Non-selective Beta Research Articles

Overexpression or Lack of beta 2-Adrenergic Receptor Correlate with Progression of Breast Cancer.

Abstract Background: Recent studies showed that stress can modulate biological behavior of ovarian carcinoma through adrenergic receptors. Since both nonselective beta-adrenergic receptor antagonist propranolol and selective beta 2-adrenergic receptor (b2AR) antagonist ICI 118,551 instead of b1AR antagonist atenolol could eliminate most of the effects, b2AR is accordingly regarded as the key molecule. In this study, we investigated the role of b2AR in breast cancer. Material and Methods: Gene expression of b2AR was analyzed by RT-PCR in human breast cancer cell lines MDA-MB-231, MDA-MB-435, MDA-MB-468, MCF-7, T47D, BT-549, HCC1937, BCaP-37 and normal mammary epithelial-like cell line HBL-100. b2AR cDNA was transfected into MDA-MB-435 cells. Protein level of b2AR was analyzed by immunohistochemistry in clinical samples, including 25 normal human breast or benign disease breast tissues and 202 breast cancer tissues. Results: b2AR was detected in majority of breast cancer cell lines, except for MDA-MB-435, MCF-7 and T47D, and all of normal or benign disease breast tissues. Both nonselective beta-adrenergic receptor agonist norepinephrine (NE) and selective b2AR agonist terbutaline promoted proliferation and invasion of spontaneous b2AR-positive MDA-MB-231 cells and transfectant MDA-MB-435-b2AR cells, these effects were completely inhibited by selective b2AR antagonist ICI 118,551. In the breast cancer patients, 125 samples (61.9%) expressed b2AR weakly or moderately just as normal breast or benign diseases tissue, and 43 (21.3%) presented significantly stronger b2AR expression, while no b2AR staining was found in other 34 samples (16.8%). Higher expression or lack of b2AR were associated with axillary lymph nodes metastasis and poor disease free survival (DFS). Discussion: Based on our preliminary results, the breast cancer patients could be classified into three subgroups: b2AR “normal”, high expression and negative groups. Overexpression or lack of b2AR associated with metastasis and clinical prognosis in breast cancer. Obviously, abnormal expression of b2AR may influence the outcome of breast cancer. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4165.

Ectopic Varices Causing Recurrent Obscure Gastrointestinal Bleeding

Purpose: To present an unusual case of obscure gastrointestinal bleeding. Methods: A 53-year old male with a history of hepatitis C and a gun-shot wound to the abdomen requiring unknown surgical interventions initially presented to our institution for melena, hematochezia, and a hemoglobin of 6.5 g/dL. Initial evaluation included an EGD which showed no source for bleeding and no endoscopic findings suggestive of portal hypertensive related complications. Colonoscopy (which included evaluation of the terminal ileum) was also negative for source. Neither abdominal imaging nor laboratory investigations were suggestive of advanced liver disease. As the patient manifested no other signs or symptoms of continued bleeding, he was subsequently discharged with instructions to have an outpatient wireless capsule endoscopy. He did not get the capsule endoscopy but presented similiarly to the hospital four more times. At each time, a variety of investigative techniques (EGD, enteroscopy, tagged RBC scan) were unrevealing for source. Due to the inability to obtain a capsule endoscopy, the patient was ultimately referred for a double balloon enteroscopy at a neighboring institution. Results: The double balloon enteroscopy revealed large, non-bleeding ileal varices which are the presumed source to the recurrent obscure GI bleeding. No endoscopic therapy was performed. The patient was initiated on a non-selective beta blocker and referred for surgical evaluation. Conclusion: Ectopic varices are an unusual and challenging cause of gastrointestinal bleeding. Unfortunately, there are no clear evidence-based guidelines to direct their management. Management of this challenging clinical entity should therefore employ a multidisciplinary approach between the gastroenterologist, the surgeon, and the interventional radiologist to define an optimal approach. In this case, we believe that the ileal varices are complications of the prior abdominal surgery rather than intrinsic liver disease.Figure: Large ileal varices identifed at double balloon enteroscopy.

