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Vincristine (VCR), a vinca alkaloid with anti-tumor and anti-oxidant properties, is acclaimed to possess cardioprotective action. However, the molecular mechanism underlying this protective effect remains unknown. This study investigated the effects of VCR on isoprenaline (ISO), a beta-adrenergic receptor agonist, induced cardiac hypertrophy in male Wistar rats. Animals were pre-treated with ISO (1 mg/kg) intraperitoneally for 14 days before VCR (25 μg/kg) intraperitoneal injection from days 1 to 28. Thereafter, mechanical, and electrical activities of the hearts of the rats were measured using a non-invasive blood pressure monitor and an electrocardiograph, respectively. After which, the heart was homogenized, and supernatants were assayed for contractile proteins: endothelin-1, cardiac troponin-1, angiotensin-II, and creatine kinase-MB, with markers of oxidative/nitrergic stress (SOD, CAT, MDA, GSH, and NO), inflammation (TNF-a and IL-6, NF-kB), and caspase-3 indicative of VCR reduced elevated blood pressure and reversed the abnormal electrocardiogram. ISO-induced increased endothelin-1, cardiac troponin-1, angiotensin-II, and creatine phosphokinase-MB, which were reversed by VCR. ISO also increased TNF-α, IL-6, NF-kB expression with increased caspase-3-mediated apoptosis in the heart. However, VCR reduced ISO-induced inflammation and apoptosis, with improved endogenous antioxidant agents (GSH, SOD, CAT) relative to ISO controls. Moreso, VCR, protected against ISO-induced histoarchitectural degeneration of cardiac myofibre. The result of this study revealed that VCR treatment significantly reverses ISO-induced cardiac hypertrophic phenotypes, via mechanisms connected to improved levels of proteins involved in excitation-contraction, and suppression of oxido-inflammatory and apoptotic pathways., Competing Interests: Declaration of competing interest The authors did not have any conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Pathological cardiac hypertrophy often precedes heart failure due to various stimuli, yet effective clinical interventions remain limited. Recently, microRNAs (miRNAs) have been identified as critical regulators of cardiovascular development. In this study, we investigated the role of miR-146b-5p and its underlying mechanisms of action in cardiac hypertrophy. Isoprenaline (ISO) treatment induced significant hypertrophy and markedly enhanced the expression of miR-146b-5p in cultured neonatal rat cardiomyocytes and hearts of C57BL/6 mice. Transfection with the miR-146b-5p mimic led to cardiomyocyte hypertrophy accompanied by autophagy inhibition. Conversely, miR-146b-5p inhibition significantly alleviated ISO-induced autophagy depression, thereby mitigating cardiac hypertrophy both in vitro and in vivo. Our results showed that the autophagy-related mediator double FYVE domain-containing protein 1 (DFCP1) is a target of miR-146b-5p. MiR-146b-5p blocked autophagic flux in cardiomyocytes by suppressing DFCP1, thus contributing to hypertrophy. These findings revealed that miR-146b-5p is a potential regulator of autophagy associated with the onset of cardiac hypertrophy, suggesting a possible therapeutic strategy involving the inhibition of miR-146b-5p., Competing Interests: Declaration of competing interest The authors declare no conflict of interest and have approved to submit the paper to journal of Molecular and Cellular Endocrinology., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Retrograde intrarenal surgery (RIRS) is associated with complications, many of which are related to the intrarenal pressure (IRP). We aim to describe the design of a novel isoprenaline-eluting guidewire ("IsoWire") and present the results from the first in vitro release studies and the first animal studies showing its effect on IRP. Materials and Methods: The IsoWire comprises a Nitinol core surrounded by a stainless-steel wire wound into a tight coil. The grooves created by this coil provided a reservoir for adding a hydrogel coating into which isoprenaline, a beta-agonist, was loaded. Animal studies were performed using a porcine model. For the control, IRP, heart rate (HR), and mean arterial pressure (MAP) were measured continuously for 6 minutes with a standard guidewire in place. For the experiment, the standard hydrophilic guidewire was removed, the IsoWire was inserted into the renal pelvis, and the same parameters were measured. Results: analysis of the isoprenaline release profile showed that most (63.9 ± 5.9%) of the loaded drug mass was released in the 1st minute, and almost all of the drug was released in the first 4 minutes exponentially. Porcine studies showed a 25.1% reduction in IRP in the IsoWire that released 10 μg in the 1st minute; however, there was a marked increase in HR. The average percentage reduction in IRP was 8.95% and 21.3% in the IsoWire that released 5 and 7.5 μg of isoprenaline, respectively, with no changes in HR or MAP. In vitro The IsoWire, which releases 5 and 7.5 μg of isoprenaline in the 1st minute, appears to be safe and effective in reducing the IRP. Further studies are needed to establish whether the isoprenaline-induced ureteral relaxation will render easier insertion of a ureteral access sheath, reduce IRP during sheathless RIRS, or even promote the practice of sheathless RIRS. Conclusions: The IsoWire, which releases 5 and 7.5 μg of isoprenaline in the 1st minute, appears to be safe and effective in reducing the IRP. Further studies are needed to establish whether the isoprenaline-induced ureteral relaxation will render easier insertion of a ureteral access sheath, reduce IRP during sheathless RIRS, or even promote the practice of sheathless RIRS.

