gαi coupling to ß2AR was observed in inflammatory FLSs as well as in FLSs with chronic ISO stimulation. This Gαi coupling was then revealed to be initiated by G protein coupled receptor kinase 2 (GRK2) but not ß-arrestin2 or protein kinase A-mediated phosphorylation of ß2AR. Inhibiting the activity of GRK2 with the novel GRK2 inhibitor paeoniflorin-6'-O-benzene sulfonate (CP-25), a derivative of paeoniflorin, or the accepted GRK2 inhibitor paroxetine effectively reversed the switch in Gαs-Gαi coupling to ß2AR during inflammation and restored the intracellular cAMP level in ISO-stimulated FLSs. As expected, CP-25 significantly inhibited the hyperplasia of FLSs in a collagen-induced arthritis (CIA) model (CIA FLSs) and normal FLSs stimulated with ISO and finally ameliorated CIA in rats. Together, our findings revealed the pathological changes in ß2AR signalling in CIA FLSs, determined the underlying mechanisms and identified the pharmacological target of the GRK2 inhibitor CP-25 in treating CIA. Video Abstract.

Red wine but not alcohol consumption improves cardiovascular function and oxidative stress of the hypertensive-SHR and diabetic-STZ rats.

AIMS: This raised the issue of whether in vivo long-term red wine treatment can act as a modulator of these targets. MAIN METHODS: We monitored SBP, glucose tolerance, oxidative stress, and cardiovascular function. Aortic and atrial tissues from normotensive-WKY, hypertensive-SHR, and diabetic-STZ animals, chronically exposed to red wine (3.715 ml/kg/v.o/day) or alcohol (12%) for 21-days, were used to measure contractile/relaxation responses by force transducers. Key findings: red wine, but not alcohol, prevented the increase of SBP and hyperglycemic peak. Additionally, was observed prevention of oxidative stress metabolites formation and an improvement in ROS scavenging antioxidant capacity of SHR. We also revealed that red wine intake enhances the endothelium-dependent relaxation, decreases the hypercontractile mediated by angiotensin-II in the aorta, and via ß1-adrenoceptors in the atrium. SIGNIFICANCE: The long-term consumption of red wine can improve oxidative stress and the functionality of angiotensin-II and ß1-adrenoceptors, inspiring new pharmacologic and dietetic therapeutic approaches for the treatment of hypertension and diabetes.Abbreviation Acronyms and/or abbreviations: [Ca2+]cyt = Cytosolic Ca2+ Concentration; ACh = Acetylcholine; ANG II = Angiotensin II; AT1 = ANG II type 1 receptor; AUC = Area Under the Curve; Ca2+ = Calcium; Endo + = Endothelium Intact; Fen = Phenylephrine (1 µM); GTT = Glucose Tolerance Test; ISO = Isoprenaline (isoproterenol); KHN = Krebs-Henseleit Nutrient; LA = Left Atria; LH = Lipid Hydroperoxide; NO = Nitric Oxide; RA = Right Atria; RAS = Renin-Angiotensin System; ROS = Reactive Oxygen Species; SBP = Systolic Blood Pressure; SHR = Spontaneously Hypertensive Rats; STZ = Streptozotocin; WKY = Normotensive Wistar Kyoto Rats.

Attenuation of lipid metabolic abnormalities, proinflammatory cytokines, and matrix metalloproteinase expression by biochanin-A in isoproterenol-induced myocardial infarction in rats.

In the present study, we assessed the therapeutic potential of Biochanin-A (BCA) (10 mg/kg BW/day) pretreatment for 30 days on lipid metabolic abnormalities, proinflammatory cytokines and matrix metalloproteinase expression in isoproterenol (ISO)-induced myocardial infarction (MI) in rats. We measured the potential role of BCA on tissue and circulatory lipid profiles as well as on lipid metabolic enzymes: serum inflammatory cytokines (TNF-α, IL-1α, IL-1ß, IL-6 and MCP1) and serum Matrix Metalloproteinases (particularly, MMP-2 and MMP-9) together with mRNA expressions of TNF-α, IL-6, MMP-2 and MMP-9 by RT-PCR analysis. Administration of ISO to rats significantly distorted their lipid metabolism and augmented inflammatory process, MMP expression and proteolytic activity. In addition, pretreatment with BCA of ISO-induced MI rats significantly reestablished the altered lipid metabolism and concealed the inflammation of cytokines. BCA suppressed the expressions of proinflammatory cytokines and MMPs in ISO-induced MI in rats when compared to normal untreated MI rats. Hence, these results established that BCA could improve the pathological processes of myocardial remodeling which was confirmed by histopathology of heart in MI rats and might be an effective beneficial ingredient for the management of heart failure disorders.

