Beta-adrenoreceptor Blockade Research Articles

Novel approach to depression in ischemic heart disease: attenuation of autonomic dysfunction lowers depression scores

Abstract Introduction Depression in ischemic heart disease (IHD) is associated with increased mortality, and autonomic nervous system dysfunction (ANSD) may link the two conditions. Regulatory functions of the autonomic nervous system with respect to IHD risk factors include heart rate, blood pressure, serum cholesterol, and glycated hemoglobin. While painful sensitivity to pressure (Pressure-Pain Sensitivity, PPS) at the sternum rises with increased depression in IHD, reduction of elevated PPS reflects lower depression scores, lower ANSD, and lower mortality rates in IHD. Beta-adrenoreceptor blockade (BB) inhibits the anti-depressive effect associated with reduced PPS measures as well as the efferent sympathetic autonomic activity. Purpose We tested the hypothesis that lowering of elevated PPS measures is associated with restored autonomic regulation of depression, measured as the association between baseline depression scores and subsequent lowering of the depression score. We determined whether autonomic regulation in depression is associated with non-pharmacological reduction of elevated PPS measures. Methods In a randomized controlled intervention trial of IHD that included 213 individuals with elevated PPS, 20% of participants had elevated Major Depression Inventory scores (MDIS). We compared subjects with previously defined minimum reduction of at least 15 PPS units (PPS reverters) with subjects without this effect (PPS non-reverters), as well as non-users with users of BB. We recorded linear regressions of depression score changes as the dependent variable versus baseline depression scores as the independent variable. We compared active and control treatments by dividing participants into three pre-study defined groups of no depression (MDIS < 15), incipient depression (15 < MDIS < 20), and manifest depression (MDIS > 20). Results For reverters (N=72) compared to non-reverters (N=93), the mean anti-depressive effect increased in favor of reverters by a rate of 0.3 MDI units (95% CI 0.10–0.5, P=0.004) per unit increase in baseline MDIS. Comparing BB non-users (N=97) with BB users (N=67), the rate in favor of BB non-users was 0.4 units (95% CI 0.2-0.6, P=0.0002). In combination, comparing reverting non-users of BB (N=27) to non-reverting BB users (N=52), the rate in favor of the former group was 0.7 MDI (95% CI 0.4-0.9, P<0.00001). For reverting BB non-users, Cohen’s effect size reached 1.5. For the comparison of active and control groups for the three levels of MDIS, the trend was significant at P=0.04. Conclusions In patients with IHD, depression is associated with disruption of specific sympathetic beta-adrenergic regulatory functions of the autonomic nervous system. The findings imply that lowering of elevated PPS measures is associated with enhanced autonomic regulation of depression scores, and with marked clinical effect in individuals with elevated depression scores, but with no effect in BB users.

Abstract 13228: Cannabis Inhalation Reduces Muscle Sympathetic Nerve Activity in Humans

Introduction: Despite widespread use, the neuro-cardiovascular responses associated with cannabis use remain incompletely understood. Acute increases in heart rate, which are abolished under beta-adrenoreceptor blockade, suggest cannabis increases cardiac sympathetic activity; however, its effects on peripheral sympathetic outflow have not been measured. The objective of this work was to quantify direct recordings of efferent post-ganglionic muscle sympathetic nerve activity (MSNA) following cannabis inhalation. Hypothesis: MSNA would be increased following cannabis inhalation. Methods: Blood pressure (BP), heart rate, and MSNA measured from the fibular nerve, were recorded in seventeen young, healthy participants (22±3y: 8F) for a 10-minute epoch before and after inhalation of aerosolized dry cannabis flower (100mg, 13.6% THC). Cardiac output was estimated from finger photoplethysmography (Modelflow method). Arterial baroreflex control of MSNA was quantified using the slope of the weighted linear regression between diastolic BP and MSNA. Results: Mean BP (79±7 vs. 84±8mmHg), heart rate (61±7 vs. 81±14bpm), cardiac output (4.8±1.1 vs. 6.8±2.5L/min), and total vascular conductance (50±11 vs. 71±26mL/min/mmHg) were increased, while MSNA burst frequency (17±7 vs. 8±6bursts/min), incidence (29±11 vs. 11±9bursts/100hb), and amplitude (38.6±6.4% vs. 23.8±8.3%), and sympathetic baroreflex sensitivity (-3.9±1.8 vs. -1.5±1.5bursts/100hb/mmHg) were decreased following cannabis inhalation (all P <0.01). The rise in cardiac output was negatively associated with the reduction in MSNA burst frequency (r 2 =0.40; P <0.01). Conclusions: These data demonstrate that MSNA is reduced following acute cannabis inhalation in humans and is mediated, in part, through a baroreflex mechanism.