Cardiovascular disorders are the leading cause of death globally. Rosuvastatin is a member of statins (inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase) with many pleiotropic properties. This study investigated cardioprotective effects of rosuvastatin in isoprenaline-induced myocardial injury. Male rats were given rosuvastatin (1, 5, or 10 mg/kg, oral) daily for 1 week and on seventh and eighth day isoprenaline (150 mg/kg, subcutaneous) was given to induce cardiac injury. On ninth day, rats were euthanized and different samples were harvested for analysis. Isoprenaline administration resulted in increased cardiac mass, increased cardiac injury marker levels (cTnI, CK-MB, ALT, and AST), increased lipid/protein oxidation, and increased cardiac nitrite levels. It also decreased superoxide dismutase, CAT, GST, and glutathione reductase activities, and total antioxidant activity. Isoprenaline also increased TNF-α and IL-6 levels. Decreased mRNA expression of Nrf2 and Bcl-2 along with increased mRNA expression of Bax, eNOS and iNOS genes was observed in isoprenaline treated animals. Histopathological evaluations of rosuvastatin pre-treated groups showed reduction of myocardial necrosis. Pretreatment with rosuvastatin (5 and 10 mg/kg) reduced many of these pathological changes. The current study showed that rosuvastatin significantly reduces myocardial injury induced by isoprenaline.

Acute myocardial infarction (AMI) remains a leading cause of morbidity and mortality worldwide. Lutein (LU) possesses numerous pharmacological activities, including anti-inflammatory, antioxidant, and antiapoptotic effects. This study aimed to investigate the cardioprotective potential of LU in isoprenaline (ISO)-induced MI and to explore its molecular mechanisms of action. AMI was induced by two consecutive subcutaneous doses of ISO (65 mg/kg; s.c.). The LU group was pretreated with LU (20 mg/kg; p.o.) for 30 days followed by ISO injections on Days 29 and 30. ISO group showed elevated serum creatine kinas-MB (CK-MB) and considerable electrocardiographic changes along with reduced ejection fraction compared to the normal group. LU pretreatment could decrease serum CK-MB activity, normalize QRS and QTc intervals and restore ejection fraction compared to the untreated group. The ISO group demonstrated infarcted-like lesions, which were ameliorated in the LU-pretreated group. Immunohistochemical investigation revealed upregulated cardiac troponin T (cTn T) and desmin expressions in the LU-pretreated group. LU pretreatment also enhanced cardiac thioredoxin (Trx) and glutathione (GSH) contents as well as reduced lipid peroxidation, compared to the untreated group. Importantly, LU pretreatment could downregulate long noncoding MI associated transcript (lncRNA MIAT) and thioredoxin-interacting protein (TXNIP) and augment micro RNA (miR)-200a and nuclear factor erythroid 2-related factor 2 (Nrf2) expressions compared to the ISO group. Moreover, a significant inverse correlation between MIAT and miR-200a was observed. In conclusion, this study revealed that LU could ameliorate ISO-induced MI in rats by modulating MIAT/miR-200a/Nrf2 pathway., (© 2021 Wiley Periodicals LLC.)

The present study was designed to assess the cardio-protective role of oleic acid in myocardial injury (MI) induced by intra-peritoneal injection of isoprenaline (ISO) in rats for 2 consecutive days. Oleic acid (OA) was administered orally (@ 5 mg/kg b.wt and 10 mg/kg b.wt) for 21 days before inducing MI. Pre-exposure to OA at higher dose significantly improved the HW/BW ratio, myocardial infarct size, lipid profiles (total cholesterol, HDL-C) and cardiac injury biomarkers (LDH, CK-MB, cardiac troponin-I, MMP-9), thus suggesting its cardio-protective role. The ameliorative potential of the higher dose of OA was further substantiated by its ability to reduce the cardiac oxidative stress as evidenced by significant decrease in lipid peroxidation coupled with increase in superoxide dismutase activity and reduced glutathione level. Significant decrease in heart rate as well as increase in RR and QT intervals in oleic acid pre-exposed rats were also observed. OA pre-treatment also reduced the histopathological alterations seen in myocardial injury group rats. The mRNA expression of cardiac UCP-2 gene, a regulator of reactive oxygen species (ROS) generation, was significantly increased in oleic acid pre-exposure group compared to the ISO-induced myocardial injury group. Thus increase in expression of UCP-2 gene in cardiac tissue seems to be one of the protective measures against myocardial injury. Based on the above findings, it may be inferred that oleic acid possesses promising cardio-protective potential against myocardial injury due to its anti-oxidative property and ability to modulate cardiac metabolic processes.