Crosstalk between ß2- and α2-Adrenergic Receptors in the Regulation of B16F10 Melanoma Cell Proliferation.

Adrenergic receptors (AR) belong to the G protein-coupled receptor superfamily and regulate migration and proliferation in various cell types. The objective of this study was to evaluate whether ß-AR stimulation affects the antiproliferative action of α2-AR agonists on B16F10 cells and, if so, to determine the relative contribution of ß-AR subtypes. Using pharmacological approaches, evaluation of Ki-67 expression by flow cytometry and luciferase-based cAMP assay, we found that treatment with isoproterenol, a ß-AR agonist, increased cAMP levels in B16F10 melanoma cells without affecting cell proliferation. Propranolol inhibited the cAMP response to isoproterenol. In addition, stimulation of α2-ARs with agonists such as clonidine, a well-known antihypertensive drug, decreased cancer cell proliferation. This effect on cell proliferation was suppressed by treatment with isoproterenol. In turn, the suppressive effects of isoproterenol were abolished by the treatment with either ICI 118,551, a ß2-AR antagonist, or propranolol, suggesting that isoproterenol effects are mainly mediated by the ß2-AR stimulation. We conclude that the crosstalk between the ß2-AR and α2-AR signaling pathways regulates the proliferative activity of B16F10 cells and may therefore represent a therapeutic target for melanoma therapy.

Impact of etiology on force and kinetics of left ventricular end-stage failing human myocardium.

BACKGROUND: Heart failure (HF) is associated with highly significant morbidity, mortality, and health care costs. Despite the significant advances in therapies and prevention, HF remains associated with poor clinical outcomes. Understanding the contractile force and kinetic changes at the level of cardiac muscle during end-stage HF in consideration of underlying etiology would be beneficial in developing targeted therapies that can help improve cardiac performance. OBJECTIVE: Investigate the impact of the primary etiology of HF (ischemic or non-ischemic) on left ventricular (LV) human myocardium force and kinetics of contraction and relaxation under near-physiological conditions. METHODS AND RESULTS: Contractile and kinetic parameters were assessed in LV intact trabeculae isolated from control non-failing (NF; n = 58) and end-stage failing ischemic (FI; n = 16) and non-ischemic (FNI; n = 38) human myocardium under baseline conditions, length-dependent activation, frequency-dependent activation, and response to the ß-adrenergic stimulation. At baseline, there were no significant differences in contractile force between the three groups; however, kinetics were impaired in failing myocardium with significant slowing down of relaxation kinetics in FNI compared to NF myocardium. Length-dependent activation was preserved and virtually identical in all groups. Frequency-dependent activation was clearly seen in NF myocardium (positive force frequency relationship [FFR]), while significantly impaired in both FI and FNI myocardium (negative FFR). Likewise, ß-adrenergic regulation of contraction was significantly impaired in both HF groups. CONCLUSIONS: End-stage failing myocardium exhibited impaired kinetics under baseline conditions as well as with the three contractile regulatory mechanisms. The pattern of these kinetic impairments in relation to NF myocardium was mainly impacted by etiology with a marked slowing down of kinetics in FNI myocardium. These findings suggest that not only force development, but also kinetics should be considered as a therapeutic target for improving cardiac performance and thus treatment of HF.

Mitochondrion as a Target of Astaxanthin Therapy in Heart Failure.

Mitochondria are considered to be important organelles in the cell and play a key role in the physiological function of the heart, as well as in the pathogenesis and development of various heart diseases. Under certain pathological conditions, such as cardiovascular diseases, stroke, traumatic brain injury, neurodegenerative diseases, muscular dystrophy, etc., mitochondrial permeability transition pore (mPTP) is formed and opened, which can lead to dysfunction of mitochondria and subsequently to cell death. This review summarizes the results of studies carried out by our group of the effect of astaxanthin (AST) on the functional state of rat heart mitochondria upon direct addition of AST to isolated mitochondria and upon chronic administration of AST under conditions of mPTP opening. It was shown that AST exerted a protective effect under all conditions. In addition, AST treatment was found to prevent isoproterenol-induced oxidative damage to mitochondria and increase mitochondrial efficiency. AST, a ketocarotenoid, may be a potential mitochondrial target in therapy for pathological conditions associated with oxidative damage and mitochondrial dysfunction, and may be a potential mitochondrial target in therapy for pathological conditions.

