Antiadrenergic Effects Research Articles

Atypical Antiadrenergic Effect of Refralon as a Mechanism of High Antiarrhythmic Effectiveness.

We studied the effect of Refralon on the electrophysiological properties of the supraventricular myocardium against the background of adrenergic (epinephrine) influence in the zone of the pulmonary veins, the area where 50-90% of atrial arrhythmias is triggered. The experiments were carried out on isolated tissue preparations of Wistar rats. The multichannel microelectrode array technique was used to record action potentials simultaneously in the atrium and in the ostium and distal parts of the pulmonary veins. Epinephrine application (12-50 nM) led to depolarization of the resting potential and the conduction block in the distal part of the pulmonary veins. Refralon (30 μg/kg) restored the resting potential in the distal part of the pulmonary veins. Against the background of epinephrine, Refralon did not significantly change the duration of the action potential at 90% repolarization in comparison with control. At the same time, the comparison drug E-4031 against the background of epinephrine significantly increased the duration of action potential in the atrium and in the ostium of the pulmonary veins, and sotalol increased it only in the ostium. Neither E-4031, nor sotalol restored conduction in their distal part. Refralon has a biphasic effect under conditions of adrenergic stimulation: the fast component is responsible for stabilizing the resting potential in the pulmonary vein and reduces the dispersion of action potential duration in the atrium and pulmonary vein and is also quickly washed away, and the slow component is responsible for the increase of the action potential duration and is slowly washed away.

Vagus nerve stimulation: Potential for treating chronic wounds.

Vagus nerve stimulation (VNS) has been approved as a treatment for various conditions, including drug-resistant epilepsy, migraines, chronic cluster headaches and treatment-resistant depression. It is known to have anti-inflammatory, anti-nociceptive and anti-adrenergic effects, and its therapeutic potential for diverse pathologies is being investigated. VNS can be achieved through invasive (iVNS) or non-invasive (niVNS) means, targeting different branches of the vagus nerve. iVNS devices require surgical implantation and have associated risks, while niVNS devices are generally better tolerated and have a better safety profile. Studies have shown that both iVNS and niVNS can reduce inflammation and pain perception in patients with acute and chronic conditions. VNS devices, such as the VNS Therapy System and MicroTransponder Vivistim, have received Food and Drug Administration approval for specific indications. Other niVNS devices, like NEMOS and gammaCore, have shown effectiveness in managing epilepsy, pain and migraines. VNS has also demonstrated potential in autoimmune disorders, such as rheumatoid arthritis and Crohn's disease, as well as neurological disorders like epilepsy and migraines. In addition, VNS has been explored in cardiovascular disorders, including post-operative atrial fibrillation and myocardial ischemia-reperfusion injury, and has shown positive outcomes. The mechanisms behind VNS's effects include the cholinergic anti-inflammatory pathway, modulation of cytokines and activation of specialised pro-resolving mediators. The modulation of inflammation by VNS presents a promising avenue for investigating its potential to improve the healing of chronic wounds. However, more research is needed to understand the specific mechanisms and optimise the use of VNS in wound healing. Ongoing clinical trials may support the use of this modality as an adjunct to improve healing.

The Utility of Surgical Cardiac Sympathetic Denervation in the Management of Ventricular Arrhythmias for all Etiologies: A Systematic Review

Background: The antiadrenergic and antifibrillatory effects of cardiac sympathectomy in pathological states such as long QT syndrome are well established. The indications for the procedure have expanded since the videoassisted thoracoscopic approach was first used. However, the procedure is currently largely used in cases where medication has failed to prevent recurrence of symptomatic ventricular arrhythmia, or in cases of medication intolerance, and large randomised controlled trials are thus non-existent in the literature. The aim of this study was to perform a systematic review of the available literature to examine the utility of cardiac denervation in the management of all ventricular arrhythmias. Methods: A total of 17 studies published between 2009 and 2019 were evaluated for bias using the Risk of Bias in Non-Randomised Studies of Interventions (ROBINS-I) tool. In addition the Harbour and Miller Grading System (2001) was used to assess the significance of the evidence in this review. Results: All studies demonstrated a protective effect of sympathectomy against ventricular arrhythmias in both primary and secondary prevention strategies. The following risk of bias was observed: low in 5 studies, moderate in 8 studies, and serious risk in 4 studies. The highest level of evidence observed was 2++ in 3 studies. Conclusion: Cardiac sympathetic denervation provides benefit for patients with ventricular arrhythmias, in cases of refractory disease or in patients who require a primary prevention strategy where first-line therapies are not tolerated.