Diabetes increases the sensitivity of myocardium to ischemic damage and impairs response of the myocardium to cardioprotective interventions. The present study aimed to elucidate the potential cardioprotective effect provided by ranolazine during myocardial infarction in nondiabetic and diabetic male rats. As AMP-activated protein kinase (AMPK) has been shown to be involved in the cellular response to ischemic injury, in this context, the present animal study evaluated the modulating role of ranolazine in the AMPK expression in isoprenaline-induced myocardial ischemic rat model. Male rats were divided into 2 experiments: experiment I and II (nondiabetic and diabetic rats) and assigned to normal control, saline control for isoprenaline, isoprenaline control, and ranolazine-treated groups. Ranolazine administration revealed effectiveness in attenuating the severity of isoprenaline-induced myocardial injury in both nondiabetic and diabetic rats as revealed by ECG signs, histopathological score, and apoptotic markers via abrogating the increments in the inflammatory and oxidative stress markers and modulating AMPK expression. Therefore, the current cardioprotective effect of ranolazine was, at least in part, mediated through inhibition of apoptosis and modulation of AMPK expression, encouraging considering the utility of ranolazine in protection from acute myocardial infarction.

Background: Takotsubo syndrome (TS) is an acute cardiac syndrome characterized by regional myocardial akinesia that is not caused by coronary artery occlusion. Exogenous as well as endogenous excess catecholamines can induce TS. The aim of this study was to explore the effects of pharmacological cardio-simulative and cardio-depressing drugs on the development of isoprenaline-induced takotsubo-like cardiac dysfunction, a rat model of TS., Methods: We randomized 295 rats into twelve groups. The animals were randomized to pre-treatment with either a low or high dose of metoprolol, propranolol, ICI 118551 (beta 2 -receptor antagonists), milrinone (phosphodiesterase inhibitor), levosimendan or saline (control) before induction of TS with isoprenaline. In one additional group, high dose of milrinone was administered alone. We measured invasively blood pressure and heart rate over a period of 90 min. Cardiac function and morphology were evaluated with high-resolution echocardiography., Results: Milrinone alone induced apical ballooning similar to isoprenaline. Pretreatment with propranolol and metoprolol but not with ICI 118551 attenuated takotsubo-like akinesia in a dose-dependent manner. Pretreatment with metoprolol decreased mortality. Pretreatment with levosimendan resulted in higher incidence of apical ballooning while pretreatment with milrinone did not change the degree of akinesia., Conclusion: The phosphodiesterase inhibitor milrinone induces takotsubo-like dysfunction in the absence of exogenous catecholamines. This finding challenges the concept that high levels of circulating catecholamines or excessive stimulation of adrenergic receptors are necessary for the development of takotsubo syndrome. Our study provides experimental evidence for the concept of avoidance of inotropes and that selective beta 1 -blockade may be beneficial in the treatment of TS-patients., (Copyright © 2018 Elsevier B.V. All rights reserved.)

New Findings: What is the central question of this study? The study was designed to assess whether pretreatment with β-glucan could exert any protective action against isoprenaline-induced myocardial injury in rats. What is the main finding and its importance? β-Glucan pretreatment could reduce myocardial injury by restoring cardiac biomarkers, antioxidant status, apoptosis and histopathological changes. Therefore, β-glucan might have the potential to be used in the prevention and/or treatment of myocardial infarction., Abstract: This study was designed to investigate the cardioprotective effect of pretreatment with β-glucan, the glucose polymer derived from the yeast Saccharomyces cerevisiae, against isoprenaline (ISO)-induced myocardial injury in rats by studying biochemical cardiac markers, antioxidant parameters, apoptosis, ECG and histopathological changes. Male Sprague-Dawley rats were randomly divided into four treatment groups, namely control, β-glucan, isoprenaline and β-glucan + isoprenaline. The β-glucan treatment group received β-glucan (50 mg kg -1  day -1 , p.o.) for 10 days. Myocardial injury was induced by ISO administration (100 mg kg -1 , s.c.) twice, at an interval of 24 h, on the 9th and 10th days. Isoprenaline administration resulted in a marked increase in heart rate, ST segment elevation, myocardial malondialdehyde content, cardiac marker levels (lactate dehydrogenase, creatine kinase-MB and high-sensitivity cardiac troponin T) and apoptotic index, and a significant decrease in R-wave amplitude and myocardial superoxide dismutase, catalase and glutathione peroxidase activities. In addition, apoptosis, congestion, necrosis, inflammatory cell infiltration and myofibrillar disorganization were observed histologically in myocardial tissue sections. The oral pretreatment with β-glucan prevented almost all the parameters of isoprenaline-induced myocardial injury in rats, and these findings were confirmed by the histopathological analysis. These findings provide evidence that β-glucan could protect rat myocardium against ISO-induced myocardial injury, and this was attributed to its antioxidant and anti-apoptotic properties., (© 2019 The Authors. Experimental Physiology © 2019 The Physiological Society.)