PSUN369 Glucagonoma-Associated Dilated Cardiomyopathy in a Young Female: A Case Report

Abstract Background Dilated cardiomyopathy has been reported in patients with glucagonoma. Since glucagon increases myocardial cAMP levels independent of beta adrenoreceptor blockade, thereby increasing heart rate and cardiac output, chronic excessive glucagon stimulation of the heart may lead to cardiomyopathy (Chang-Chretien, 2004). Clinical Case A 26 year old female presented with a 2-year history of palpable epigastric mass, vomiting and weight loss. Abdominal CT showed a heterogeneously enhancing, lobulated pancreatic head-body mass measuring 6.7×6.1×9.9 cm and a hypo-enhancing nodule in hepatic segment IVb, worrisome for metastasis. Endoscopy-guided FNAB of the pancreatic mass revealed a well-differentiated pNET, Grade 3. Chromogranin and synaptophysin stains were positive, Ki-67 index was 33.6%. She was lost to follow-up. After 4 months, she was admitted due to 1 week history of increased vomiting episodes up to 10x daily and abdominal discomfort with 2 day history of incomprehensible speech and right-sided weakness. On examination, she was weak-looking, tachycardic (114 bpm), underweight (BMI 17.45 kg/m2) and with palpable, hard, non-tender epigastric mass measuring 10×7 cm. She also had hyperpigmented patches on both legs initially manifesting as intermittent oozing excoriations over the past 2 years. Cranial MRI revealed subacute CVD infarct. Anticoagulation was given. On the second day, she started having diarrheal episodes. Supportive management was given. Serum glucagon was markedly elevated (>25,000 pg/mL, normal <80). Serum PP (6562 pg/mL, normal <228) and gastrin (621 pg/mL, normal 13-115) were elevated. Serum VIP (<50 pg/mL, normal <75) was normal. Further investigations showed prediabetes (FBS 112 mg/dL, HbA1c 5.7%) and normocytic, normochromic anemia. Screening for MEN1 was unremarkable. On the third day, she had progression of slurred speech and right-sided weakness. Cranial MRI revealed acute lacunar infarcts. As part of hypercoagulability workup, 2D-Echocardiogram showed depressed ejection fraction (20.9%), dilated LV with normal relative wall thickness, and global hypokinesia of the LV wall, confirming dilated cardiomyopathy. Carotid and Venous Duplex scans were normal. Anti-heart failure regimen was initiated. Due to her current neurologic, cardiac and metabolic conditions, she cannot proceed with surgery and chemotherapy. She was given octreotide injection 30 mg every 4 weeks for 3 doses. Post-treatment, repeat abdominal CT and 2D-Echocardiogram showed no significant change. In the meantime, she had improved appetite and no recurrence of vomiting nor diarrhea. She denies palpitations and can better tolerate walking and climbing stairs. Conclusion We reported a rare case of glucagonoma in a young female with documented constellation of symptoms and complications associated with the syndrome, prominently including dilated cardiomyopathy. It is therefore recommended that cardiovascular evaluation should be initiated at the time of glucagonoma diagnosis for timely and appropriate management. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Cardiac pacemaker channel (HCN4) inhibition and atrial arrhythmogenesis after releasing cardiac sympathetic activation

Clinical trials and studies with ivabradine implicate cardiac pacemaker channels (HCN4) in the pathogenesis of atrial arrhythmias. Because acute changes in cardiac autonomic tone predispose to atrial arrhythmias, we studied humans in whom profound cardiac sympathetic activation was rapidly relieved to test influences of HCN4 inhibition with ivabradine on atrial arrhythmias. We tested 19 healthy participants with ivabradine, metoprolol, or placebo in a double blind, randomized, cross-over fashion on top of selective norepinephrine reuptake inhibition with reboxetine. Subjects underwent combined head up tilt plus lower body negative pressure testing followed by rapid return to the supine position. In the current secondary analysis with predefined endpoints before data unblinding, continuous finger blood pressure and ECG recordings were analyzed by two experienced cardiac electrophysiologists and a physician, blinded for treatment assignment. The total atrial premature activity (referred to as atrial events) at baseline did not differ between treatments. After backwards tilting, atrial events were significantly higher with ivabradine compared with metoprolol or with placebo. Unlike beta-adrenoreceptor blockade, HCN4 inhibition while lowering heart rate does not protect from atrial arrhythmias under conditions of experimental cardiac sympathetic activation. The model in addition to providing insight in the role of HCN4 in human atrial arrhythmogenesis may have utility in gauging potential atrial pro-arrhythmic drug properties.