An Overview of the Potential Effects of Melatonin Supplementation on Athletic Performance

Context: Melatonin is a hormone synthesized principally in the pineal gland that has been classically associated with endocrine actions. Exogenous melatonin is often used to treat insomnia and enhance sleep quality in a range of situations, including jet lag. However, the benefit and safety profile of daytime melatonin dosing prior to exercise are unknown and warrant additional exploration. Objectives: We aimed to give (i) a brief overview of the beneficial effects of exogenous melatonin administration on sports performance and (ii) some recommendations for acute use of melatonin with a special focus on humans’ physical activity and athletic performance. Evidence Acquisition: To ascertain the effect of exogenous melatonin administration on humans, a systematic search of the literature was undertaken using PubMed, ScienceDirect, Medline, Google Scholar, and Scopus. Numerous studies in animals have demonstrated the positive impact of melatonin treatment during physical exercise. However, uncertainty remains regarding exogenous melatonin administration on human’s physical performance. Therefore, the present review focuses almost entirely on data obtained from humans. Results: The gathered data indicate that consuming melatonin at night improves sleep quality. In terms of physical activity and sports performance, previous research has demonstrated that melatonin administration has a good effect on decreasing oxidative stress and inflammation induced by exercise. However, in some specific situations, the daily administration of melatonin may have an unfavourable influence on performance during acute and strenuous exercise. Conclusions: Exogenous melatonin administration prior to exercise shows significant chronobiotic, antioxidant, antiadrenergic, and hypothermic effects and may represent a fascinating potential weight loss method. However, consuming a high amount of melatonin (6 mg) 50 minutes prior to commencing exercise is not recommended as it may interfere with the physiological reactions to physical activity. Melatonin-related adverse effects were mainly transient and were associated with daytime doses. Melatonin should therefore be consumed at night whenever possible.

Management of Psychiatric Disorders in Patients with Respiratory Diseases.

Management of Psychiatric Disorders in Patients with Respiratory Diseases.

Effect of intraoperative use of dexmedetomidine on post-operative analgesia in patients undergoing elective spine surgery under general anaesthesia

Background: Dexmedetomidine is an alpha2 agonist which shows sedative, analgesic and anti-adrenergic effects and is useful as an adjuvant agent in general anaesthesia (GA) in major surgeries.
 Aims and Objectives: In this study, we evaluated the analgesic efficacy of intra-operative infusion of dexmedetomidine in alleviating post-operative pain in elective spine surgery using multiple efficacy parameters.
 Materials and Methods: Patients (n=60) scheduled to undergo elective spine surgery under GA were randomised to receive either dexmedetomidine (treatment arm) or normal saline (control arm) in the intra-operative period. The analgesic efficacy of the drug in the post-operative period was assessed using- the time to first rescue analgesic, total requirement of analgesic, Visual Analog Scale (VAS) score and the number of back-up analgesic required.
 Results: There was no statistically significant difference in the baseline clinical and demographic characteristics between the two groups. The time to first rescue analgesic, total requirement of analgesic, Visual Analog Scale (VAS) score and the number of back-up analgesic required, were all statistically significant in favour of the treatment arm (P<0.001).
 Conclusion: Dexmedetomidine provides effective postoperative analgesia and reduces tramadol requirements in elective spine surgery performed under general anaesthesia.