Nourin-Associated miRNAs: Novel Inflammatory Monitoring Markers for Cyclocreatine Phosphate Therapy in Heart Failure.

BACKGROUND: Cyclocreatine phosphate (CCrP) is a potent bioenergetic cardioprotective compound known to preserve high levels of cellular adenosine triphosphate during ischemia. Using the standard Isoproterenol (ISO) rat model of heart failure (HF), we recently demonstrated that the administration of CCrP prevented the development of HF by markedly reducing cardiac remodeling (fibrosis and collagen deposition) and maintaining normal ejection fraction and heart weight, as well as physical activity. The novel inflammatory mediator, Nourin is a 3-KDa formyl peptide rapidly released by ischemic myocardium and is associated with post-ischemic cardiac inflammation. We reported that the Nourin-associated miR-137 (marker of cell damage) and miR-106b-5p (marker of inflammation) are significantly upregulated in unstable angina patients and patients with acute myocardial infarction, but not in healthy subjects. OBJECTIVES: To test the hypothesis that Nourin-associated miR-137 and miR-106b-5p are upregulated in ISO-induced "HF rats" and that the administration of CCrP prevents myocardial injury (MI) and reduces Nourin gene expression in "non-HF rats". METHODS: 25 male Wistar rats (180-220 g) were used: ISO/saline (n = 6), ISO/CCrP (0.8 g/kg/day) (n = 5), control/saline (n = 5), and control/CCrP (0.8 g/kg/day) (n = 4). In a limited study, CCrP at a lower dose of 0.4 g/kg/day (n = 3) and a higher dose of 1.2 g/kg/day (n = 2) were also tested. The Rats were injected SC with ISO for two consecutive days at doses of 85 and 170 mg/kg/day, respectively, then allowed to survive for an additional two weeks. CCrP and saline were injected IP (1 mL) 24 h and 1 h before first ISO administration, then daily for two weeks. Serum CK-MB (U/L) was measured 24 h after the second ISO injection to confirm myocardial injury. After 14 days, gene expression levels of miR-137 and miR-106b-5p were measured in serum samples using quantitative real-time PCR (qPCR). RESULTS: While high levels of CK-MB were detected after 24 h in the ISO/saline rats indicative of MI, the ISO/CCrP rats showed normal CK-MB levels, supporting prevention of MI by CCrP. After 14 days, gene expression profiles showed significant upregulation of miR-137 and miR-106b-5p by 8.6-fold and 8.7-fold increase, respectively, in the ISO/saline rats, "HF rats," compared to the control/saline group. On the contrary, CCrP treatment at 0.8 g/kg/day markedly reduced gene expression of miR-137 by 75% and of miR-106b-5p by 44% in the ISO/CCrP rats, "non-HF rats," compared to the ISO/Saline rats, "HF rats." Additionally, healthy rats treated with CCrP for 14 days showed no toxicity in heart, liver, and renal function. CONCLUSIONS: Results suggest a role of Nourin-associated miR-137 and miR-106b-5p in the pathogenesis of HF and that CCrP treatment prevented ischemic injury in "non-HF rats" and significantly reduced Nourin gene expression levels in a dose-response manner. The Nourin gene-based mRNAs may, therefore, potentially be used as monitoring markers of drug therapy response in HF, and CCrP-as a novel preventive therapy of HF due to ischemia.

A Case of J Wave Syndrome Due to Severe Hypercalcemia with Ventricular Fibrillation Storm and Successful Treatment of Isoproterenol Infusion.

A case of J wave syndrome with ventricular fibrillation (VF) storm and severe hypercalcemia due to primary hyperparathyroidism is presented. VF storm subsided with an isoproterenol infusion. Prominent J waves and a Brugada-like electrocardiogram pattern disappeared after parathyroidectomy. Ventricular tachyarrhythmia was not induced during an electrophysiological study. The patient remained asymptomatic up to the 12-month follow-up.

