Metabolomics of repetitive myocardial stunning in chronic multivessel coronary artery stenosis: Effect of non-selective and selective ß1-receptor blockers.

Chronic coronary artery stenosis can lead to regional myocardial dysfunction in the absence of myocardial infarction by repetitive stunning, hibernation or both. The molecular mechanisms underlying repetitive stunning-associated myocardial dysfunction are not clear. We used non-targeted metabolomics to elucidate responses to chronically stunned myocardium in a canine model with and without ß-adrenergic blockade treatment. After development of left ventricular systolic dysfunction induced by ameroid constrictors on the coronary arteries, animals were randomized to 3 months of placebo, metoprolol or carvedilol. We compared these two ß-blockers with their different ß-adrenergic selectivities on myocardial function, perfusion and metabolic pathways involved in tissue undergoing chronic stunning. Control animals underwent sham surgery. Dysfunction in stunned myocardium was associated with reduced fatty acid oxidation and enhanced ketogenic amino acid metabolism, together with alterations in mitochondrial membrane phospholipid composition. These changes were consistent with impaired mitochondrial function and were linked to reduced nitric oxide and peroxisome proliferator-activated receptor signalling, resulting in a decline in adenosine monophosphate-activated protein kinase. Mitochondrial changes were ameliorated by carvedilol more than metoprolol, and improvement was linked to nitric oxide and possibly hydrogen sulphide signalling. In summary, repetitive myocardial stunning commonly seen in chronic multivessel coronary artery disease is associated with adverse metabolic remodelling linked to mitochondrial dysfunction and specific signalling pathways. These changes are reversed by ß-blockers, with the non-selective inhibitor having a more favourable impact. This is the first investigation to demonstrate that ß-blockade-associated improvement of ventricular function in chronic myocardial stunning is associated with restoration of mitochondrial function. KEY POINTS: The mechanisms responsible for the metabolic changes associated with repetitive myocardial stunning seen in chronic multivessel coronary artery disease have not been fully investigated. In a canine model of repetitive myocardial stunning, we showed that carvedilol, a non-selective ß-receptor blocker, ameliorated adverse metabolic remodelling compared to metoprolol, a selective ß1-receptor blocker, by improving nitric oxide synthase and adenosine monophosphate protein kinase function, enhancing calcium/calmodulin-dependent protein kinase, probably increasing hydrogen sulphide, and suppressing cyclic-adenosine monophosphate signalling. Mitochondrial fatty acid oxidation alterations were ameliorated by carvedilol to a larger extent than metoprolol; this improvement was linked to nitric oxide and possibly hydrogen sulphide signalling. Both ß-blockers improved the cardiac energy imbalance by reducing metabolites in ketogenic amino acid and nucleotide metabolism. These results elucidated why metabolic remodelling with carvedilol is preferable to metoprolol when treating chronic ischaemic left ventricular systolic dysfunction caused by repetitive myocardial stunning.

Arsenite-Induced Drug-Drug Interactions in Rats.

Arsenite is an important heavy metal. Some Chinese traditional medicines contain significant amounts of arsenite. The aim of this study was to investigate subacute exposure of arsenite on activities of cytochrome P450 enzymes and pharmacokinetic behaviors of drugs in rats. Midazolam, tolbutamide, metoprolol, omeprazole, caffeine, and chlorzoxazone, the probe substrates for cytochrome P450 (CYP) s3A, 2C6, 2D, 2C11, 1A, and 2E, were selected as probe drugs for the pharmacokinetic study. Significant decreases in areas under the curves of probe substrates were observed in rats after consecutive 30-day exposure to As at 12 mg/kg. Microsomal incubation study showed that the subacute exposure to arsenite resulted in little change in effects on the activities of P450 enzymes examined. However, everted gut sac study demonstrated that such exposure induced significant decreases in intestinal absorption of these drugs by both passive diffusion and carrier-mediated transport. In addition, in vivo study showed that the arsenite exposure decreased the rate of peristaltic propulsion. The decreases in intestinal permeability of the probe drugs and peristaltic propulsion rate most likely resulted in the observed decreases in the internal exposure of the probe drugs. Exposure to arsenite may lead to the reduction of the efficiencies of pharmaceutical agents coadministered resulting from the observed drug-drug interactions. SIGNIFICANCE STATEMENT: Exposure to arsenite may lead to the reduction of the efficiencies of pharmaceutical agents coadministered resulting from the observed drug-drug interactions. The present study, we found that P450 enzyme probe drug exposure was reduced in arsenic-exposed animals (areas under the curve) and the intestinal absorption of the drug was reduced in the animals. Subacute arsenic exposure tends to cause damage to intestinal function, which leads to reduced drug absorption.