Beta-adrenoreceptor blockade abolishes atomoxetine-induced risk taking

RationaleClinical studies have shown that patients with exaggerated risk-taking tendencies have high baseline levels of norepinephrine. In this work, we systemically manipulated norepinephrine levels in rats and studied their behavioral changes in a probabilistic discounting task, which is a paradigm for gauging risk taking. MethodsThis study aims to explore the effects of the selective norepinephrine reuptake inhibitor (atomoxetine at doses of 0.6, 1.0 and 1.8mg/kg), and receptor selective antagonists (propranolol at a single dose of 1.0/kg, and prazosin at a single dose of 0.1mg/kg), on risk taking using a probabilistic discounting task. In this task, there were two levers available to rats: pressing the ‘small/certain’ lever guaranteed a single food pellet, and pressing the ‘large/risky’ lever yielded either four pellets or none. The probability of receiving four food pellets decreased across the four experimental blocks from 100% to 12.5%. ResultsAtomoxetine increased the tendency to choose the large/risky lever. It significantly reduced the lose-shift effect (i.e. pressing a different lever after losing a trial), but did not affect the win-stay effect (i.e. pressing the same lever after winning a trial). Furthermore, co-administration of beta-adrenoreceptor antagonist, propranolol, eliminated the effects of atomoxetine on risk taking and the lose-shift effect; but co-administration of alpha1-adrenoreceptor antagonist, prazosin, did not. ConclusionsAtomoxetine boosted NE levels and increased risk taking. This was because atomoxetine decreased rats' sensitivity to losses. These effects were likely mediated by beta-adrenoreceptor.

Treatment of hypertension in peripheral arterial disease

Peripheral arterial disease (PAD) causes considerable morbidity and mortality. Hypertension is a risk factor for PAD. Treatment for hypertension must be compatible with the symptoms of PAD. Controversy regarding the effects of beta-adrenoreceptor blockade for hypertension in patients with PAD has led many physicians to stop prescribing beta-adrenoreceptor blockers. Little is known about the effects of other classes of anti-hypertensive drugs in the presence of PAD. This is the second update of a Cochrane review first published in 2003. To determine the effects of anti-hypertensive drugs in patients with both raised blood pressure and symptomatic PAD in terms of the rate of cardiovascular events and death, symptoms of claudication and critical leg ischaemia, and progression of atherosclerotic PAD as measured by ankle brachial index (ABI) changes and the need for revascularisation (reconstructive surgery or angioplasty) or amputation. For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Cochrane Peripheral Vascular Diseases Group Specialised Register (last searched March 2013) and CENTRAL (2013, Issue 2). Randomised controlled trials (RCTs) of at least one anti-hypertensive treatment against placebo or two anti-hypertensive medications against each other, with interventions lasting at least one month. Trials had to include patients with symptomatic PAD. Data were extracted by one author (DAL) and checked by the other (GYHL). Potentially eligible studies were excluded when the results presentation prevented adequate extraction of data and enquiries to authors did not yield raw data. Eight RCTs were included with a total of 3610 PAD patients. Four studies compared a recognised class of anti-hypertensive treatment with placebo and four studies compared two anti-hypertensive treatments with each other. Studies were not pooled due to the variation of the comparisons and the outcomes presented. Overall the quality of the available evidence was unclear, primarily as a result of a lack of detail in the study reports on the randomisation and blinding procedures and incomplete outcome data. Two studies compared angiotensin converting enzyme (ACE) inhibitors against placebo. In one study there was a significant reduction in the number of cardiovascular events in patients receiving ramipril (odds ratio (OR) 0.72, 95% confidence interval (CI) 0.58 to 0.91; n = 1725). In the second trial using perindopril (n = 52) there was a marginal increase in claudication distance but no change in ABI and a reduction in maximum walking distance. A trial comparing the calcium antagonist verapamil versus placebo in patients undergoing angioplasty (n = 96) suggested that verapamil reduced restenosis (per cent diameter stenosis (± SD) 48.0% ± 11.5 versus 69.6% ± 12.2; P < 0.01), although this was not reflected in the maintenance of a high ABI (0.76 ± 0.10 versus 0.72 ± 0.08 for verapamil versus placebo). Another study (n = 80) demonstrated no significant difference in arterial intima-media thickness (IMT) in men receiving the thiazide diuretic hydrochlorothiazide (HCTZ) compared to those receiving the alpha-adrenoreceptor blocker doxazosin (-0.12 ± 0.14 mm and -0.08 ± 0.13 mm, respectively; P = 0.66). A study (n = 36) comparing telmisartan to placebo found a significant improvement in maximum walking distance at 12 months with telmisartan (median (interquartile range (IQR)) 191 m (157 to 226) versus 103 m (76 to 164); P < 0.001) but no differences in ABI (median (IQR) 0.60 (0.60 to 0.77) versus 0.52 (0.48 to 0.67)) or arterial IMT (median (IQR) 0.08 cm (0.07 to 0.09) versus 0.09 cm (0.08 to 0.10)). Two studies compared the beta-adrenoreceptor blocker nebivolol with either the thiazide diuretic HCTZ or with metoprolol. Both studies found no significant differences in intermittent or absolute claudication distance, ABI, or all-cause mortality between the anti-hypertensives. A subgroup analysis of PAD patients (n = 2699) in a study which compared a calcium antagonist-based strategy (verapamil slow release (SR) ± trandolapril) to a beta-adrenoreceptor blocker-based strategy (atenolol ± hydrochlorothiazide) found no significant differences in the composite endpoints of death, non-fatal myocardial infarction or non-fatal stroke with or without revascularisation (OR 0.90, 95% CI 0.76 to 1.07 and OR 0.96, 95% CI 0.82 to 1.13, respectively). Evidence on the use of various anti-hypertensive drugs in people with PAD is poor so that it is unknown whether significant benefits or risks accrue. However, lack of data specifically examining outcomes in PAD patients should not detract from the overwhelming evidence on the benefit of treating hypertension and lowering blood pressure.