Aim: The objective of this study is to determine if exuberant sympathetic nerve activity is involved in muscle satellite cell differentiation and myoblast fusion., Methods and Results: By using immunoassaying and western blot analyses, we found that β1 and β2-adrenergic receptors (AdR) were expressed in C2C12 cells. The differentiated satellite cells exhibited an increased expression of β2-AdR, as compared with the proliferating cells. Continuous exposure of isoprenaline (ISO), a β-AdR agonist, delayed C2C12 cell differentiation, and myoblast fusion in time- and dose-dependent manner. ISO also increased short myotube numbers while decreasing long myotube numbers, consistent with the greater reduction in MyHC1, MyHC2a, and MyHC2x expression. Moreover, continuous exposure of ISO gradually decreased the ratio of PKA RI/RII, and PKA RI activator efficiently reversed the ISO effect on C2C12 cell differentiation and myoblast fusion while PKA inhibitor H-89 deteriorated the effects. Continuous single-dose ISO increased β1-AdR expression in C2C12 cells. More importantly, the cells showed enhanced phospho-ERK1/2 levels, resulting in increasing phospho-β2-AdR levels while decreasing β2-AdR levels, and the specific effects could be abolished by ERK1/2 inhibitor. Furthermore, continuous exposure of ISO induced FOXO1 nuclear translocation and increased the levels of FOXO1 in nuclear extracts while reducing pAKT, p-p38MAPK, and pFOXO1 levels. Conversely, blockade of ERK1/2 signaling partially abrogated ISO effects on AKT, p38MAPK, and FOXO1signaling, which partially restored C2C12 cell differentiation and myoblast fusion, leading to an increase in the numbers of medium myotube along with the increased expression of MyHC1 and MyHC2a., Conclusion: Continuous exposure of ISO impedes satellite cell differentiation and myoblast fusion, at least in part, through PKA-ERK1/2-FOXO1 signaling pathways, which were associated with the reduced β2-AdR and increased β1-AdR levels.

A chemometrically optimized procedure has been developed for the determination of isoprenaline (ISO) in the parent substance as well as in its respective pharmaceutical preparation. It is worth mentioning that although spectroscopic determination of Isoprenaline metal complexes has been described in literature, yet, no methods for the quantification of Isoprenaline with Samarium nor any other lanthanide metal have been reported. Fractional factorial design (FFD) was implemented in the initial screening procedure of the four designated factors, namely, reaction time (RT), metal volume (MV), pH and temperature (T) followed by Response Surface Methodology (RSM) optimization tool performed by the aid of Box Behnken design (BBD).The proposed techniques are based on a multivariate approach where a complexation reaction between Isoprenaline (ISO) and Samarium III (Sm 3+ ) metal was exploited for the first time to synthesize novel fluorescence and absorbance probes of ISO-Sm. Maximum fluorescence intensity (Y1) as well as maximum absorbance (Y2) of the produced complex were attained at λ ex /λ em  = 315/450 and λ 295 nm for spectrofluorimetric and spectrophotometric determinations, respectively, against blank solutions. Using assessment quality tools such as, Pareto charts, normal probability plots and statistical analysis of variance testing (ANOVA), significant factors were successfully indicated (p < 0.05). Furthermore, the proposed methods verified specificity and accuracy for the determination of Isoprenaline in its pure and pharmaceutical preparation using spectrofluorimetric (Technique A) and spectrophotometric (Technique B) techniques, respectively. Linearity was obtained in the range of (0.02-0.50 μg/mL) and (2-12 μg/mL) upon employing both techniques A and B, respectively. Furthermore, limit of detection (LOD) and limit of quantification (LOQ), were found to be 5.1877 ∗ 10 -3  μg/mL, 0.01572 μg/mL and 0.5593 μg/mL, 1.6949 μg/mL, upon employing techniques A and B, respectively. Standard addition method was applied for both techniques. The analysis was successfully applied to the assay of pure powder and pharmaceutical dosage forms after which the corresponding mean recoveries were computed and were found to be in the range of 99.546%-100.257% (Technique A) and 99.872%-99.887% (Technique B) with RSD (<1)., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The contractile function of the heart was studied in adult frogs Rana temporaria under the influence of a toxic dose of isoprenaline under conditions of natural sinoatrial rhythm and during heart pacing. The dynamics of ventricular pressure was recorded with a Prucka MacLab 2000 instrument via a catheter introduced into the ventricle through the ventricular wall. Reduced (p<0.05) parameters of the pump function (HR, maximum ventricular systolic pressure, isovolumic indices dP/dt max and dP/dt min ) and lengthening of QRS complex and QT interval on ECG attested to impairment of contractile function and electrical processes after exposure to isoprenaline. Electrical stimulation of the right atrium improved myocardial contractility and ECG parameters after the administration of isoprenaline.