Effects of Zoniporide and BMA-1321 Compound on the Rate of Oxygen Absorption by Cardiomyocyte Mitochondria in Rats with Experimental Chronic Heart Failure.

Uncoupling of respiration and ATP production by myocardial mitochondria was observed in rats with chronic isoproterenol intoxication (L-isoproterenol subcutaneously, 1 mg/kg, for 10 days) in comparison with controls (injected with the solvent). Inhibitors of NHE-1 zoniporide (1 mg/kg intraperitoneally, 13 days) and BMA-1321 compound (0.92 mg/kg intraperitoneally, 13 days) improved the mitochondrial function in rats with isoproterenol-induced cardiac failure: respiratory control coefficients increased, more so for the respiratory chain complex II, the main source of ROS in heart failure. The effect of BMA-1321 was more manifest (53%; p<0.05) in comparison with zoniporide (35%; p<0.05).

Low-dose l-isoproterenol versus salbutamol in hospitalized pediatric patients with severe acute exacerbation of asthma: A double-blind, randomized controlled trial.

BACKGROUND: Although the guidelines in most countries do not recommend continuous inhalation of l-isoproterenol to treat pediatric patients with acute severe exacerbation of asthma, lower dose of l-isoproterenol has been widely used in Japan. To determine whether the efficacy of low-dose l-isoproterenol was superior to that of salbutamol, we conducted a double-blind, randomized controlled trial. METHODS: Hospitalized patients aged 1-17 years were eligible if they had severe asthma exacerbation defined by the modified pulmonary index score (MPIS). Patients were randomly assigned (1:1) to receive inhalation of l-isoproterenol (10 µg/kg/h) or salbutamol (500 µg/kg/h) for 12 hours via a large-volume nebulizer with oxygen. The primary outcome was the change in MPIS from baseline to 3 hours after starting inhalation. Trial registration number UMIN000001991. RESULTS: From December 2009 to October 2013, 83 patients (42 in the l-isoproterenol group and 41 in the salbutamol group) were enrolled into the study. Of these, one patient in the l-isoproterenol group did not receive the study drug and was excluded from the analysis. Compared with salbutamol, l-isoproterenol reduced MPIS more rapidly. Mean (SD) changes in MPIS at 3 hours were -2.9 (2.5) in the l-isoproterenol group and -0.9 (2.3) in the salbutamol group (difference -2.0, 95% confidence interval -3.1 to -0.9; P < 0.001). Adverse events occurred in 1 (2%) and 11 (27%) patients in the l-isoproterenol and salbutamol groups, respectively (P = 0.003). Hypokalemia and tachycardia occurred only in the salbutamol group. CONCLUSIONS: Low-dose l-isoproterenol has a more rapid effect with fewer adverse events than salbutamol.

Ventricular tachycardia in a 16-year-old boy with primary hyperparathyroidism.

We report a case of primary hyperparathyroidism with hypercalcaemia in a 16-year-old boy who had spontaneous attack of ventricular tachycardia. To our knowledge, presentation of ventricular tachycardia caused by primary hyperparathyroidism in such a young patient has not been reported in medical literature so far.

Consecutive Isoproterenol and Adenosine Treatment Confers Marked Protection against Reperfusion Injury in Adult but Not in Immature Heart: A Role for Glycogen.

Consecutive treatment of adult rat heart with isoproterenol and adenosine (Iso/Aden), known to consecutively activate PKA/PKC signaling, is cardioprotective against ischemia and reperfusion (I/R). Whether this is cardioprotective in an immature heart is unknown. Langendorff-perfused hearts from adult and immature (60 and 14 days old) male Wistar rats were exposed to 30 min ischemia and 120 min reperfusion, with or without prior perfusion with 5 nM Iso for 3 min followed by 30 µM Aden for 5 min. Changes in hemodynamics (developed pressure and coronary flow) and cardiac injury (Lactate Dehydrogenase (LDH) release and infarct size) were measured. Additional hearts were used to measure glycogen content. Iso induced a similar inotropic response in both age groups. Treatment with Iso/Aden resulted in a significant reduction in time to the onset of ischemic contracture in both age groups whilst time to peak contracture was significantly shorter only in immature hearts. Upon reperfusion, the intervention reduced cardiac injury and functional impairment in adults with no protection of immature heart. Immature hearts have significantly less glycogen content compared to adult. This work shows that Iso/Aden perfusion confers protection in an adult heart but not in an immature heart. It is likely that metabolic differences including glycogen content contribute to this difference.