A triple blind, randomised, placebo controlled, add-on trial to assess the efficacy and safety of dexmedetomidine in facilitation of general anaesthesia in patients undergoing elective spine surgery

Background: Dexmedetomidine is a centrally acting sympatholytic drug acting as an agonist on alpha2 receptors. Of late, the drug has become popular in anaesthesia because of its sedative, analgesic and anti-adrenergic effects.
 Aims and Objectives: We conducted a single centre, randomised, placebo controlled, triple blinded add-on trial to assess the efficacy and safety of the drug as an adjuvant in general anaesthesia (GA) during elective spine surgery.
 Materials and Methods: Anaesthesia was induced and maintained using standard method in all the patients (N=60). Concomitantly, patients in the treatment arm (n=30) and control arm (n=30) were infused with dexmedetomidine and normal saline respectively. The anaesthetic sparing effect, hemodynamic stability, and adverse events of dexmedetomidine were assessed using pre-defined outcome parameters.
 Results: Anaesthetic Sparing Effect: Dexmedetomidine produced statistically significant reduction in the requirement of propofol and fentanyl during GA (p<0.001). There was no significant difference in requirement of rocuronium (p=0.25). Hemodynamic Stability: The cardiovascular stimulation during surgery, in general, and during stress of artificial endotracheal access, in particular, were attenuated in the treatment arm. The heart rate (HR) and mean arterial pressure (MAP), in the control and treatment arm became greater and lesser than the baseline value respectively, at all the time points following induction. The HR and MAP remained close to baseline values during intubation and extubation in the treatment arm but surged significantly in the control arm (p<0.001). Adverse Events: The number of episodes of hypotension, hypertension and bradycardia in the control arm was 1, 18 and 1 respectively. In the treatment arm, 2 episode each of hypotension and bradycardia and none of hypertension occurred.
 Conclusion: Dexmedetomidine, which is being increasingly used as an adjuvant in GA in various types of surgeries, also plays an auxiliary role in facilitation of GA in spine surgery. It decreases requirement of the primary anaesthetic agents, and also mitigates intra-operative cardiovascular instability without causing any significant adverse effect.

An Overview of the Potential Effects of Melatonin Supplementation on Athletic Performance

Context: Melatonin is a hormone synthesized principally in the pineal gland that has been classically associated with endocrine actions. Exogenous melatonin is often used to treat insomnia and enhance sleep quality in a range of situations, including jet lag. However, the benefit and safety profile of daytime melatonin dosing prior to exercise are unknown and warrant additional exploration. Objectives: We aimed to give (i) a brief overview of the beneficial effects of exogenous melatonin administration on sports performance and (ii) some recommendations for acute use of melatonin with a special focus on humans’ physical activity and athletic performance. Evidence Acquisition: To ascertain the effect of exogenous melatonin administration on humans, a systematic search of the literature was undertaken using PubMed, ScienceDirect, Medline, Google Scholar, and Scopus. Numerous studies in animals have demonstrated the positive impact of melatonin treatment during physical exercise. However, uncertainty remains regarding exogenous melatonin administration on human’s physical performance. Therefore, the present review focuses almost entirely on data obtained from humans. Results: The gathered data indicate that consuming melatonin at night improves sleep quality. In terms of physical activity and sports performance, previous research has demonstrated that melatonin administration has a good effect on decreasing oxidative stress and inflammation induced by exercise. However, in some specific situations, the daily administration of melatonin may have an unfavourable influence on performance during acute and strenuous exercise. Conclusions: Exogenous melatonin administration prior to exercise shows significant chronobiotic, antioxidant, antiadrenergic, and hypothermic effects and may represent a fascinating potential weight loss method. However, consuming a high amount of melatonin (6 mg) 50 minutes prior to commencing exercise is not recommended as it may interfere with the physiological reactions to physical activity. Melatonin-related adverse effects were mainly transient and were associated with daytime doses. Melatonin should therefore be consumed at night whenever possible.