Isoprenaline, an activator of β-adrenergic receptor, has been found to induce cardiac hypertrophy in vivo and in vitro, but the exact mechanism is still unclear. ClC-3 is a member of the chloride channel family and is highly expressed in mammalian myocardium. In the present study, the role of ClC-3 in isopronaline-induced cardiac hypertrophy was investigated. We found that ClC-3 expression was reduced in isoprenaline-induced hypertrophic H9c2 cells, primary rat neonatal cardiomyocytes and myocardium of C57/BL/6 mice, and this reduction was prevented by the pretreatment of propranolol. Adeno-associated virus 9 (AAV9)-mediated ClC-3 expression in myocardium decreased heart mass index, thinned interventricular septum and left ventricular wall and lowered the mRNA expression of natriuretic peptide type A (ANF) and β-myosin heavy chain (β-MHC). Our results showed that ClC-3 played an important role in β-adrenergic cardiac hypertrophy which could be associated with ANF and β-MHC, and all these findings suggested that ClC-3 may be a novel therapeutic target for the prevention or treatment of myocardiac hypertrophy., (Copyright © 2017 Elsevier B.V. All rights reserved.)

In this paper, we describe a rapid, low-cost and highly sensitive colorimetric method for the detection of isoprenaline, based on 2-amino-5-mercapto-1,3,4-thiadiazol (AMTD) functionalized gold nanoparticles (AMTD-AuNPs) as a sensing element. Hydrogen bonding interaction between isoprenaline and AMTD resulted in the aggregation of AuNPs and a consequent color change of AuNPs from red to blue. The concentration of isoprenaline could be detected with the naked eye or a UV-visible spectrometer. Results showed that the absorbance ratio (A650/A524) was linear with isoprenaline concentrations in the range of 0.2 to 2.6μM (R=0.997). The detection limit of this method was 0.08μM. The proposed method is simple, without using complicated instruments and adding salts for enhancing sensitivity. This probe could be successfully applied to the determination of isoprenaline in human serum samples and urine samples after deproteinization., (Copyright © 2017. Published by Elsevier B.V.)

Object We aimed to identify the β-adrenoceptor (β-AR) subtypes involved in isoprenaline-induced relaxation of guinea pig colonic longitudinal smooth muscle using pharmacological and biochemical approaches. Methods Longitudinal smooth muscle was prepared from the male guinea pig ascending colon and contracted with histamine prior to comparing the relaxant responses to three catecholamines (isoprenaline, adrenaline, and noradrenaline). The inhibitory effects of subtype-selective β-AR antagonists on isoprenaline-induced relaxation were then investigated. Results The relaxant potencies of the catecholamines were ranked as: isoprenaline > noradrenaline ≈ adrenaline, whereas the rank order was isoprenaline > noradrenaline > adrenaline in the presence of propranolol (a non-selective β-AR antagonist; 3 × 10 -7 M). Atenolol (a selective β 1 -AR antagonist; 3 × 10 -7 -10 -6  M) acted as a competitive antagonist of isoprenaline-induced relaxation, and the pA 2 value was calculated to be 6.49 (95% confidence interval: 6.34-6.83). The relaxation to isoprenaline was not affected by ICI-118,551 (a selective β 2 -AR antagonist) at 10 -9 -10 -8  M, but was competitively antagonized by 10 -7 -3 × 10 -7  M, with a pA 2 value of 7.41 (95% confidence interval: 7.18-8.02). In the presence of propranolol (3 × 10 -7 M), the relaxant effect of isoprenaline was competitively antagonized by bupranolol (a non-selective β-AR antagonist), with a pA 2 value of 5.90 (95% confidence interval: 5.73-6.35). Conclusion These findings indicated that the β-AR subtypes involved in isoprenaline-induced relaxation of colonic longitudinal guinea pig muscles are β 1 -AR and β 3 -AR.