The selective α1 adrenoceptor antagonist HEAT reduces L‐DOPA‐induced dyskinesia in a rat model of Parkinson's disease

In Parkinson's disease (PD), the long term use of L-DOPA results in major adverse effects including dyskinesia or abnormal involuntary movements. The present study focuses on the effect of the selective alpha(1) adrenoceptor antagonist HEAT (2-[[beta-(-4-hydroxyphenyl)ethyl]aminomethyl]-1-tetralone) in the 6-hydroxydopamine rat model of L-DOPA-induced dyskinesia. We demonstrate that the selective alpha(1) adrenoceptor antagonist HEAT (1 and 2 mg kg(-1)), the alpha(2) adrenoceptor antagonist idazoxan (9 mg kg(-1)), and the nonselective beta(1)/beta(2) adrenoceptor antagonist propranolol (20 mg kg(-1)) alleviate dyskinetic movements induced by L-DOPA. Furthermore, the adrenoceptor antagonists at the doses used did not influence exploratory behavior in the open field system indicating that the antidyskinetic effect is not due to a reduction in general motor activity. Intrastriatal administration of the selective alpha(1) adrenoceptor agonist cirazoline via reverse in vivo microdialysis did not induce dyskinesia. Additionally, we measured plasma, brain, and CSF levels of HEAT. HEAT is a CNS active compound with a brain/plasma and CSF/plasma ratio of 4.29 and 0.15, respectively, which is appropriate for the investigation of alpha(1)-mediated mechanisms in CNS disorders. In conclusion, these results demonstrated for the first time that a alpha(1) adrenoceptor antagonist reduced L-DOPA-induced dyskinesia in a rat model. Further studies assessing the risk benefit in comparison to existing therapies are needed before considering alpha(1) adrenoceptor antagonists as a target for the development of new antidyskinetic compounds.

Suppression of Collagen Production in Norepinephrine Stimulated Cardiac Fibroblasts Culture: Differential Effect of α and β-Adrenoreceptor Antagonism

Prolonged sympathetic activation is damaging to the heart and experimental norepinephrine (NE) infusion induces the deposition of myocardial collagen. This study investigated the effects of NE on collagen and transforming growth factor-beta1 (TGF-beta1) gene expression in rat cardiac fibroblasts (CF) culture, and compared the anti-fibrotic effect of alpha and beta (both selective and non-selective adrenergic receptor antagonists) receptors. Rat CF were cultured in the presence of NE (0.01 to 100 muM) for 24 hours. Procollagen types I and III as well as TGF-beta1 gene expressions were measured by real-time quantitative PCR method. Collagen protein level was measured by Sirius red-based colorimetric method and Western blot analysis. The optimal dose of NE on fibrogenesis was 0.1 muM. Incubation for 24 hours increased procollagen I, III and TGF-beta1 gene expression by 1.35 +/- 0.23, 1.26 +/- 0.16 and 1.35 +/- 0.21 fold, respectively (all p < 0.05). The collagen protein was increased by both Sirius-red assay (0.120 +/- 0.03 vs 0.093 +/- 0.04 microg/total microg of protein, p < 0.05) and Western blot analysis (1.29 +/- 0.26 fold, p < 0.05), when compared with the control group. Addition of carvedilol (a non-selective beta-blocker with alpha-blockage activity) inhibited the effect of NE on procollagen I (0.64 +/- 0.17 vs 1.28 +/- 0.08 fold, p < 0.01), procollagen III gene (0.47 +/- 0.16 vs 1.45 +/- 0.29 fold, p < 0.01) and collagen protein expressions (0.99 +/- 0.12 vs 1.26 +/- 0.31 fold, p < 0.05, respectively). Doxazosin (an alpha-blocker) also inhibited the effect of NE on procollagen I (0.88 +/- 0.30 vs 1.28 +/- 0.08 fold, p < 0.01), procollagen III gene (0.64 +/- 0.13 vs 1.45 +/- 0.29 fold, p < 0.01) and collagen protein expression (0.90 +/- 0.11 vs 1.26 +/- 0.31 fold, p < 0.01 respectively). Such inhibitory effects were not seen in metoprolol (a beta1-selective blocker) and propranolol (a non-selective beta blocker). Furthermore, all the 4 drugs were unable to inhibit the NE induced TGF-beta1 gene over-expression. In conclusion, NE increased collagen gene and protein expressions in CF culture. This effect is likely mediated through alpha-receptor as they were normalized by pretreatment with carvedilol and doxazosin, but not beta-blockers such as propranolol and metoprolol. Also, TGF-beta1 doesn't seem to play a role in carvedilol inhibition of NE induced fibrogenesis.