Sympathetic Activation Promotes Cardiomyocyte Apoptosis in a Rabbit Susceptibility Model of Hyperthyroidism-Induced Atrial Fibrillation via the p38 MAPK Signaling Pathway.

Excess thyroid hormone secretion can cause endocrine metabolic disorders, which can lead to cardiovascular diseases, including heart enlargement, atrial fibrillation (AF), and heart failure. The present study investigated the molecular mechanisms of hyperthyroidism-induced AF. A rabbit susceptibility model of hyperthyroidism-induced AF was constructed, and metoprolol treatment was administered. Norepinephrine levels were determined using enzyme-linked immunosorbent assay; quantitative reverse transcription polymerase chain reaction and immunohistochemistry were used to detect the expression of markers for sympathetic remodeling (growth associated protein 43 and tyrosine hydroxylase in atrial myocardial tissues and stellate ganglia). Primary rabbit cardiomyocytes were cultured and identified by immunofluorescence staining, and terminal deoxynucleotidyl transferase dUTP nick end labeling staining was used to measure cardiomyocyte apoptosis; western blot was used to detect the expression of apoptosis-related proteins, including Bax, Bcl-2, and cleaved caspase-3, as well as to measure the phosphorylation states of p38 mitogen-activated protein kinase (MAPK) pathway proteins. Metoprolol inhibited sympathetic activation and cardiomyocyte apoptosis in the rabbit model by inhibiting the p38 MAPK signaling pathway. Immunofluorescence staining results revealed that the rabbit cardiomyocytes were isolated successfully. Inhibition of p38 MAPK signaling alleviated norepinephrine-induced apoptosis in cardiomyocytes. Sympathetic activation promotes apoptosis in cardiomyocytes with hyperthyroidism-induced AF via the p38 MAPK signaling pathway. The results of the present study provide a novel theoretical basis for the potential clinical treatment of patients with hyperthyroidism and AF.

No robust reduction of infarct size and no-reflow by metoprolol pretreatment in adult Göttingen minipigs.

Whereas prior experiments in juvenile pigs had reported infarct size reduction by intravenous metoprolol early during myocardial ischaemia, two major clinical trials in patients with reperfused acute myocardial infarction were equivocal. We, therefore, went back and tested the translational robustness of infarct size reduction by metoprolol in minipigs. Using a power analysis-based prospective design, we pretreated 20 anaesthetised adult Göttingen minipigs with 1 mg kg-1 metoprolol or placebo and subjected them to 60-min coronary occlusion and 180-min reperfusion. Primary endpoint was infarct size (triphenyl tetrazolium chloride staining) as a fraction of area at risk; no-reflow area (thioflavin-S staining) was a secondary endpoint. There was no significant reduction in infarct size (46 ± 8% of area at risk with metoprolol vs. 42 ± 8% with placebo) or area of no-reflow (19 ± 21% of infarct size with metoprolol vs. 15 ± 23% with placebo). However, the inverse relationship between infarct size and ischaemic regional myocardial blood flow was modestly, but significantly shifted downwards with metoprolol, whereas ischaemic blood flow tended to be reduced by metoprolol. With an additional dose of 1 mg kg-1 metoprolol after 30-min ischaemia in 4 additional pigs, infarct size was also not reduced (54 ± 9% vs. 46 ± 8% in 3 contemporary placebo, n.s.), and area of no-reflow tended to be increased (59 ± 20% vs. 29 ± 12%, n.s.).Infarct size reduction by metoprolol in pigs is not robust, and this result reflects the equivocal clinical trials. The lack of infarct size reduction may be the result of opposite effects of reduced infarct size at any given blood flow and reduced blood flow, possibly through unopposed alpha-adrenergic coronary vasoconstriction.