Application of electro reflexotherapy in bronchopneumonia of calves against background of necrobacteriosis management

One of the main reasons for the high incidence of young cattle of bronchopneumonia is the low level of the immunological response due to the imperfect immune system of the young organism, as well as the ill-being of livestock farming with one or a number of diseases caused by pathogens related to opportunistic and/or stationary microflora. To obtain a positive result of the treatment of bronchopneumonia, it is necessary to provide the first line of nonspecific protection of the calves’ body, as well as reducing the effects of the infectious and inflammatory stressor on the sick organism. The object of the study was young cattle with florid clinical signs of catarrhal bronchopneumonia. Three groups were formed from the selected calves: control and two experienced. In the control, a generally accepted treatment regimen for bronchopneumonia was used, and in the experiment, electroreflexotherapy was additionally used. Combination treatment of catarrhal bronchopneumonia of calves with the use of electroreflexotherapy contributes to: activation of the inflammatory process, stimulation of specific and non-specific immunobiological surveillance, providing direct and indirect bacteriostatic and bactericidal effects and has some antiadrenergic effect.

Relaxant and antiadrenergic effects of ranolazine in human saphenous vein.

Ranolazine improves vascular function in animal models. We evaluate the effects of ranolazine on vascular function and adrenergic response in human saphenous vein. Rings from 53 patients undergoing coronary artery bypass grafting were mounted in organ baths. Concentration-response curves to ranolazine were constructed in rings precontracted with phenylephrine, endothelin-1, vasopressin, KCl and the thromboxane A2 analogue U-46619. In rings precontracted with phenylephrine, relaxation to ranolazine was tested in the absence and presence of endothelial factors inhibitors, K+ channel blockers and verapamil. The effects of ranolazine on frequency-response and concentration-response curves to phenylephrine were performed in the absence and presence of endothelial factors inhibitors and K+ channel blockers. Endothelial nitric oxide synthase, α1 adrenergic receptor and large conductance Ca2+-activated K+ channel protein expressions were measured by Western blotting. Ranolazine (10-9-10-4 M) produced a concentration-dependent relaxation only in rings precontracted with phenylephrine that was reduced by endothelial denudation, NG-nitro-l-arginine methyl ester (10-4 M), charybdotoxin (10-7 M) and verapamil (10-6 M). Ranolazine diminished adrenergic contractions induced by electrical field stimulation (2-4 Hz) and phenylephrine (10-9-10-5 M) that were prevented by tetraethylammonium (10-3 M) and charybdotoxin (10-7 M). Ranolazine significantly decreased α1 adrenergic receptor and increased large conductance Ca2+-activated K+ channel protein expression in the saphenous vein. Ranolazine diminishes the adrenergic vasoconstriction, acting as α1 antagonist, and by increasing large conductance Ca2+-activated K+ channel involvement. The relaxant effects of ranolazine are partially mediated by endothelial nitric oxide, large conductance Ca2+-activated K+ channels and the blockade of voltage-dependent Ca2+ channels.

Effect of lidocaine with adrenaline and landiolol on hemodynamics in spontaneously hypertensive rats.

Administration of local anesthetics with adrenaline can cause tachycardia and hypertension. This study assessed whether combined administration of landiolol with adrenaline and lidocaine would induce local anesthesia without causing hemodynamic changes. Normal saline (NS), lidocaine with adrenaline (LA), and lidocaine with adrenaline and landiolol (LLA) were injected into Wistar Kyoto (WKY/Izm) or spontaneously hypertensive (SHR/Izm) rats, followed by measurement of the pulse rate (PR), and the systolic, diastolic and mean blood pressures (SBP, DBP and MBP). In the LLA group, the increase in PR was significantly suppressed in both SHR/Izm and WKY/Izm rats relative to those in the LA group. Although SBP was significantly reduced in WKY/Izm rats given LLA, relative to those given NS or LA, it was elevated in SHR/Izm rats given LLA. Landiolol-induced changes in PR may be due to blockade of adrenaline-induced β1 receptor stimulation, which suppresses cardiac hyperactivity, whereas the early surge of blood pressure in SHR/Izm rats given LLA may be due to the dominant alpha-adrenergic effects of β1 receptor inhibition. The anti-adrenergic effects of LLA were safe and effective in WKY/Izm rats, although the unexpected early hypertensive surge in SHR/Izm rats indicates the need for caution.

Ranolazine may exert its beneficial effects by increasing myocardial adenosine levels.