Venoarteriolar Response Is Unaltered By Beta-adrenergic Blocker Or Exercise Training In Postural Orthostatic Tachycardia Syndrome

Postural Orthostatic Tachycardia Syndrome (POTS) is characterized by excessive tachycardia during orthostasis. We previously found that POTS patients have enhanced venoarteriolar response (VAR) when compared to healthy sedentary women. Whether a standard pharmacologic treatment for POTS such as beta blockers, or non-pharmacological treatment like exercise training could normalize the VAR in these patients is unknown. PURPOSE: We tested the hypothesis that short-term exercise training would attenuate cutaneous VAR to a greater extent than beta blocker treatment. METHODS: Nineteen patients (18 females, 1 male), age 15-44 years were studied. First, patients were given a random, double-blind assignment to receive either placebo (n=10) or non-selective beta blocker (n=9, propanolol, 80 mg q.d.) treatment for 4 wk, and then patients (n=17) completed a 3-mo exercise training program. Female patients were tested during mid-luteal phases of their menstrual cycles before and after medication treatment, and after exercise training. Skin blood flow (SkBF, laser-Doppler flowmetry), was measured in the calf at heart level (baseline, BL) and during leg dependency of 17-35 cm below the heart for 2 min each while supine. RESULTS: Blood pressure (BP, Portapres) and heart rate (HR, ECG) were monitored continuously. Both HR and BP were not different at BL compared to during leg dependency, except diastolic BP was slightly higher during leg dependency in the pre exercise training group [BL 62±11 (SD) mmHg vs. leg dependency 63±12, P=0.037]. HR was significantly lower after beta blocker (BL 86±16 bpm vs. 71±13, P=0.002) and after exercise training (81±14 bpm vs. 72±15, P=0.002). Only the group taking beta blocker had significant reductions in systolic and diastolic BP (P=0.013 and 0.008) after treatment. VAR, determined by the relative decrease in SkBF during leg dependency, was not different after placebo (-45±10% vs. -42±13, P=0.571), beta blocker (-42±12% vs. -38 ±14, P=0.471) or exercise training (-41±13% vs. -46±11, P=0.314). CONCLUSION: These results suggest that the enhanced VAR observed in POTS patients is not affected by beta blocker or exercise training. However, the pathophysiology for such enhanced VAR and the effective therapy still need to be determined. Supported by NIH K23 (HL0752 83) and the GCRC grant (RR00633).

Improved survival with nonselective beta blockers

Improved survival with nonselective beta blockers

Multi-objective optimization of simulated moving bed and Varicol processes for enantio-separation of racemic pindolol

Rigorous multi-objective optimization of simulated moving bed (SMB) and Varicol processes for enantio-separation of racemic pindolol, a nonselective beta blocker in terms of cardio-selectivity, was carried out in this study using an experimentally verified mathematical model and isotherm parameters. Several two-objective optimization problems were solved simultaneously maximizing product purity and recovery for both SMB and Varicol processes. The shift in Pareto optimal solutions was investigated to study the effect of feed concentration, eluent flow rate as well as column geometry and column configuration. A state-of-the-art optimization technique, non-dominated sorting genetic algorithm with jumping genes (NSGA-II-JG) was used to obtain the Pareto optimal solutions. Significant performance improvement was achieved when rigorous optimization was performed. Subsequently, the optimized solutions were verified experimentally. The results show that operating conditions for SMB and Varicol processes should be selected as a compromise between separation performance and robustness.

INCREASED AEROBIC GLYCOLYSIS THROUGH β2 STIMULATION IS A COMMON MECHANISM INVOLVED IN LACTATE FORMATION DURING SHOCK STATES