Background: The role of stress signals in regulating gastric cancer initiation and progression is not quite clear. It is known that stress signals modulate multiple processes such as immune function, cell migration and angiogenesis. However, few studies have investigated the mechanisms of how stress signals contribute to gastric cancer angiogenesis., Methods: Here, we used β2-adrenergic receptor (β2-AR) agonist isoprenaline to imitate a stress signal and demonstrated the molecular mechanism underlying stress's influence on tumor angiogenesis., Results: We found that isoprenaline stimulated vascular endothelial growth factor (VEGF) secretion in gastric cancer cells and plexin-A1 expression was induced by human recombinant VEGF165 in both gastric cancer cells and vascular endothelial cells. Furthermore, interfere with plexin-A1 expression in gastric cancer cells influence HUVEC tube formation, migration and tumor growth in vivo., Conclusions: These findings suggest that isoprenaline stimulate VGEF secretion and subsequently up-regulate the expression of plexin-A1 and VEGFR2 in gastric cancer cells, which form a positive impetus to promote tumor angiogenesis. This study reveals a novel molecular mechanism that a stress signal like isoprenaline may enhance angiogenesis via activating plexin-A1/VEGFR2 signaling pathway in gastric cancer, which may be a potential target in development of an anti-angiogenic therapy for gastric cancer.

Background: Various protocols exist for performing head-up tilt test (HUTT). Serious ventricular arrhythmias have been reported during HUTT using Isoprenaline (ISO) provocation and their incidence with sublingual Nitroglycerine provocation is unknown. This study aims to assess the efficacy, pattern of response, tolerability, and frequency of arrhythmias during head-up tilt test with sublingual Nitroglycerine (NTG) provocation compared to ISO) provocation., Methods: This is a retrospective observational study., Result: From 2007 to 2015, a total of 816 patients (68% men, median age 49 IQR 25.75-65 years) underwent head-up tilt testing using sublingual NTG provocation whereas ISO was used in 189 patients (66.1% men, median age 48 IQR 36-60 years). A positive response was more frequently observed in the NTG group than the ISO group (48.4% vs 35.9%, p=0.002), with more frequent type II b (cardio-inhibition with >3sec asystole) and type III (vasodepressor) responses ([15. 9% vs 4.1%, p=0.001] and 0% vs 29.4%, p=0.004) respectively. Bradyarrhythmias occurring always as a part of a positive HUTT response were the commonest arrhythmias (29% in NTG group vs 25.4% in ISO group, p=0.31). Tachyarrhythmias (or premature beats) were more frequent in the ISO group (12.7% vs 7.9%, p=<0.005). The use of NTG was significantly associated with a positive response (OR 1.775, 95% CI 1.269-2.483, p=0.001), whereas the use of ISO predicted the occurrence of premature beats/tachyarrhythmias (OR 3.06, 95% CI 2.195-4.267, p<0.005). Intolerance needing termination of the test was significantly more frequent in the ISO group than NTG group (1.6% vs 0.12%, p= 0.02)., Conclusion: Head-up tilt test with NTG provocation has a higher yield of a positive response, lower incidence of unwanted arrhythmias and better tolerability compared to ISO. The occurrence of VASIS type II b and type III response was more with Nitroglycerine than Isoprenaline., (Copyright © 2016 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Infarct-like lesion induced by isoprenaline is a well-known model to study myocardial infarction (MI). Vitamin D has been shown to have anti-inflammatory and antioxidant effects. Recent studies highlighted cross talk between vitamin D and peroxisome proliferator-activated receptor gamma (PPAR-γ). The present study was designed to investigate the effect of pretreatment with vitamin D on the isoprenaline-induced infarct-like lesion in rats and the role of PPAR-γ as a novel mechanism in vitamin-D-mediated cardioprotective effect. Markers chosen to assess cardiac damage included serum level of creatine kinase (CK), lactate dehydrogenase (LDH), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6). Cardiac contents of malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH) were also assessed. Furthermore, ECG monitoring and measurement of injury extension were carried out. Isoprenaline increased the level of cardiac enzymes, as well as inflammatory and oxidative stress biomarkers. In addition, it produced ST-segment elevation. Pretreatment with vitamin D significantly improved previous parameters. The prior treatment with bisphenol A diglycidyl ether (BADGE), a PPAR-γ antagonist, significantly attenuated the protective effect of vitamin D. In conclusion, vitamin D can be demonstrated as a promising cardioprotective agent in MI and PPAR-γ significantly contributes toward vitamin-D-mediated protection.