We hypothesized that ranolazine-induced adenosine release is responsible for its beneficial effects in ischemic heart disease. Sixteen open-chest anesthetized dogs with noncritical coronary stenosis were studied at rest, during dobutamine stress, and during dobutamine stress with ranolazine. Six additional dogs without stenosis were studied only at rest. Regional myocardial function and perfusion were assessed. Coronary venous blood was drawn. Murine endothelial cells and cardiomyocytes were incubated with ranolazine and adenosine metabolic enzyme inhibitors, and adenosine levels were measured. Cardiomyocytes were also exposed to dobutamine and dobutamine with ranolazine. Modeling was employed to determine whether ranolazine can bind to an enzyme that alters adenosine stores. Ranolazine was associated with increased adenosine levels in the absence (21.7 ± 3.0 vs. 9.4 ± 2.1 ng/mL, P < 0.05) and presence of ischemia (43.1 ± 13.2 vs. 23.4 ± 5.3 ng/mL, P < 0.05). Left ventricular end-systolic wall stress decreased (49.85 ± 4.68 vs. 57.42 ± 3.73 dyn/cm2, P < 0.05) and endocardial-to-epicardial myocardial blood flow ratio tended to normalize (0.89 ± 0.08 vs. 0.76 ± 0.10, P = nonsignificant). Adenosine levels increased in cardiac endothelial cells and cardiomyocytes when incubated with ranolazine that was reversed when cytosolic-5'-nucleotidase (cN-II) was inhibited. Point mutation of cN-II aborted an increase in its specific activity by ranolazine. Similarly, adenosine levels did not increase when cardiomyocytes were incubated with dobutamine. Modeling demonstrated plausible binding of ranolazine to cN-II with a docking energy of -11.7 kcal/mol. We conclude that the anti-adrenergic and cardioprotective effects of ranolazine-induced increase in tissue adenosine levels, likely mediated by increasing cN-II activity, may contribute to its beneficial effects in ischemic heart disease.NEW & NOTEWORTHY Ranolazine is a drug used for treatment of angina pectoris in patients with ischemic heart disease. We discovered a novel mechanism by which this drug may exhibit its beneficial effects. It increases coronary venous levels of adenosine both at rest and during dobutamine-induced myocardial ischemia. Ranolazine also increases adenosine levels in endothelial cells and cardiomyocytes in vitro, by principally increasing activity of the enzyme cytosolic-5'-nucleotidase. Adenosine has well-known myocardial protective and anti-adrenergic properties that may explain, in part, ranolazine's beneficial effect in ischemic heart disease.

R-propranolol is a small molecule inhibitor of the SOX18 transcription factor in a rare vascular syndrome and hemangioma.

Propranolol is an approved non-selective β-adrenergic blocker that is first line therapy for infantile hemangioma. Despite the clinical benefit of propranolol therapy in hemangioma, the mechanistic understanding of what drives this outcome is limited. Here, we report successful treatment of pericardial edema with propranolol in a patient with Hypotrichosis-Lymphedema-Telangiectasia and Renal (HLTRS) syndrome, caused by a mutation in SOX18. Using a mouse pre-clinical model of HLTRS, we show that propranolol treatment rescues its corneal neo-vascularisation phenotype. Dissection of the molecular mechanism identified the R(+)-propranolol enantiomer as a small molecule inhibitor of the SOX18 transcription factor, independent of any anti-adrenergic effect. Lastly, in a patient-derived in vitro model of infantile hemangioma and pre-clinical model of HLTRS we demonstrate the therapeutic potential of the R(+) enantiomer. Our work emphasizes the importance of SOX18 etiological role in vascular neoplasms, and suggests R(+)-propranolol repurposing to numerous indications ranging from vascular diseases to metastatic cancer.