During septic shock, muscle produces lactate by way of an exaggerated NaK-adenosine triphosphatase (ATPase)-stimulated aerobic glycolysis associated with epinephrine stimulation possibly through beta2 adrenoreceptor involvement. It therefore seems logical that a proportion of hyperlactatemia in low cardiac output states would be also related to this mechanism. Thus, in low-flow and normal-to-high-flow models of shock, we investigate (1) whether muscle produces lactate and (2) whether muscle lactate production is linked to beta2 adrenergic stimulation and Na+K+-ATPase. We locally modulated the adrenergic pathway and Na+K+-ATPase activity in male Wistar rats' skeletal muscle using microdialysis with nonselective and selective beta blockers and ouabain in different models of rodent shock (endotoxin, peritonitis, and hemorrhage). Blood flow at the probe site was evaluated by ethanol clearance. We measured the difference between muscle lactate and blood lactate concentration, with a positive gradient indicating muscle lactate or pyruvate production. Epinephrine levels were elevated in all shock groups. All models were associated with hypotension and marked hyperlactatemia. Muscle lactate concentrations were consistently higher than arterial levels, with a mean gradient of 2.5+/-0.3 in endotoxic shock, 2.1+/-0.2 mM in peritonitis group, and 0.9+/-0.2 mM in hemorrhagic shock (P<0.05 for all groups). Muscle pyruvate concentrations were also always higher than arterial levels, with a mean gradient of 260+/-40 microM in endotoxic shock, 210+/-30 microM in peritonitis group, and 90+/-10 microM in hemorrhagic shock (P<0.05 for all groups). Despite a decrease in blood flow, lactate formation was decreased by all the pharmacological agents studied irrespective of shock mechanism. This demonstrates that lactate production during shock states is related, at least in part, to increased NaK-ATPase activity under beta2 stimulation. In shock state associated with a reduced or maintained blood flow, an important proportion of muscle lactate release is regulated by a beta2 receptor stimulation and not secondary to a reduced oxygen availability.

Bolus isoproterenol infusions provide a reliable method for assessing interoceptive awareness

Interoception, defined as the perception of internal body states, plays a central role in classic and contemporary theories of emotion. In particular, deviations from baseline body states have been hypothesized to be integral to the experience of emotion and feeling. Consequently, reliable measurement of interoception is critical to the testing of emotion theories. Heartbeat perception tasks have been considered the standard method for assessing interoceptive awareness, primarily due to their non-invasive nature and technical feasibility. However, these tasks are limited by the fact that above chance group performance rates on heartbeat detection (or the frequency of ‘good detectors’) are rarely higher than 40%, meaning that such tasks (as they are typically utilized) do not obtain a measure of interoceptive awareness in the majority of individuals. Here we describe a novel protocol for inducing and assessing a range of deviations in body states via bolus infusions of isoproterenol, a non-selective beta adrenergic agonist. Using a randomized, double-blinded, and placebo-controlled experimental design, we found that bolus isoproterenol infusions elicited rapid and transient increases in heart rate and concomitant ratings of heartbeat and breathing sensations, in a dose-dependent manner. Our protocol revealed changes in interoceptive awareness in all 15 participants tested, thus overcoming a major limitation of heartbeat detection tasks. These findings indicate that bolus isoproterenol infusions provide a reliable method for assessing interoceptive awareness, which sets a foundation for further investigation of the role of interoceptive sensations in the experience of emotion.

Hepatoportal Sclerosis Presenting as Massive Gastric Variceal Hemorrhage

Purpose: A 48-year-old man with ulcerative colitis (UC) presented to the emergency department with chest pain and was found to have a NSTEMI and hemoglobin of 4.1. Ten days earlier he had a single episode of hematemesis followed by black tarry stools for two days, but he did not seek medical attention. He had no history of liver or heart disease and no history of upper GI bleeding. He was immediatley transfused and started on a beta blocker. Methods: Physical exam revealed a distended abdomen, nontender hepatomegaly, and bilateral lower extremity edema. On endoscopy there were multiple large gastric varices with stigmata of recent hemorrhage and grade I varices in the distal esophagus. Serological evaluation for liver disease was negative and the patient denied significant alcohol use. His UC had been well controlled for several years on aminosalicylates. He had never taken azathioprine or 6MP. Transaminases and alkaline phosphatase levels were normal. The total bilirubin and platelets were at the limits of normal, 1.5 and 184, respectively. His INR was elevated at 1.34. An abdominal ultrasound with Doppler and later 4-phase CT confirmed patent abdominal vasculature, but hypercoagulable workup found protein C deficiency. A liver biopsy was performed with measurements indicating a wedge pressure of 6 mmHg, free hepatic pressure of 16 mmHg, gradient of 10 mmHg, and mean right atrial pressure of 5 mmHg. Microscopic examination found no significant fibrosis on Trichrome staining. Instead, there was loss of portal veins with dilation of intralobular vessels and increased perisinusoidal and cross hair patterns on reticulin staining, findings all consistent with a diagnosis of hepatoportal sclerosis (HPS). Results: HPS is a form of non-cirrhotic portal hypertension in which perisinusoidal pressure is elevated, likely due to thrombotic or sclerotic obliteration of small and medium sized portal venules. It has been associated with underlying coagulopathies such as protein C deficiency. Shunts may be necessary to control recurrent bleeding and given the lack of cirrhosis, patients with HPS may be good candidates for surgical decompressive shunts. Conclusion: This patient was discharged on a nonselective beta blocker for bleeding prophylaxis and then begun on oral anticoagulation at follow-up. HPS and other forms of non-cirrhotic portal hypertension should be considered in patients who present with portal hypertensive complications but lack clinical or laboratory signs of liver disease. Liver biopsy is necessary to confirm the diagnosis and patients should be evaluated for hypercoagulability.