Case report: electrical storm during induced hypothermia in a patient with early repolarization.

BACKGROUND: Population based studies showed an association of early repolarization in the electrocardiogram (ECG) and a higher rate of sudden cardiac death presumably due to ventricular fibrillation. The triggers for ventricular fibrillation in patients with early repolarization are not fully understood. CASE PRESENTATION: We describe the case of a young patient with a survived ventricular fibrillation arrest while asleep followed by multiple episodes of recurrent ventricular fibrillation. The admission ECG showed an early repolarization pattern with substantial J-point elevation in most of the ECG-leads. After initiation of a hypothermia protocol, the patient developed an electrical storm with multiple ventricular fibrillation episodes requiring multiple cardioversions. Intravenous isoproterenol infusion successfully suppressed the malignant arrhythmia. CONCLUSION: Hypothermia appears proarrhythmic in patients with early repolarization and may trigger ventricular fibrillation. This knowledge is particularly important when initiating temperature management protocols in patients after a survived cardiac arrest. During the acute phase of an early repolarization associated electrical storm, isoproterenol is the most effective treatment suppressing the ventricular fibrillation-inducing premature ventricular complexes at higher heart rates.

A Perfect Storm: Tyrosine Kinase Inhibitor-Associated Polymorphic Ventricular Tachycardia.

BACKGROUND: Oral tyrosine kinase inhibitors (TKIs) are becoming increasingly common in oncology practice due to ease of administration and patient preference. This class of medications is relatively unknown to emergency physicians. CASE REPORT: Here we present a case of electrical storm (ES) thought to be associated with ibrutinib, a TKI. The ES was unabated despite antidysrhythmic therapy and electrical cardioversion, and was treated with supportive care, which eventually included the use of extracorporeal membrane oxygenation. This patient had no risk factors or apparent causes of recurrent ventricular tachycardia. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: ES has not previously been described with ibrutinib, but may be associated with off-target effects of the drug.

Hemodynamic changes in systolic and diastolic function during isoproterenol challenge predicts symptomatic response to myectomy in hypertrophic cardiomyopathy with labile obstruction.

OBJECTIVES: We aimed to assess the utility of changes in systolic and diastolic function by isoproterenol challenge in predicting symptom resolution post-myectomy in selected patients with hypertrophic cardiomyopathy (HCM) and labile obstruction. BACKGROUND: In a subset of symptomatic HCM patients without resting/provocable obstruction on noninvasive assessment, isoproterenol challenge during hemodynamic catheterization may elicit labile left ventricular outflow tract (LVOT) obstruction, and demonstrate the effect of obstruction on diastolic function. These changes may determine whether patients achieve complete symptom resolution post-myectomy. METHODS: Between February 2003 and April 2009, 18 symptomatic HCM patients without LVOT obstruction on noninvasive testing underwent isoproterenol provocation and septal myectomy due to presence of provocable gradient and were followed for 4 (IQR 3-7) years. RESULTS: Thirteen (72.2%) had complete symptom resolution, while 5 (27.8%) had improved, but persistent symptoms. Those with provoked gradient >100 mm Hg or increase in left atrial pressure (LAP) with isoproterenol had symptom resolution. CONCLUSIONS: Symptomatic HCM patients without LVOT gradient on noninvasive testing may demonstrate labile obstruction with isoproterenol. With isoproterenol, patients with high LVOT gradient or increase in LAP concomitant with an increase in gradient achieved complete symptom resolution post-myectomy. Thus, improved diastolic filling as well as outflow gradient production in patients with HCM may predict symptom response to myectomy. © 2016 Wiley Periodicals, Inc.

Slowed depolarization and irregular repolarization in catecholaminergic polymorphic ventricular tachycardia: a study from cellular Ca2+ transients and action potentials to clinical monophasic action potentials and electrocardiography.