Evaluation of the Effect of Metoprolol Dosage on Fat Graft Survival.

AIM: The aim of this study was to evaluate the effect of different metoprolol doses on fat graft survival. MATERIAL AND METHOD: A total of 10 Sprague-Dawley rats were used in the study. The dorsal regions of the rats were separated into four quadrants: right and left cranial, and right and left caudal. Each quadrant was determined as a separate group. Fat grafts were harvested from the groin areas and incubated in 5 ml solutions containing 0.9% sodium chloride (control group), 1 mg/mL metoprolol (Group 1), 2 mg/mL metoprolol (Group 2), and 3 mg/mL metoprolol (Group 3), respectively. The fat grafts were then placed in pockets dissected in each of the 4 dorsal quadrants. After 3 months all the rats were euthanized. The fat grafts were removed together with the surrounding area to which they had passed. Histopathological examination was made with hematoxylin and eosin (HE) and Masson Trichrome staining, and immunohistochemical examination with fibroblast growth factor-2 and perilipin staining. RESULTS: In the examinations made with HE and Masson Trichrome staining, the scores of Group 2 and Group 3 were determined to be significantly higher than those of the control group (p < 0.05). The Group 3 scores were significantly higher than those of Group 1 (p < 0.05). In the examinations made with fibroblast growth factor-2 staining, the scores of Group 2 and Group 3 were determined to be significantly higher than those of the control group (p < 0.05). The Group 3 scores were significantly higher than those of Group 1 and Group 2 (p < 0.05). In the examinations made with perilipin staining, the scores in Groups 1, 2, and 3 were higher than those of the control group (p < 0.05). CONCLUSION: Although metoprolol has previously been shown to prolong the survival of fat grafts, the results of this study demonstrated immunohistochemically that as the metoprolol dose increased, so the quality and vitality of fat graft also increased. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Beta Blockade Prevents Cardiac Morphological and Molecular Remodelling in Experimental Uremia.

Heart failure and chronic kidney disease (CKD) share several mediators of cardiac pathological remodelling. Akin to heart failure, this remodelling sets in motion a vicious cycle of progressive pathological hypertrophy and myocardial dysfunction in CKD. Several decades of heart failure research have shown that beta blockade is a powerful tool in preventing cardiac remodelling and breaking this vicious cycle. This phenomenon remains hitherto untested in CKD. Therefore, we set out to test the hypothesis that beta blockade prevents cardiac pathological remodelling in experimental uremia. Wistar rats had subtotal nephrectomy or sham surgery and were followed up for 10 weeks. The animals were randomly allocated to the beta blocker metoprolol (10 mg/kg/day) or vehicle. In vivo and in vitro cardiac assessments were performed. Cardiac tissue was extracted, and protein expression was quantified using immunoblotting. Histological analyses were performed to quantify myocardial fibrosis. Beta blockade attenuated cardiac pathological remodelling in nephrectomised animals. The echocardiographic left ventricular mass and the heart weight to tibial length ratio were significantly lower in nephrectomised animals treated with metoprolol. Furthermore, beta blockade attenuated myocardial fibrosis associated with subtotal nephrectomy. In addition, the Ca++- calmodulin-dependent kinase II (CAMKII) pathway was shown to be activated in uremia and attenuated by beta blockade, offering a potential mechanism of action. In conclusion, beta blockade attenuated hypertrophic signalling pathways and ameliorated cardiac pathological remodelling in experimental uremia. The study provides a strong scientific rationale for repurposing beta blockers, a tried and tested treatment in heart failure, for the benefit of patients with CKD.

Differential Effects of the Betablockers Carvedilol, Metoprolol and Bisoprolol on Cardiac Kv4.3 (Ito) Channel Isoforms.