Comparative Proteomic Analysis of Extracellular Proteins Reveals Secretion of T-Kininogen from Vascular Smooth Muscle Cells in Response to Incubation with S-Enantiomer of Propranolol

Propranolol, a nonselective beta blocker, exerts blocking activity both on beta1 adrenoceptors and beta2 ones, with the S-enantiomer being more active than the R-enantiomer. The aim of the study was to investigate the secreted proteins with differential protein expression levels in culture medium of vascular smooth muscle cells (A7r5) incubated separately with individual enantiomers of propranolol using isobaric tags for relative and absolute quantitation (iTRAQ)-coupled two-dimensional LC-MS/MS approach. Our results indicated that secretion of T-kininogen by S-enantiomer of propranolol incubated cells was greatly enhanced as compared with that of R-enantiomer incubated cells or control cells. It can be inferred that the S-enantiomer of propranolol will induce more Ile-Ser-bradykinin (BK) (T-kinin), the vasoactive peptides. This therefore provides molecular evidence and possible link of T-kininogen with treatment of cardiovascular disease associated with propranolol treatment.

Beneficial effects of non-selective beta blockers on mechanical and electrical activities of diabetic rat heart

Beneficial effects of non-selective beta blockers on mechanical and electrical activities of diabetic rat heart

The Effects of Aspirin and Nonselective Beta Blockade on the Acute Prothrombotic Response to Psychosocial Stress in Apparently Healthy Subjects

We hypothesized that the 2 cardiovascular drugs aspirin and propranolol attenuate the prothrombotic response to acute psychosocial stress relative to placebo medication. We randomized 56 healthy subjects, double-blind, to 5-day treatment with an oral dose of either 100 mg of aspirin plus 80 mg of propranolol combined, single aspirin, single propranolol, or placebo medication. Thereafter, subjects underwent a 13-minute psychosocial stressor. Plasma levels of von Willebrand factor antigen (VWF:Ag), fibrinogen, coagulation factor VII (FVII:C) and XII (FXII:C) activity, and D-dimer were determined in blood samples collected immediately pre- and post-stress and 45 minutes post-stress. The stress-induced changes in prothrombotic measures were adjusted for gender, age, body mass index, mean arterial blood pressure, smoking status, and sleep quality. There was an increase in VWF:Ag levels from immediately pre-stress to 45 minutes post-stress in the placebo group relative to the 3 subject groups with verum medication (P's </= 0.019; relative increase in VWF:Ag between 17% and 21%); however, the VWF:Ag response to stress was not significantly different between the three groups with verum medication. The stress responses in fibrinogen, FVII:C, FXII:C, and D-dimer were similar in all 4 medication groups. The combination of aspirin with propranolol, single aspirin, and single propranolol all attenuated the acute response in plasma VWF:Ag levels to psychosocial stress. This suggests that these cardiovascular drugs might exert limited protection from the development of stress-triggered coronary thrombosis.