A validated, rapid UPLC–MS/MS method for simultaneous ivabradine, reboxetine, and metoprolol analysis in human plasma and its application to clinical trial samples

A recent clinical trial assessing human autonomic cardiovascular regulation applied pacemaker channel inhibition with ivabradine, norepinephrine transporter blockade with reboxetine, and beta-adrenoreceptor blockade with metoprolol. To verify patient adherence, we developed and validated a fast UPLC-MS/MS assay measuring all three compounds simultaneously. Deuterium-labeled drugs, d3-ivabradine, d5-reboxetine and d7-metoprolol, served as internal standards. Sample preparation of 200μL human plasma consisted of a single liquid-liquid extraction step by means of ethyl acetate. Chromatographic separation was performed on a 50-mm long BEH C18 column with gradient elution using a mixture of water and methanol each containing 2mM ammonium acetate over 4.5min. The mass spectrometer was operated in the positive electrospray ionization (ESI+) mode. Characteristic product ions resulting from collision-induced dissociation of unlabeled and deuterium-labeled drugs with argon were used for quantification in the selected-reaction monitoring mode. We validated the method according to the European Medicines Agency (EMA) guideline on bioanalytical method validation over the range from 1ng/mL to 500ng/mL for all three analytes. Linear responses with correlation coefficients>0.99 over that range were acquired. The LOQ value was 1ng/mL for each drug. Regulatory criteria for accuracy (80-120%) and precision (RSD<15%) were met for all drugs. The internal standard-normalized matrix factor was close to 1 for low and high analyte concentrations. We successfully measured ivabradine, reboxetine, and metoprolol concentrations in 107 human plasma samples from a clinical trial. Quality control samples processed in parallel confirmed the method's reliability in a clinical setting.

Role of the Adrenergic System in a Mouse Model of Oxygen-induced Retinopathy: Antiangiogenic Effects of Beta-adrenoreceptor Blockade

Role of the Adrenergic System in a Mouse Model of Oxygen-induced Retinopathy: Antiangiogenic Effects of Beta-adrenoreceptor Blockade, by Ristori C, Filippi L, Dal Monte M, et al. Invest Ophthalmol Vis Sci. 2011;52(1):155–70

Значення адрено- і холіноблокаторів у забезпеченні автономного балансу серцевого ритму за різних типів погоди

In the experiments of 4.5-5 months old rats, we studied the influences of adrenal and cholinoblockators on the autonomic balance of cardiac rhythm during the I, II and III types of weather. Blockade of beta-adrenoreceptors and M-cholinoreceptors was evoked by anapriline (1.5 mg/kg) and atropine sulfate (1.0 mg/kg), respectively. Electrocardiograms for further analysis were registered in control and 30 minutes after injections of the blockers. It was shown that male rats have the highest activity of sympathetic nervous system under weather type I. High reactivity of beta-adrenoreceptors was determined under all weather types in males and females. In males, atropine blocks the autonomic M-cholinoreceptors under weather types II and III, while in females this effect is detected under all weather types. Furthermore, in males we detected a compensatory increase of sympathetic nervous system during all weather types, while in females such an increase was detected during weather types I and II. Collectively, we determined sex differences in adaptation to weather type changes which are connected to different reactivity of adreno- and cholinoreceptors.