Cardiac Kv4.3 channels contribute to the transient outward K+ current, Ito, during early repolarization of the cardiac action potential. Two different isoforms of Kv4.3 are present in the human ventricle and exhibit differential remodeling in heart failure (HF). Cardioselective betablockers are a cornerstone of HF with reduced ejection fraction therapy as well as ventricular arrhythmia treatment. In this study we examined pharmacological effects of betablockers on both Kv4.3 isoforms to explore their potential for isoform-specific therapy. Kv4.3 isoforms were expressed in Xenopus laevis oocytes and incubated with the respective betablockers. Dose-dependency and biophysical characteristics were examined. HEK 293T-cells were transfected with the two Kv4.3 isoforms and analyzed with Western blots. Carvedilol (100 µM) blocked Kv4.3 L by 77 ± 2% and Kv4.3 S by 67 ± 6%, respectively. Metoprolol (100 µM) was less effective with inhibition of 37 ± 3% (Kv4.3 L) and 35 ± 4% (Kv4.3 S). Bisoprolol showed no inhibitory effect. Current reduction was not caused by changes in Kv4.3 protein expression. Carvedilol inhibited Kv4.3 channels at physiologically relevant concentrations, affecting both isoforms. Metoprolol showed a weaker blocking effect and bisoprolol did not exert an effect on Kv4.3. Blockade of repolarizing Kv4.3 channels by carvedilol and metoprolol extend their pharmacological mechanism of action, potentially contributing beneficial antiarrhythmic effects in normal and failing hearts.

Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy (PRADA): Extended Follow-Up of a 2×2 Factorial, Randomized, Placebo-Controlled, Double-Blind Clinical Trial of Candesartan and Metoprolol.

BACKGROUND: Adjuvant breast cancer therapy containing anthracyclines with or without anti-human epidermal growth factor receptor-2 antibodies and radiotherapy is associated with cancer treatment-related cardiac dysfunction. In the PRADA trial (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy), concomitant treatment with the angiotensin receptor blocker candesartan attenuated the reduction in left ventricular ejection fraction (LVEF) in women receiving treatment for breast cancer, whereas the ß-blocker metoprolol attenuated the increase in cardiac troponins. This study aimed to assess the long-term effects of candesartan and metoprolol or their combination to prevent a reduction in cardiac function and myocardial injury. METHODS: In this 2×2 factorial, randomized, placebo-controlled, double-blind, single-center trial, patients with early breast cancer were assigned to concomitant treatment with candesartan cilexetil, metoprolol succinate, or matching placebos. Target doses were 32 and 100 mg, respectively. Study drugs were discontinued after adjuvant therapy. All 120 validly randomized patients were included in the intention-to-treat analysis. The primary outcome measure was change in LVEF assessed by cardiovascular magnetic resonance imaging from baseline to extended follow-up. Secondary outcome measures included changes in left ventricular volumes, echocardiographic peak global longitudinal strain, and circulating cardiac troponin concentrations. RESULTS: A small decline in LVEF but no significant between-group differences were observed from baseline to extended follow-up, at a median of 23 months (interquartile range, 21 to 28 months) after randomization (candesartan, 1.7% [95% CI, 0.5 to 2.8]; no candesartan, 1.8% [95% CI, 0.6 to 3.0]; metoprolol, 1.6% [95% CI, 0.4 to 2.7]; no metoprolol, 1.9% [95% CI, 0.7 to 3.0]). Candesartan treatment during adjuvant therapy was associated with a significant reduction in left ventricular end-diastolic volume compared with the noncandesartan group (P=0.021) and attenuated decline in global longitudinal strain (P=0.046) at 2 years. No between-group differences in change in cardiac troponin I and T concentrations were observed. CONCLUSIONS: Anthracycline-containing adjuvant therapy for early breast cancer was associated with a decline in LVEF during extended follow-up. Candesartan during adjuvant therapy did not prevent reduction in LVEF at 2 years, but was associated with modest reduction in left ventricular end-diastolic volume and preserved global longitudinal strain. These results suggest that a broadly administered cardioprotective approach may not be required in most patients with early breast cancer without preexisting cardiovascular disease. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01434134.