Carvedilol-induced antagonism of angiotensin II: a matter of α1-adrenoceptor blockade

To investigate whether renin-angiotensin system blockade might underlie the favorable metabolic effects of the nonselective beta + alpha1-adrenoceptor blocker carvedilol as compared with the selective beta1-adrenoceptor blocker metoprolol. Human coronary microarteries (HCMAs), obtained from 32 heart valve donors, were mounted in myographs. Angiotensin II and the alpha1-adrenoceptor agonist phenylephrine constricted HCMAs to maximally 63 +/- 10 and 46 +/- 15% of the contraction to 100 mmol/l K. Neither carvedilol, metoprolol, the nonselective beta-adrenoceptor antagonist propranolol, nor the alpha1-adrenoceptor antagonist prazosin affected the constrictor response to angiotensin II. alpha1-adrenoreceptors and beta-adrenoceptors are thus not involved in the direct constrictor effects of angiotensin II. When added to the organ bath at a subthreshold concentration, angiotensin II greatly amplified the response to phenylephrine. Both carvedilol and the angiotensin II type 1 (AT1) receptor antagonist irbesartan inhibited this angiotensin II-induced potentiation. Furthermore, carvedilol blocked the angiotensin II-induced amplification of phenylephrine-induced inositol phosphate accumulation in cardiomyocytes. AT1-alpha1-receptor crosstalk, involving inositol phosphates, sensitizes HCMAs to alpha1-adrenoceptor agonists. Our results suggest that, in the presence of an increased sympathetic tone, carvedilol provides AT1 receptor blockade via its alpha1-adrenoceptor blocking effects. This could explain the favorable effects of carvedilol versus metoprolol.

Prophylaxis with beta blockers as a performance measure of quality health care in cirrhosis

Prophylaxis with beta blockers as a performance measure of quality health care in cirrhosis

Pharmacodynamics of Carvedilol in Conscious, Healthy Dogs

The purpose of the study reported here was to determine the magnitude and duration of beta‐blocking efficacy, determine an effective dose and dosing interval, and document safety and tolerability of carvedilol given orally in clinically normal dogs. Pharmacodynamic data were evaluated in conscious, unrestrained, healthy hound dogs at baseline and after long‐term oral administration of carvedilol (1.5 mg/kg of body weight PO q12h for &gt;5 days). At baseline, heart rate (HR) and blood pressure (BP) data were collected continuously for 24 hours, and complete echocardiography was performed. This protocol was repeated after long‐term oral carvedilol administration. Additionally, isoproterenol was administered to evaluate the magnitude and duration of the nonselective beta‐blocking efficacy of carvedilol. An isoproterenol challenge was performed 0.75, 1.5, 2.25, 4, 6, 12, and 24 hours after carvedilol administration, with echocardiography being performed once at 2 hours. Plasma samples were obtained prior to each challenge time point for determination of plasma carvedilol concentration. Time series regression analysis indicated no difference between baseline and carvedilol‐induced HR or BP trend lines in 6 of 8 dogs. In 2 of 8 dogs, HR, after long‐term carvedilol administration, was reduced. Carvedilol attenuated isoproterenol‐induced changes in HR by 54–76% through 12 hours and by 30% at 24 hours. The BP changes were attenuated by 80–100% through 12 hours. These data suggest that carvedilol (1.5 mg/kg PO q12h) in healthy, conscious dogs confers nonselective beta blockade for 12 hours, with minimal effects on resting HR, BP, and echocardiographic variables. Additionally, the magnitude of beta blockade correlated strongly to peak plasma carvedilol concentration, suggesting that therapeutic drug monitoring may be clinically useful.

Pharmacodynamics of Carvedilol in Conscious, Healthy Dogs

The purpose of the study reported here was to determine the magnitude and duration of beta-blocking efficacy, determine an effective dose and dosing interval, and document safety and tolerability of carvedilol given orally in clinically normal dogs. Pharmacodynamic data were evaluated in conscious, unrestrained, healthy hound dogs at baseline and after long-term oral administration of carvedilol (1.5 mg/kg of body weight PO q12h for >5 days). At baseline, heart rate (HR) and blood pressure (BP) data were collected continuously for 24 hours, and complete echocardiography was performed. This protocol was repeated after long-term oral carvedilol administration. Additionally, isoproterenol was administered to evaluate the magnitude and duration of the nonselective beta-blocking efficacy of carvedilol. An isoproterenol challenge was performed 0.75, 1.5, 2.25, 4, 6, 12, and 24 hours after carvedilol administration, with echocardiography being performed once at 2 hours. Plasma samples were obtained prior to each challenge time point for determination of plasma carvedilol concentration. Time series regression analysis indicated no difference between baseline and carvedilol-induced HR or BP trend lines in 6 of 8 dogs. In 2 of 8 dogs, HR, after long-term carvedilol administration, was reduced. Carvedilol attenuated isoproterenol-induced changes in HR by 54-76% through 12 hours and by 30% at 24 hours. The BP changes were attenuated by 80-100% through 12 hours. These data suggest that carvedilol (1.5 mg/kg PO q12h) in healthy, conscious dogs confers nonselective beta blockade for 12 hours, with minimal effects on resting HR, BP, and echocardiographic variables. Additionally, the magnitude of beta blockade correlated strongly to peak plasma carvedilol concentration, suggesting that therapeutic drug monitoring may be clinically useful.