Objectives: Rutin, quercetin-3-O-rutinoside, a natural flavonol glycoside, has shown various in vitro benefits with potential use treating human diseases, especially cardiovascular system disorders. Antioxidant properties are assumed to underlie the majority of these benefits. Yet rutin pro-oxidant properties have been reported as well. Our research group has recently shown aggravating effects on isoprenaline (ISO)-induced cardiotoxicity in Wistar:Han rats after 24 hours., Methods: This study was designed to examine in more detail the reasons for the negative effects of rutin (11.5 and 46 mg/kg, i.v.) after administration of ISO (100 mg/kg, s.c.) in rats within 2 hours of continuous experiment and in the H9c2 cardiomyoblast-derived cell line., Results: Like our previous findings, rutin did not (11.5 or 46 mg/kg, i.v.) reduce the ISO-induced mortality within 2 hours although the lower dose significantly reduced cardiac troponin T (cTnT) and partly improved the histological findings. In contrast, the higher dose increased the mortality in comparison with solvent (1.26% w/v sodium bicarbonate). This was not caused by any specific haemodynamic disturbances. It appears to be associated with oxidative stress as rutin enhanced intracellular reactive oxygen species formation in vitro and had the tendency to increase it in vivo., Conclusions: Rutin, likely due to its pro-oxidative effects, can exacerbate catecholamine cardiotoxicity depending on the dose used.

The effects of magnesium (Mg 2+ ) on ischaemic complications of pathological cardiac hypertrophy are unclear. In this study, we investigated effects of Mg 2+ pretreatment on ischaemia/reperfusion (I/R) injury in isoprenaline (ISO)-induced hypertrophic hearts. Wistar rats were treated for 7 days with different combinations of ISO (1.25 mg/kg) subcutaneously, MgSO 4 (270 mg/kg) intraperitoneally, or vehicle (saline). On the eighth day, hearts were either subjected to regional I/R during Langendorff perfusion or histologically stained with haematoxylin and eosin and Masson's trichrome. Haemodynamic and electrocardiographic parameters were recorded using the PowerLab data-acquisition system. Infarcts were identified by triphenyltetrazolium chloride staining. Plasma Mg 2+ was measured using photometric assays. Mg 2+ pretreatment significantly decreased I/R-induced infarct size (p = 0.001) and the overall arrhythmia score (p < 0.001) of I/R-induced ventricular ectopics, ventricular tachycardia, and ventricular fibrillation in hypertrophic hearts, but not non-hypertrophied hearts. Mg 2+ also improved post-I/R left ventricular developed pressure in hypertrophic hearts. However, Mg 2+ did not reverse the ISO-induced myocyte thickening and interstitial fibrosis or increases in heart weight. Plasma Mg 2+ was not different among treatment groups. These results suggest that Mg 2+ pretreatment may protect against I/R-induced injury and malignant arrhythmias in hypertrophic hearts, possibly via mechanisms unrelated to long-lasting changes in plasma Mg 2+ or prevention of structural changes such as fibrosis.

β3-adrenoceptor agonists influence overactive bladder in humans and animal models. However, data is emerging that the mode of action of these drugs is complex. The present study explored the actions of the β3-adrenergic agonist mirabegron and the non-selective agonist isoprenaline on the contractile systems in the rat and guinea pig bladder. Intravesical pressure was measured in isolated whole bladders from female adult animals. In both species spontaneous contractile activity was observed. The muscarinic agonist arecaidine produced complex responses consisting of an initial transient pressure rise followed by complex phasic activity. Three contractile elements were identified: intrinsic micro-contractile activity, initial transient response and steady state phasic activity. The intrinsic and steady state activity could be further divided into a baseline pressure with superimposed phasic activity. The effects of isoprenaline and mirabegron were investigated on these elements. In the rat, the micro-contractile activity could be completely inhibited by isoprenaline (full agonist). The arecaidine-induced initial and steady state baseline pressures were partially reduced, while the phasic activity was little affected. In the guinea pig, both the arecaidine-induced baseline pressure and the phasic activity were affected by isoprenaline. Mirabegron didn't produce significant inhibitory effects in any of the contractile elements in either species. These results show that complex contractile systems operate in the rat and guinea pig bladder that can be modulated by β1/β2-adrenoceptor mechanisms. No evidence was obtained for any β3-dependent regulation of contraction. These data support similar data in humans. Therefore the primary site of therapeutic action of β3-adrenergic agonists remains unknown., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Inclusion complex formation of isoprenaline (ISOP) and methyldopa (MDOP) with α-CD and β-CD were investigated. Solid inclusion complex nanomaterials were characterized by SEM, TEM, FTIR, DSC, (1)H NMR and XRD methods. Spectral results showed that single emission (monomer) noticed in aqueous solution where as dual emission (excimer) in CD. Both drugs formed 1:2 (CD-drug2) inclusion complexes with CDs. Time-resolved fluorescence studies show that single exponential decay observed in water whereas biexponential decay observed in CD. Nano-sized particles were found in ISOP/CD while vesicles were obtained in MDOP/CD complexes. DSC results revealed that the thermal stability of drugs was improved when it was included in the CD nanocavity. Based on PM3 calculations, the inclusion structure of ISOP/CD and MDOP/CD complexes were proposed. Thermodynamic parameters and binding affinity of complexation of CD were determined by PM3 method., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Excessive levels of catecholamines are believed to contribute to cardiac dysfunction in a variety of disease states, including myocardial infarction and heart failure, and are particularly implicated in stress-induced cardiomyopathy, an increasingly recognized cardiomyopathy associated with significant morbidity and mortality. We have previously shown that a high dose of isoprenaline induces reversible regional dysfunction of the left ventricle in mice. We now hypothesize that adenosine can prevent cardiac dysfunction in this mouse model of stress-induced cardiomyopathy. Hundred male C57BL/6 mice were injected with 400mg/kg isoprenaline and then randomized to either 400mg/kg adenosine or saline. Cardiac function was evaluated by echocardiography at baseline and 2, 24, 48, 72, 96 and 120 min post isoprenaline. Myocardial fibrosis was quantified after 10 days. Intracellular lipid accumulation was quantified after 2 and 24h. Electrophysiological parameters and degree of lipid accumulation were evaluated in cultured HL1 cardiomyocytes. Two hours post isoprenaline treatment, echocardiographic parameters of global and posterior wall regional function were significantly better in adenosine-treated mice (P<0.05). This difference persisted at 24h, but saline-treated mice gradually recovered over the next 96 h. Intracellular lipid accumulation was also significantly lower in adenosine mice. We found no sign of fibrosis in the adenosine mice, whereas the extent of fibrosis in isoprenaline mice was 1.3% (P<0.05). Furthermore, adenosine-treated HL1 cells showed preserved electrophysiological function and displayed less severe intracellular lipid accumulation in response to isoprenaline. In conclusion, adenosine attenuates isoprenaline-induced cardiac dysfunction in mice and cells., (© 2013 Elsevier B.V. All rights reserved.)