Identification of Metoprolol Tartrate-Derived Reactive Metabolites Possibly Correlated with Its Cytotoxicity.

As a selective ß1-receptor antagonist, metoprolol tartrate (MTA) is commonly used to treat cardiovascular diseases such as hypertension and angina pectoris. There have been cases of liver injury induced by MTA, but the mechanism of hepatotoxicity induced by MTA is not clear. The purposes of this study were to identify the reactive metabolites of MTA, to determine the pathway for the metabolic activation of MTA, and to define a possible correlation between the metabolic activation and cytotoxicity of MTA. Three oxidative metabolites (M1-M3), a glutathione (GSH) conjugate (M4), and an N-acetyl cysteine (NAC) conjugate (M5) were detected in rat liver microsomal incubations containing MTA and GSH or NAC. M4 was also detected in cultured rat primary hepatocytes and bile of rats given MTA, and M5 was detected in the urine of MTA-treated rats. A quinone methide intermediate may be produced from the metabolic activation process in vitro and in vivo. The metabolite was reactive to glutathione and N-acetyl cysteine. MTA induced marked cytotoxicity in cultured rat primary hepatocytes. Pretreatment of aminobenzotriazole, a nonselective P450 enzyme inhibitor, attenuated the susceptibility of hepatocytes to MTA cytotoxicity.

Possible effects of the central adrenergic and dopaminergic receptors on hypophagia induced by neuromedin S in neonatal layer-type chicks.

The current study was aimed to determine the possible effects of the central adrenergic and dopaminergic receptors in neuromedin S (NMS)-induced hypophagia in neonatal layer-type chickens. In the first experiment, control solution, and NMS (0.25, 0.5, and 1 nmol), were injected (intracerebroventricular (ICV)) in chickens. In the second experiment, birds were injected with a control solution,SCH23390 (D1receptor antagonist, 5 nmol), NMS (1 nmol), and a combination of the SCH23390 + NMS. Experiments 3-11 were similar to experiment 2, except that chickens were injected withAMI-193 (D2receptor antagonist, 5 nmol), NGB2904(D3receptor antagonist, 6.4 nmol), L-741,742(D4receptor antagonist, 6 nmol), 6-OHDA(6-hydroxydopamine, 2.5 nmol),Prazosin(α1receptor antagonist, 10 nmol),Yohimbine(α2receptor antagonist, 13 nmol),Metoprolol(ß1receptor antagonist receptor, 24 nmol),ICI 118,551 (ß2receptor antagonist, 5 nmol),SR 59230R (ß3 receptor antagonist, 20 nmol) instead ofSCH23390. Then, cumulative food intake was recorded at 30, 60, and 120 min following the injection. According to the results, food intake was significantly decreased after ICV injection of NMS in a dose -dependent manner (P < 0.05). Also, the co-injection of the SCH23390 + NMS significantly attenuated NMS-induced hypophagia (P < 0.05). The co-administration of AMI-193 + NMS significantly reduced NMS- induced hypophagia (P < 0.05). In addition, the co-injection of ICI 118,551 + NMS and 6-OHDA + NMS considerably decreased NMS-induced food consumption (P < 0.05). However, NGB2904, L-741742, Prazosin, Yohimbine, Metoprolol and SR 59230R had no effect on hypophagia induced by NMS (P > 0.05). These results demonstrated thatNMS- induced hypophagia might be mediated by D1/D2 dopaminergic andß2adrenergic receptors in neonatal layer-type chickens.

Macrophage polarization is involved in liver fibrosis induced by ß 1-adrenoceptor autoantibody.