To band or to block for primary prophylaxis against variceal bleeding?

To band or to block for primary prophylaxis against variceal bleeding?

Pathophysiology of portal hypertension in HCV-related cirrhosis: Putative role of assessment of portal pressure gradient in Peginterferon-treated patients

Chronic HCV infection is the leading aetiologic factor for cirrhosis, end-stage liver disease, hepatocellular carcinoma and liver transplantation worldwide. Pegylation of alfa interferons has improved the management of this disease. Interferon treatment has antifibrotic and immunomodulatory activities. Recent evidence supports the contention that Hepatitis C virus-related cirrhosis of the liver should no more be considered an irreversible disease; fibrosis is a potentially reversible process. Fibrosis and even cirrhosis reversal have been previously demonstrated either in experimental or clinical studies of other liver diseases. Development of portal hypertension is the main drive to the complications of advanced liver diseases: prognosis worsens significantly when portal hypertension becomes clinically significant. It is thus conceivable that within therapeutic trials involving patients with advanced fibrosis of the liver, measurement of the hepatic venous pressure gradient, the gold standard in the clinical assessment of portal hypertension and its management, could provide information on the portal pressure-lowering effects of interferon treatment affecting the fibrosis score. This can be accomplished by either sustained virological response either by fibrosis reduction achieved by chronic low-dose Peginterferon administration. If the introduction of drug therapy with non-selective beta blockers in the treatment of portal hypertension represents a milestone in the treatment of patients with cirrhosis and high-degree portal hypertension, the next step must then be prophylactic reversal of initial portal hypertension prompted by either HCV eradication and pharmacological inhibition of fibrosis progression by long-term Peginterferon before higher degrees of portal hypertension ensue.

Carvedilol reverses hyperthermia and attenuates rhabdomyolysis induced by 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) in an animal model*

Hyperthermia is a potentially fatal manifestation of severe 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) intoxication. No proven effective drug treatment exists to reverse this potentially life-threatening hyperthermia, likely because mechanisms of peripheral thermogenesis are poorly understood. Using a rat model of MDMA hyperthermia, we evaluated the acute drug-induced changes in plasma catecholamines and used these results as a basis for the selection of drugs that could potentially reverse this hyperthermia. Prospective, controlled, randomized animal study. A research institute laboratory. Male, adult Sprague-Dawley rats. Based on MDMA-induced changes in plasma catecholamine levels, rats were subjected to the nonselective (beta1 + beta2) adrenergic receptor antagonists propranolol or nadolol or the alpha1- + beta1,2,3-adrenergic receptor antagonist carvedilol before or after a thermogenic challenge of MDMA. Plasma catecholamines levels 30 mins after MDMA (40 mg/kg, subcutaneously) were determined by high-pressure liquid chromatography and electrochemical detection. Core temperature was measured by a rectal probe attached to a thermocouple. Four hours after MDMA treatment, blood was drawn and serum creatine kinase levels were measured as a marker of rhabdomyolysis using a Vitros analyzer. MDMA induced a 35-fold increase in norepinephrine levels, a 20-fold increase in epinephrine, and a 2.4-fold increase in dopamine levels. Propranolol (10 mg/kg, intraperitoneally) or nadolol (10 mg/kg, intraperitoneally) administered 30 mins before MDMA had no effect on the thermogenic response. In contrast, carvedilol (5 mg/kg, intraperitoneally) administered 15 mins before or after MDMA prevented this hyperthermic response. Moreover, when administered 1 hr after MDMA, carvedilol completely reversed established hyperthermia and significantly attenuated subsequent MDMA-induced creatine kinase release. These data show that alpha1 and beta3-adrenergic receptors may contribute to the mediation of MDMA-induced hyperthermia and that drugs targeting these receptors, such as carvedilol, warrant further investigation as novel therapies for the treatment of psychostimulant-induced hyperthermia and its sequelae.