Study protocol: safety and efficacy of propranolol in newborns with Retinopathy of Prematurity (PROP-ROP): ISRCTN18523491

BackgroundDespite new therapeutic approaches have improved the prognosis of newborns with retinopathy of prematurity (ROP), an unfavourable structural and functional outcome still remains high. There is high pressure to develop new drugs to prevent and treat ROP. There is increasing enthusiasm for anti-VEGF drugs, but angiogenic inhibitors selective for abnormal blood vessels would be considered as an optimal treatment.In an animal experimental model of proliferative retinopathy, we have recently demonstrated that the pharmacological blockade of beta-adrenoreceptors improves retinal neovascularization and blood retinal barrier breakdown consequent to hypoxia. The purpose of this study is to evaluate the propranolol administration in preterm newborns suffering from a precocious phase of ROP in terms of safety and efficacy in counteracting the progression of retinopathy.Methods/DesignPreterm newborns (gestational age at birth lower than 32 weeks) with stage 2 ROP (zone II-III without plus) will be randomized, according to their gestational age, to receive propranolol added to standard treatment (treatment adopted by the ETROP Cooperative Group) or standard treatment alone. Propranolol will be administered until retinal vascularization will be completely developed, but not more than 90 days. Forty-four participants will be recruited into the study. To evaluate the safety of propranolol administration, cardiac and respiratory parameters will be continuously monitored. Blood samplings will be performed to check renal, liver and metabolic balance. To evaluate the efficacy of propranolol, the progression of the disease, the number of laser treatments or vitrectomies, the incidence of retinal detachment or blindness, will be evaluated by serial ophthalmologic examinations. Visual function will be evaluated by means of behavioural standardized tests.DiscussionThis pilot study is the first research that explores the possible therapeutic role of beta blockers in ROP. The objective of this research is highly ambitious: to find a treatment simple, inexpensive, well tolerated and with few adverse effects, able to counteract one of the major complications of the prematurity. Any favourable results of this research could open new perspectives and original scenarios about the treatment or the prevention of this and other proliferative retinopathies.Trial RegistrationCurrent Controlled Trials ISRCTN18523491; ClinicalTrials.gov Identifier NCT01079715; EudraCT Number 2010-018737-21

Beta-Adrenoreceptor Modulation of Metabolic, Endocrine and Immunologic Function During Critical Illness

Acute critical illness is characterized by a hypermetabolic and catabolic response where profound endocrine, metabolic and immunologic changes are initiated and sustained through the activation, in part, of beta-adrenergic receptors. The modulation of beta-adrenergic receptor mediated endocrine, immunological and metabolic control may be beneficial in sepsis through a number of mechanisms. However, the complex interaction between beta-adrenoreceptor-mediated, apparently disparate systems may confer both positive and negative clinical outcomes. Chronic cardiac failure and sepsis/critical illness share several similar endocrine, immunologic and metabolic pathological features. Beneficial beta-adrenergic modulation of various pathophysiological changes has been demonstrated in both experimental and clinical heart failure. Investigations in critical illness rarely take into account the role of beta-adrenoreceptor stimulation in patients with such co-morbidities, who are among the most vulnerable to sepsis. Despite similar phenotypes and possibly common mechanisms, few clinical studies have explored whether beta-adrenoreceptor modulation may confer outcome benefit during critical illness. Recent experimental and observational clinical data illustrate that carefully monitored, patient/subject-specific beta-adrenoreceptor modulation may provide a useful intervention to ameliorate the detrimental effects of hyperacute and/or prolonged beta-adrenergic receptor stimulation. Most notably, human studies demonstrate that (non-specific) beta-adrenoreceptor blockade does not increase inflammation, sepsis, or infectious episodes. Furthermore, hemodynamically tailored beta-1 adrenoreceptor antagonism improves outcome in experimental sepsis through novel cardiac and non-cardiac mechanisms. Understanding the dynamic complexity of beta-adrenergic physiology during critical illness offers further insights into the mechanisms underlying maladaptive metabolic and immunologic changes and potentially novel therapeutic interventions.

Шляхи впливу таурину на шлункову секрецію

In chronic experiments with dogs with gastric fistulas the influence of amino acid taurine on the gastric secretion was investigated. We showed that taurine did not cause acid gastric secretion out of digestion, but increased the gastric secretion stimulated by histamine, increased the contents of gastric acid and pepsine in gastric secretes. When administered either 15 minutes or two hours prior histamine injection, taurine affected the Na+ and K+ concentrations in gastric juice. The greatest changes in the basic indices of gastric secretion were observed 14 hours after administration of taurine. In these experiments the contents of total proteins and components of adenile system in gastric secretes was increased also. Blockade of cholinoreceptors by atropine, benzohexonium and IEM-1678 decreased the effects of taurine on gastric secretion stimulated by histamine. Blockade of a-adrenoreceptors by phentolamine did not prevent the taurine-induced effects on histamine-stimulated gastric secretion. It is established that under conditions of the blockade of beta-adrenoreceptors by obsidane, taurine does not manifest entirely its potentiating influence on the gastric secretion stimulating by histamine. The data obtained indicate that taurine affects gastric secretion stimulated by histamine and realization of this effect occurs through M- and N-cholino- and B-adrenoreceptors.