Accumulating evidence suggests that liver injury can be induced by the over-expression of ß 1-adrenergic receptors (ß 1-ARs). High titers of autoantibodies specific to ß 1-adrenergic receptors (ß 1-AA) are detected in the sera of heart failure patients, potentially playing agonist-like roles. However, the role of ß 1-AA in liver function has not been characterized. In this study, we collect the sera of primary biliary cholangitis (PBC) patients, a condition which easily develops into liver fibrosis, and analyze the relationship between PBC and ß 1-AA. A passive immunization model is established to assess the effect of ß 1-AA on the liver. Subsequently, the effect of ß 1-AA on macrophages is investigated in vitro. Results show that PBC patients have a high titer and ratio of ß 1-AA, compared to controls. Liver injury and fibrosis are induced by ß 1-AA. In vitro experiments with ROS probe demonstrate that ß 1-AA induces macrophages to produce ROS and secrete TNFα. These effects can be partially reversed by metoprolol, a blocker for ß 1-AR. Results from the transwell and phagocytosis assays show that ß 1-AA promotes macrophage migration and phagocytosis. FCM tests suggest that ß 1-AA induces the alteration of M1 rather than M2 markers in macrophages. Finally, the Annexin V/PI assay indicates that macrophage culture supernatants stimulated by ß 1-AA cause hepatocyte apoptosis. Overall, these results suggest that ß 1-AA is involved in PBC. The ß 1-AA-induced activation, phagocytosis and phenotypic modification of macrophages may play an important role in the development of hepatic fibrosis and injury.

The effects of carvedilol, metoprolol and propranolol on cisplatin-induced kidney injury.

The ß-adrenoceptor blockers may have anti-oxidant properties or induce ß-arrestin recruitment beyond classical desensitization of receptor/G protein coupling, offering potential therapeutic benefits. Here, we investigated the effects of carvedilol, metoprolol and propranolol in an animal model of cisplatin-induced nephrotoxicity. Rats received the ß-blockers (3 or 12 mg/kg/day) with or without cisplatin, and kidney function was investigated using renal scintigraphy, histopathology, and serum variables. Metoprolol and propranolol as well as low-dose carvedilol did not alter kidney function, per se. Meanwhile, high-dose carvedilol reduced renal accumulation of Technetium-99m (99mTc)-labeled dimercaptosuccinic acid (99mTc-DMSA) without significant effect on other variables. Furthermore, low-dose carvedilol prevented cisplatin-induced reduction of tracer uptake, but high-dose of this drug aggravated the situation. In this regard, both low and high -doses of carvedilol significantly inhibited cisplatin effects on kidney histology, BUN and creatinine levels. Also, high-dose propranolol inhibited cisplatin adverse effects on radiotracer uptake, histological manifestations, BUN and creatinine levels, while metoprolol failed to cause a notable effect. Taken together, carvedilol and high-dose propranolol may offer potential benefits in cisplatin nephrotoxicity.

What is the Best Agent for Rate Control of Atrial Fibrillation With Rapid Ventricular Response?

BACKGROUND: Atrial fibrillation (AF) is a common dysrhythmia associated with significant morbidity and mortality. Although many patients have stable AF, some patients can present with a rapid ventricular response (RVR). In these patients, it is important to lower their heart rate. However, there are several options available for rate control in the emergency department setting. CLINICAL QUESTION: What is the most effective agent for rate control for the patient with AF in RVR? EVIDENCE REVIEW: Studies retrieved included two prospective, randomized, double-blind studies and six retrospective cohort studies. These studies provide estimates of the efficacy and safety of calcium channel blockers and ß-blockers for rate control in those with AF with RVR. CONCLUSION: Based upon the available literature, diltiazem likely achieves rate control faster than metoprolol, though both agents seem safe and effective. Clinicians must consider the individual patient, clinical situation, and comorbidities when selecting a medication for rate control.

Pharmacokinetics and pharmacodynamics of oral and intravenous metoprolol tartrate in clinically healthy horses.