Films of bacterial cellulose with lipid nanoparticles of sanguinarine as a basis for creating antimicrobial coating materials

Sanguinarine is a benzophenanthridine alkaloid contained in Chelidonium majus, Macleaya microcarpa, Sanguinaria canadensis etc. Sanguinarine has a broad spectrum of biological activity, including antimicrobial and antifungal, antiinflammatory, antiadrenergic and antitumour effect. Using a modified emulsion method with solvent evaporation, lipid nanoparticles including sanguinarine were obtained, with a size of 182.3±6.7 nm and a zeta potential of -20.6 ± 1.3 mV. The efficiency of the inclusion of sanguinarine in nanoparticles was 72.9 ± 1.5%. The release of the active substance from nanoparticles had prolonged nature (only 18.2% of sanguinarine was released after 4 h of the experiment, and 39.4% after 24 h). Lipid nanoparticles with sanguinarine were able to effectively sorb and gradually release from the matrix of bacterial cellulose produced by the strain Komagataeibacter nataicola BC-B0007. The maximum inclusion of sanguinarine in the composition of nanoparticles in hydrated films of bacterial cellulose was achieved in 3 h and was 848.0 ± 43.2 μg/g. The obtained bacterial cellulose films carrying lipid nanoparticles with sanguinarine were investigated for their ability to exert an antimicrobial effect in vitro. The sanguinarine released from the films effectively suppressed the growth of Gram-negative and Gram-positive bacteria, and also showed fungistatic activity against conditionally pathogenic fungi.

Low and high cardiac FKBP12.6 overexpression are associated with distinct phenotypes

The ryanodine receptors RyR2 have a key role in cardiac excitation-contraction coupling (ECC) and are regulated, among others, by FK506 binding proteins (FKBP). FKBP12 is more abundant than FKBP12.6 in cardiomyocytes with a low affinity for RyR2, whereas FKBP12.6 with stronger affinity is less abundant. In heart failure, FKBP expression decreases and RyR2 are hyperphosphorylated, both mechanisms involved in arrhythmia development. Cardiac FKBP12.6 overexpression protects against arrhythmias due to ß-adrenergic stimulation, but this mechanism is still unknown. Our hypothesis is that FKBP12.6 overexpression, with its stronger affinity for RyR2, displaces FKBP12, therefore reducing RyR2 sensitivity to sympathetic stimulation. To address this issue, we developed 2 transgenic mouse lines with low (TG1) and high (TG2) levels of cardiac-specific FKBP12.6 overexpression. We characterized ECC of both lines in basal conditions and after ß-adrenergic stimulation to confirm the anti-adrenergic effects of FKBP12.6 overexpression in link with the expression levels and the stoichiometry of the 2 FKBP isoforms. ECC was characterized by confocal microscopy and expression levels of both isoforms by Western blot with commercial and homemade antibodies. Our first results showed that TG1 mice had normal cardiac phenotype, whereas TG2 mice exhibited cardiac hypertrophy. In TG1 mice, basal Ca2+ transient (Catr) amplitude was slightly higher than that in wild type mice (WT), while time constant of Catr decay was unchanged, the latter being slower in TG2 mice. When 50 nM isoproterenol was added, the increase of Catr amplitude was smaller in TG1 (31%) than in WT (50%) and TG2 (60%) mice. Similarly, the acceleration of Catr decay was smaller in TG1 than in TG2 mice (−27% vs. −56%, respectively). These preliminary results suggest that low FKBP12.6 overexpression protects partially against sympathetic stimulation, whereas high FKBP12.6 overexpression is associated with cardiomyopathy development.

The cardioprotective effect of rosmarinic acid on acute myocardial infarction and genes involved in Ca2+ homeostasis