Differential effects of β‐adrenoreceptor antagonists on central and peripheral blood pressure at rest and during exercise

Differential effects of beta-adrenoreceptor antagonists (beta-ARB) on central and peripheral blood pressure may relate to change in heart rate and/or vasodilator tone and thus be exaggerated during exercise. To examine acute effects of selective and nonselective beta-ARB on central and peripheral blood pressure, cardiac output and peripheral vascular resistance during exercise. Healthy volunteers (n= 20, 18 men, 19-54 years) received propranolol 80 mg, bisoprolol 20 mg, and placebo 1 h before bicycle ergometry (50, 75 and 100 W each for 3 min) in a randomized, cross-over study. Cardiac output was determined by pulmonary uptake of soluble and inert gas tracers (InnoCor, Innovision). Central systolic blood pressure (SBP) was determined from the late systolic shoulder of the digital artery pressure waveform (Finometer, Finopres). At rest, both beta-ARB reduced brachial but not central SBP (compared with placebo). During exercise, beta-ARB reduced brachial SBP (reductions of 19.9 +/- 4.3 mmHg and 23.2 +/- 2.7 mmHg for propranolol and bisoprolol, respectively, at 100 W, each P < 0.0001) but not central SBP. The difference between peripheral and central SBP was reduced, relative to that during placebo, by 21.5 mmHg (95% confidence interval 8.8, 34.1) and 26.4 mmHg (18.1, 34.8) for propranolol and bisoprolol, respectively, at 100 W (each P < 0.01). There was no significant effect of beta-ARB on diastolic blood pressure or peripheral vascular resistance. Despite reducing brachial blood pressure, acute beta-adrenoreceptor blockade in man at rest and during exercise does not reduce central blood pressure.

Paced Electrogram Fractionation Analysis of Arrhythmogenic Tendency in ΔKPQ Scn5a Mice

Gain-of-function mutations within Scn5a, including the DeltaKPQ 1505-1507 deletion in the inactivation domain compromising myocardial repolarization, are implicated in human long QT 3 syndrome (LQT3), associated with ventricular arrhythmogenesis and sudden death. Patch clamp studies on isolated ventricular Scn5a+/Delta myocytes from DeltaKPQ mice produced by homologous recombination in embryonic stem (ES) cells confirmed such altered electrophysiological properties of the mutant channel. Programmed electrical stimulation (PES) with decremental pacing from the basal right ventricular epicardial surface and paced electrogram fractionation analysis (PEFA) of electrograms recorded from the basal left ventricular epicardial surface of Langendorff-perfused whole heart preparations demonstrated ventricular tachycardia (VT) in 8 of 9 Scn5a+/Delta mutant (but no Scn5a+/+ (wild-type (WT)) controls; n = 17), with increased electrogram durations (EGD) and more dispersed conduction curves. Isoproterenol (100 nM) was without effect on tachycardic Scn5a+/Delta hearts (n = 9) yet propranolol (1 microM) prevented VT in all isoproterenol-infused WT control (n = 4) but no Scn5a+/Delta hearts (n = 4). Furthermore propranolol itself increased EGD and dispersion in Scn5a+/Delta hearts. In contrast, mexiletine (10 microM) suppressed VTs in 4 of 5 Scn5a+/Delta hearts without altering EGD or dispersion. Beta-adrenoreceptor blockade does not confer an antiarrhythmic effect and may even enhance arrhythmogenesis by increasing reentrant substrate in Scn5a+/Delta hearts while mexiletine protects against VT without modifying conduction characteristics. Together these findings permit a scheme where VT in LQT3 is initiated by triggered mechanisms but propagated by reentry.