Heart failure is the common final pathway of several cardiovascular conditions and a major cause of morbidity and mortality worldwide. Aberrant activation of the adaptive immune system in response to myocardial necrosis has recently been implicated in the development of heart failure. The ß‐adrenergic agonist isoproterenol hydrochloride is used for its cardiac effects in a variety of different dosing regimens with high doses causing acute cardiomyocyte necrosis. To assess whether isoproterenol‐induced cardiomyocyte necrosis triggers an adaptive immune response against the heart, we treated C57BL/6J mice with a single intraperitoneal injection of isoproterenol. We confirmed tissue damage reminiscent of human type 2 myocardial infarction. This is followed by an adaptive immune response targeting the heart as demonstrated by the activation of T cells, the presence of anti‐heart auto‐antibodies in the serum as late as 12 weeks after initial challenge and IgG deposition in the myocardium. All of these are hallmark signs of an established autoimmune response. Adoptive transfer of splenocytes from isoproterenol‐treated mice induces left ventricular dilation and impairs cardiac function in healthy recipients. In summary, a single administration of a high dose of isoproterenol is a suitable high‐throughput model for future studies of the pathological mechanisms of anti‐heart autoimmunity and to test potential immunomodulatory therapeutic approaches. [ABSTRACT FROM AUTHOR]

Background: Acute myocardial infarction is a major cause of death all over the world. Irisin is a novel myokine released after exercise. This work aimed to study the correlation between the serum irisin level and the severity of the acute myocardial infarction in the exercise-trained rats. Methods: Forty-eight male rats were classified into four groups (12 for each): group I, control sedentary (C); group II, exercise-trained (EX) (swimming for 8 weeks); group III, isoprenaline-induced infarct (MI); and group IV, exercise-trained infarct (EX-MI) (swimming for 8 weeks followed by isoprenaline-induced infarction). ECG was recorded at start and end of the study, before and after induction of infarction. The serum level of irisin, lipid peroxidation [malondialdehyde (MDA)], total antioxidant status (TAS), creatine phosphokinase-MB (CK-MB), and troponin I was determined. The hearts were excised for histopathology and immunohistochemistry for caspase-3. Results: The infarct rats showed significant prolongation in QTc interval and elevation in the ST segment as well as significant elevation of serum CK-MB, troponin I, and MDA, whereas TAS and serum irisin level were significantly decreased. With exercise, we observed a high positive correlation between the serum irisin and QRS duration (+0.643), amplitude (+0.860), and TAS (+0.887). In addition, there was a high negative correlation between the serum irisin and ST elevation (−0.865), QTc (−0.886), CK-MB (−0.891), troponin (−0.882), and MDA (−0.868). This was confirmed by the negative correlation between serum irisin and both collagen deposition and caspase-3 expression (–0.823 and –0.822, respectively). Conclusions: We recommend regular exercise or taking recombinant irisin as a supplement to protect at-risk individuals against acute myocardial infarction. [ABSTRACT FROM AUTHOR]