Acute myocardial infarction (AMI) is a common cause of hospitalisation and high mortality due to lethal arrhythmias. Sarcoplasmic reticulum Ca2+ ATPase (SERCA2) and ryanodine receptor (RyR2) regulate the cytosolic Ca2+ ion concentration. Rosmarinic acid (RA) is one of the most common caffeic esters in Rosmarinus officinalis. The present study was conducted to test the hypothesis whether RA can protect cardiac function against AMI and arrhythmias induced by isoproterenol through the regulatory effect of SERCA2 and RyR2 gene expression. To this aim, male Sprague–Dawley rats were allocated into in vivo and ex vivo studies and received RA (10, 15, and 30 mg/kg; 14 days). AMI was induced by two consecutive subcutaneous injections of 100 mg/kg isoproterenol. Blood pressure (BP), heart rate, electrocardiography (ECG) parameters, plasma levels of cardiac biomarkers, and antioxidative enzymes were evaluated (in vivo study). Cardiac functions were measured in isolated hearts using Langendorff set up. Gene expressions of SERCA2 and RyR2 were measured in left ventricular heart. Isoproterenol administration showed a significant decline in BP, QRS voltage, activities of antioxidant enzymes, cardiac function, and gene expressions of SERCA2 and RyR2. The results also indicated a significant increase in heart rate, ST-elevation, cardiac biomarkers, and antioxidant enzymes. RA at 30 mg/kg dosage showed the best effect on the improvement of the mentioned factors. This study suggests that RA has potent cardioprotective effects against AMI and arrhythmia, which may be due to its ability to enhance expression of plasma antioxidant enzymes and genes involved in Ca2+ homeostasis SERCA2 and RyR2. The protective role of RA is also possibly related to its antiadrenergic effects.

Use of loop diuretics in heart failure: Current aspects

Loop diuretics take the lead in the treatment of patients with symptomatic heart failure. Torasemide is the most effective and safe loop diuretic with the optimal pharmacokinetic profile, the additional properties associated with simultaneous blockade of the renin-angiotensin-aldosterone system and with the antiadrenergic effects of the drug, its positive impact on myocardial fibrosis and minimal severe potential negative effects. Sustained-release torasemide provides a more comfortable removal of excess liquid and does not deteriorate quality of life.

ALPHA ANTIADRENERGIC EFFECT OF Achyrocline bogotensis EXTRACT (“Vira Vira”) IN ISOLATED RAT AORTIC RING

Background: The treatment of symptoms of prostatic hyperplasia is among the traditional uses of Achyrocline bogotensis (Kunth) [N.V. “Vira Vira”, Compositae] in Colombia. Pharmacological therapy for this disorder depends mainly on alpha-1 antiadrenergic agents, and the mechanism has not been studied previously using A. bogotensis. Objectives: To assess the alpha-1 antiadrenergic effect of the extract obtained from the aerial parts of A. bogotensis in isolated aortic rings from Wistar rats. Methods: The study compared the effects of the ethanol extract of A. bogotensis, prazosin (reference) and DMSO (control) in rings stimulated with phenylephrine (PE) or KCl. The capacity to reduce the PE pressor effect by the ethanol extract (pD2’ value) was determined. To quantify the A. bogotensis relaxant potency, increasing concentrations of the ethanol extract (0.1 µg/mL-0.1 mg/mL), were added cumulatively to isolated aortic rings pre-contracted with PE (0.1 µM) or KCl (80 mM). To explore the possible participation of nitric oxide (NO), L-NAME (100 µM) was administered to aortic rings exposed to cumulatively increasing concentrations of PE in isolated aortic rings in the presence of the extract (10 µg/mL). Aqueous, butanol and dichloromethane fractions (10 µg/mL) obtained from the ethanol extract were assayed. Phytochemical screening was also performed. Results: Prazosin and A. bogotensis extract notably reduced the contraction induced by PE whereas their inhibitory effect in rings contracted with KCl were lower. A. bogotensis ethanol extract showed a high capacity for reducing the PE pressor response (pD´2 : 5.51) as well as total efficacy for relaxing rings previously precontracted with PE. The relaxant efficacy and potency of A. bogotensis extract against rings previously contracted with KCl were notably lower. L-NAME partly reverted the inhibitory effect of A. bogotensis. Aqueous, butanol and dichloromethane fractions gave inhibitory responses lower than that obtained with the ethanol extract. Phytochemical screening of A. bogotensis extract revealed the significant presence of flavonoid and triterpene metabolites. Conclusions: These results suggest that A. bogotensis elicits a smooth muscle relaxant effect related to the alpha-1 antiadrenergic mechanism. This response is partially NO dependent and seems to be due to interactions among active metabolites likely to be of flavonoid and/or terpenoid nature.