AIMS: Spontaneous Ca2+ release leads to afterdepolarizations and triggered arrhythmia in catecholaminergic polymorphic ventricular tachycardia (CPVT). Irregular Ca2+ release is hypothesized to manifest as slowed depolarization and irregular repolarization. Our goal was to study depolarization and repolarization abnormalities in CPVT, as they remain largely uninvestigated. METHODS AND RESULTS: We studied intracellular Ca2+ handling and action potentials (APs) in an induced pluripotent stem cell (iPSC) model of CPVT. Induced pluripotent stem cell cardiomyocytes from a RyR2-P2328S patient showed increased non-alternating variability of Ca2+ transients in response to isoproterenol. ß-Agonists decreased AP upslope velocity in CPVT cells and in monophasic AP recordings of CPVT patients. We compared 24 h electrocardiograms (ECGs) of 19 CPVT patients carrying RyR2 mutations and 19 healthy controls. Short-term variability (STV) of the QT interval was 6.9 ± 0.5 ms in CPVT patients vs. 5.5 ± 0.4 ms in controls (P < 0.05) and associated with a history of arrhythmic events. Mean T-wave alternans (TWA) was 25 ± 1.4 µV in CPVT patients vs. 31 ± 2.0 µV in controls (P < 0.05). Older CPVT patients showed lower maximal upslope velocity of the ECG R-spike than control patients. CONCLUSION: Catecholaminergic polymorphic ventricular tachycardia patients show higher STV of repolarization but lower TWA on the 24 h ECG than control patients, which is likely to reflect increased non-alternating variability of Ca2+ release by mutant RyR2s as observed in vitro. ß-Agonists slow depolarization in RyR2-mutant cells and in CPVT patients. These findings may constitute a marker of arrhythmogenicity.

The ß-adrenoceptor agonist isoproterenol rescues acetaminophen-injured livers through increasing progenitor numbers by Wnt in mice.

UNLABELLED: Acetaminophen (APAP)-induced acute liver injury (AILI) is a major health problem. Accumulating evidence suggests that the sympathetic nervous system (SNS) regulates neuronal and hematopoietic progenitors. SNS signaling affects hepatic progenitor/oval cells (HPCs) and ß-adrenoceptor agonism will expand HPCs to reduce AILI. Dopamine ß-hydroxylase-deficient mice (Dbh-/-), lacking catecholamine SNS neurotransmitters, isolated HPCs, and immature ductular 603B cells were initially used to investigate SNS involvement in HPC physiology. Subsequently, control mice were treated with APAP (350 mg/kg) followed by the ß-adrenoceptor agonist, isoproterenol (ISO), or the ß-adrenoceptor antagonist, propranolol. Mechanistic studies examined effects of non-SNS HPC expansion on AILI, involvement of the canonical Wnt/ß-catenin pathway (CWP) in the action of ISO on HPC expansion and comparison of ISO with the current standard of care, N-acetylcysteine (NAC). Dbh-/- mice lacking catecholamines had low HPC numbers, reconstituted by ISO. In vitro, ISO-induced proliferation of 603B cells was CWP dependent. In control mice, AILI raised HPC numbers, further increased by ISO, with attenuation of liver injury. Delayed administration of NAC did not, but delayed ISO did, reverse AILI. Propranolol worsened AILI. AILI activated the CWP, and ISO enhanced Wnt-ligand production. HPCs were the major source of Wnt ligands. Recombinant Wnt3a and ISO-603B-conditioned media, but not ISO alone, protected isolated hepatocytes from death, reversed by DKK1-a Wnt antagonist. Additionally, tumor-associated weak inducer of apoptosis expanded HPCs and protected against AILI. Furthermore, allotransplantation of HPCs from APAP+ISO-treated mice to other APAP-injured mice improved AILI, an effect antagonized by DKK1. CONCLUSION: SNS catecholamines expand HPCs, which are both targets and sources of Wnt ligands. Hepatoprotection by ISO is mediated by para- and autocrine effects of Wnt signaling. ISO represents novel pharmacotherapy for AILI.

Listeria meningitis-associated bradyarrhythmia treated with isoproterenol.

In the setting of increased intracranial pressure (ICP), various rhythm disturbances have been associated, ranging from tachyarrhythmias to bradyarrhythmias with atrioventricular dissociation. Although most of these observations have been in patients with traumatic brain injuries, it is known that children with acute bacterial meningitis may also have severe intracranial hypertension. We present the case of a previously healthy 2-year-old boy diagnosed with listeria meningitis. Along with clinical signs suggestive of increased ICP and brainstem involvement, our patient had persistent bradyarrhythmia with hemodynamic compromise that was refractory to epinephrine and successfully managed with isoproterenol.