Controversial Effects of Sibutramine on Autonomic Cardiovascular Regulation

Background: Sibutramine, a serotonin and norepinephrine transporter blocker, is widely used as an adjunctive treatment of obesity. Genetic variability in the norepinephrine transporter gene and selective pharmacological blockade elicit profound changes in cardiovascular regulation, particularly with standing. Whether or not sibutramine elicits a similar response is unknown. Methods: In 11 healthy subjects (7 men, age 27±2 years, BMI 23.1±0.7 kg/m), we compared the effect of 20mg Sibutramine or matching placebo ingested 26h, 14h and 2h before testing. In addition, we tested sibutramine in combination with the beta-1 adrenoreceptor blocker metoprolol. The study was conducted in a randomized, double-blind, crossover fashion. We determined cardiovascular responses to autonomic reflex tests and to a graded head-up tilt test (HUT). Results: While supine, heart rate was 62±2 bpm with sibutramine, 58±2 bpm with placebo and 54±2 bpm with sibutramine and metoprolol. At 75° HUT, heart rate was 97±3 bpm with sibutramine, 85±2 bpm with placebo, and 66±3bpm with sibutramine and metoprolol (p<0.01 sibutramine vs placebo), respectively. Supine systolic arterial pressure was 121±3 mmHg with sibutramine, 113±3 mmHg with placebo and 111±2 mmHg with sibutramine and metoprolol and 120±4 mmHg, 108±3mmHg and 104±3mmHg with sibutramine, placebo and sibutramine with metoprolol at 75° HUT (p<0.01 sibutramine vs placebo). The rate pressure products, a rough estimate of myocarial oxygen consumption, was markedly increased with sibutramine and decreased with sibutramine and metoprolol. Sibutramine attenuated the blood pressure response to hand grip and cold pressor testing. Conclusion: In normotensive subjects, sibutramine increases resting blood pressure while attenuating the response to sympathetic stimuli. Sibutramine causes a marked increase in upright heart rate, which can be prevented with beta adrenoreceptor blockade.

Water-induced thermogenesis.

Drinking lots of water is commonly espoused in weight loss regimens and is regarded as healthy; however, few systematic studies address this notion. In 14 healthy, normal-weight subjects (seven men and seven women), we assessed the effect of drinking 500 ml of water on energy expenditure and substrate oxidation rates by using whole-room indirect calorimetry. The effect of water drinking on adipose tissue metabolism was assessed with the microdialysis technique. Drinking 500 ml of water increased metabolic rate by 30%. The increase occurred within 10 min and reached a maximum after 30-40 min. The total thermogenic response was about 100 kJ. About 40% of the thermogenic effect originated from warming the water from 22 to 37 C. In men, lipids mainly fueled the increase in metabolic rate. In contrast, in women carbohydrates were mainly used as the energy source. The increase in energy expenditure with water was diminished with systemic beta-adrenoreceptor blockade. Thus, drinking 2 liters of water per day would augment energy expenditure by approximately 400 kJ. Therefore, the thermogenic effect of water should be considered when estimating energy expenditure, particularly during weight loss programs.

Gender differences in the regulation of amino acid metabolism.

Exercising men, compared with women, have a greater increase in leucine oxidation but not lysine rate of appearance. The cause for this sexual dimorphism is unknown; however, an inhibition of beta-adrenoreceptor activity has previously been shown to mediate amino acid metabolism (Lamont LS, McCullough AJ, and Kalhan SC. Am J Physiol Endocrinol Metab 268: E910-E916, 1995; Lamont LS, Patel DG, and Kalhan SC. J Appl Physiol 67: 221-225, 1989). This study was a gender comparison of leucine and lysine kinetics during a beta-adrenoreceptor blockade (beta1,beta2-blockade) and a placebo control by using a double-blind crossover protocol. Subjects exercised at 50% of their trial-specific maximal O2 consumption (1 h) after 7 days of dietary control. During exercise with beta-blockade, men had an increased nonprotein respiratory exchange ratio (P < 0.001), whereas women had an increased circulation of free fatty acids (P < 0.001). The genders also displayed distinct differences in exercise amino acid kinetics. The men, but not the women, increased leucine oxidation (P < 0.005) and lysine rate of appearance (P < 0.009) when exercising during beta-adrenergic blockade. This study indicates that during beta-blockade, exercising men increase their need for amino acids (and carbohydrate) to fuel energy needs, whereas women increase their mobilization of fat, thereby requiring less alternative fuels such as carbohydrate and amino acids. Gender-specific fuel preferences during exercise are regulated by beta-adrenergic-receptor activity. Substrate availability during exercise appears to modulate the amino acid oxidation differences between genders.

Effects of birth on baroreceptor-mediated changes in heart rate variability in lambs and fetal sheep.