Vasostatin-1 Stops Structural Remodeling and Improves Calcium Handling via the eNOS-NO-PKG Pathway in Rat Hearts Subjected to Chronic β-Adrenergic Receptor Activation

Chronically elevated catecholamine levels activate cardiac β-adrenergic receptors, which play a vital role in the pathogenesis of heart failure. Evidence suggests that vasostatin-1 (VS-1) exerts anti-adrenergic effects on isolated and perfused hearts in vitro. Whether VS-1 ameliorates hypertrophy/remodeling by inducing the chronic activation of β-adrenergic receptors is unknown. The present study aims to test the efficacy of using VS-1 to treat the advanced hypertrophy/remodeling that result from chronic β-adrenergic receptor activation and to determine the cellular and molecular mechanisms that underlie this response. Rats were subjected to infusion with either isoprenaline (ISO, 5mg/kg/d), ISO plus VS-1 (30mg/kg/d) or placebo for 2weeks. VS-1 suppressed chamber dilation, myocyte hypertrophy and fibrosis and improved in vivo heart function in the rats subjected to ISO infusion. VS-1 increased phosphorylated nitric oxide synthase levels and induced the activation of protein kinase G. VS-1 also deactivated multiple hypertrophy signaling pathways that were triggered by the chronic activation of β-adrenergic receptors, such as the phosphoinositide-3 kinase (PI3K)/Akt and Ca2+/calmodulin-dependent kinase (CaMK-II) pathways. Myocytes isolated from ISO+VS-1 hearts displayed higher Ca2+ transients, shorter Ca2+ decays, higher sarcoplasmic reticulum Ca2+ levels and higher L-type Ca2+ current densities than the ISO rat hearts. VS-1 treatment restored the protein expression of sarcoplasmic reticulum Ca2+ uptake ATPase, phospholamban and Cav1.2, indicating improved calcium handling. Chronic VS-1 treatment inhibited the progression of hypertrophy, fibrosis, and chamber remodeling, and improved cardiac function in a rat model of ISO infusion. In addition, Ca2+ handling and its molecular modulation were also improved by VS-1. The beneficial effects of VS-1 on cardiac remodeling may be mediated by the enhanced activation of the eNOS-cGMP-PKG pathway.

Experience with bisoprolol in long-QT1 and long-QT2 syndrome.

The protective effect of beta-blockers in patients with inherited Long-QT syndrome is well established. Recent reports have suggested that beta-blockers are not equally effective in Long-QT (LQT). Bisoprolol is an attractive candidate for use in LQT because of its cardioselective properties and favorable side-effect profile. We performed a retrospective cohort study of 114 consecutive patients with gene-positive Long-QT syndrome type 1 (LQT1) or Long-QT syndrome type 2 (LQT2) treated with bisoprolol, nadolol or atenolol with a total of 580 person-years of follow-up. Electrocardiogram (ECG) parameters and cardiac events during follow-up were compared. In addition, exercise treadmill testing was performed in bisoprolol-treated patients. Fifty-nine patients were treated with bisoprolol, 39 with atenolol and 16 with nadolol. Overall, 59% were females and 62% had LQT1. Baseline heart rate and corrected QT (QTc) interval were similar between the groups. QTc shortening was observed in individuals on bisoprolol (ΔQTc -5 ± 31ms; p = 0.049) and nadolol (ΔQTc -13 ± 16ms; p = 0.02) but not on atenolol (ΔQTc +9 ± 24ms; p = 0.16). Median follow-up was similar for bisoprolol and nadolol (3years), but longer for atenolol (6years; p = 0.03); one cardiac event occurred in the bisoprolol group (1.7%) and two events occurred in the atenolol group (5.1%; p = 0.45), whereas none occurred in nadolol-treated patients. Beta-blocker efficacy was not affected by the underlying genotype. The antiadrenergic effect of bisoprolol correlated with the reduction of peak heart rates at exercise testing. Bisoprolol treatment results in QTc shortening in gene-positive LQT1 and LQT2 patients and is well tolerated during long-term administration. The equivalence of bisoprolol for protection from ventricular arrhythmia in LQT patients compared to established beta-blockers remains unknown. Further large-scale studies are required.