1. In adult unanaesthetized sheep, there is a V-shaped relationship between mean arterial pressure (MAP) and heart rate variability (HRV), measured in both time and frequency domains. In contrast, in fetal sheep, there is only a positive direct relationship between MAP and HRV, which is determined by the cardiac vagus. We postulated that by the time lambs were 8-10 days old, the 'adult like' V-shaped relationship between MAP and HRV would be present and it may appear at or after birth. To test these hypotheses, experiments were performed in six chronically catheterized fetal sheep (aged 132-138 days gestation), 10 newborn sheep (within 10 h of birth) and 10 lambs (aged 8-10 days). The relationships between MAP and HRV (in both time and frequency domains) were studied before and during beta-adrenoreceptor blockade with propranolol and before and during cardiac vagal blockade with atropine. 2. In 8-10-day-old lambs, V-shaped relationships between MAP and HRV (measured in both time and frequency domain) were obtained. The negative limb of this V-shaped relationship between MAP and HRV was present after cardiac vagal blockade. The positive slope of the V was present after beta-adrenoreceptor blockade. 3. In 4-h-old newborn sheep, there was no relationship between MAP and HRV (measured in the time domain), but between 7 and 10 h of age a negative relationship was found during treatment with atropine and a positive relationship was found during beta-adrenoreceptor blockade, when HRV was measured in both time and frequency domains. 4. As described previously, there was only a positive relationship between MAP and HRV in fetal sheep, which was abolished by atropine but not affected by beta-adrenoreceptor blockade. 5. Thus, until relatively late in fetal life, baroreceptor- modulated changes in efferent cardiac sympathetic tone, determined by measuring the effects of autonomic blockade on HRV, could not be elicited, although reflex vagal pathways were active. By 7-10 h after birth, baroreceptor-modulated changes in efferent cardiac sympathetic tone were present. It was possible using measurements of HRV made in the time domain to show that these baroreceptor-modulated cardiac sympathetic effects became stronger over the first 10 days of life (P < 0.01). These studies are the first to show that the influence of baroreceptor-mediated changes in cardiac sympathetic tone on HRV increases in early life. This is probably because maturation of sympathetic innervation of the fetal sheep heart is occurring at this age.

Effect of cold on fetal heart rate and its variability.

1. The effects of cold saline (25 mL) injected over the fetal skin on fetal heart rate (HR) and HR variability (HRV), measured as the coefficient of variation (CV) in pulse interval (PI) and by power spectral analysis (PSA), were measured in 10 chronically catheterized fetal sheep aged 140-144 days. To determine the extent to which effects on HR and HRV were mediated by the sympathoadrenal neuroendocrine axis and the cardiac vagus, experiments were performed before and after beta-adrenoreceptor blockade with propranolol (n = 12 fetuses) or before and after cardiac vagal blockade with atropine (n = 4 fetuses). 2. Injection of ice-cold saline over the skin caused an immediate rise in mean arterial pressure (MAP) from 46+/-1 to 55+/-1 mmHg (P < 0.001) and HR from 156+/-2 to 182+/-2 b.p.m. (P < 0.001). Heart rate variability, measured as CV of PI, rose from 3.5+/-0.2 to 8.0+/-0.2% (P < 0.001) and total power spectral density (PSD) increased from 78+/-6 to 278+/-16 units (P < 0.001) as measured by PSA. Within 100s, MAP, HR and HRV had returned to baseline. 3. Beta-adrenoreceptor blockade abolished all these changes in HR, HRV and PSD, but had no effect on changes in MAP. Atropine had no demonstrable effect on the responses to cold. 4. Therefore, the increase in fetal MAP, HR and HRV that occurred with stimulation of peripheral thermoreceptors was the result of increased activity of the sympathetic nervous system. Alterations in efferent cardiac vagal tone were not involved in the cardiac response to cold.

Subtype specific downregulation of thyroid hormone receptor mRNA by beta-adrenoreceptor blockade in the myocardium.

The beta-adrenergic system is very important in cardiovascular medicine. Thyroid hormone (T3) affects beta-adrenergic receptors. In cell culture, isoproterenol, a beta-adrenergic agonist, has been shown to upregulate thyroid hormone receptor (TR) mRNA, thus indicating a bi-directional regulation. The aim of this study was to evaluate if beta-adrenoreceptor blockade may affect subtype TR mRNA expression in vivo. Propranolol or vehicle was delivered by implanting an Alzet osmotic pump subcutaneously in mice for 14d. The concentration of TRalpha1, alpha2, beta1 and beta2 subtype mRNA concentrations were quantified by reverse transcription-polymerase chain reaction and ELISA. Propranolol downregulated the levels of TRalpha1 by 44% (p < 0.0005) and beta1 mRNA by 39% (p < 0.0005) in mouse heart, in comparison to the control, while no difference in the TRalpha2 or beta2 mRNA levels occurred. The heart rate was reduced by 10% (p < 0.05) in the propranolol group, whereas no reduction was detected in the control group. In mouse treated with propranolol serum, T3 levels were 21% lower, (p < 0.05) while serum T4 levels were 23% higher (p < 0.05) in comparison to the control. This is the first study suggesting that a beta-adrenoreceptor blockade subtype selectively regulates TR mRNA subtypes, thus giving us further knowledge about the interaction between the beta-adrenergic system and the thyroid hormone sytem.