Cardiac drugs with defined pharmacological parameters in horses are limited. The objective of this study was to characterize the pharmacokinetic properties and cardiovascular effects of intravenous and oral metoprolol tartrate (MET) in horses. In a 2-period randomized cross-over design, MET was administered IV (0.04 mg/kg) and PO (6 mg/kg) once to six healthy adult horses. Horses were monitored via continuous telemetry and non-invasive blood pressure (NIBP). Blood samples were serially collected for 72 h post-administration, and concentrations were determined by LC-MS/MS. Pharmacokinetics were modeled using a 3-compartment model and non-linear least squares regression. Median (range) MET concentration was 110 (40.1-197) ng/ml collected 1 min (0.0167 h) after a bolus IV administration. Maximum concentration (Cmax ) after PO administration was 2135 (1590-4170) ng/ml at 0.5 (0.25-0.5) hours. Oral bioavailability was 54% (17-100%). Median apparent volume of distribution was 0.39 (0.17-0.58) l/kg, clearance was 12.63 (11.41-18.94) ml/kg/min, and elimination half-life was 21.1 (7.46-34.36) minutes. No clinically relevant effects of IV or PO metoprolol were noted on cardiac rhythm or NIBP. Sweating was the most common side effect. The metoprolol doses used in this study achieve plasma concentrations reported to achieve ß-blockade in humans.

Carvedilol Selectively Stimulates ßArrestin2-Dependent SERCA2a Activity in Cardiomyocytes to Augment Contractility.

Heart failure (HF) carries the highest mortality in the western world and ß-blockers [ß-adrenergic receptor (AR) antagonists] are part of the cornerstone pharmacotherapy for post-myocardial infarction (MI) chronic HF. Cardiac ß1AR-activated ßarrestin2, a G protein-coupled receptor (GPCR) adapter protein, promotes Sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2a SUMO (small ubiquitin-like modifier)-ylation and activity, thereby directly increasing cardiac contractility. Given that certain ß-blockers, such as carvedilol and metoprolol, can activate ßarrestins and/or SERCA2a in the heart, we investigated the effects of these two agents on cardiac ßarrestin2-dependent SERCA2a SUMOylation and activity. We found that carvedilol, but not metoprolol, acutely induces ßarrestin2 interaction with SERCA2a in H9c2 cardiomyocytes and in neonatal rat ventricular myocytes (NRVMs), resulting in enhanced SERCA2a SUMOylation. However, this translates into enhanced SERCA2a activity only in the presence of the ß2AR-selective inverse agonist ICI 118,551 (ICI), indicating an opposing effect of carvedilol-occupied ß2AR subtype on carvedilol-occupied ß1AR-stimulated, ßarrestin2-dependent SERCA2a activation. In addition, the amplitude of fractional shortening of NRVMs, transfected to overexpress ßarrestin2, is acutely enhanced by carvedilol, again in the presence of ICI only. In contrast, metoprolol was without effect on NRVMs' shortening amplitude irrespective of ICI co-treatment. Importantly, the pro-contractile effect of carvedilol was also observed in human induced pluripotent stem cell (hIPSC)-derived cardiac myocytes (CMs) overexpressing ßarrestin2, and, in fact, it was present even without concomitant ICI treatment of human CMs. Metoprolol with or without concomitant ICI did not affect contractility of human CMs, either. In conclusion, carvedilol, but not metoprolol, stimulates ßarrestin2-mediated SERCA2a SUMOylation and activity through the ß1AR in cardiac myocytes, translating into direct positive inotropy. However, this unique ßarrestin2-dependent pro-contractile effect of carvedilol may be opposed or masked by carvedilol-bound ß2AR subtype signaling.

Sildenafil administration improves right ventricular function on 4D flow MRI in young adults born premature.

Extreme preterm birth conveys an elevated risk of heart failure by young adulthood. Smaller biventricular chamber size, diastolic dysfunction, and pulmonary hypertension may contribute to reduced ventricular-vascular coupling. However, how hemodynamic manipulations may affect right ventricular (RV) function and coupling remains unknown. As a pilot study, 4D flow MRI was used to assess the effect of afterload reduction and heart rate reduction on cardiac hemodynamics and function. Young adults born premature were administered sildenafil (a pulmonary vasodilator) and metoprolol (a ß blocker) on separate days, and MRI with 4D flow completed before and after each drug administration. Endpoints include cardiac index (CI), direct flow fractions, and ventricular kinetic energy including E/A wave kinetic energy ratio. Sildenafil resulted in a median CI increase of 0.24 L/min/m2 (P = 0.02), mediated through both an increase in heart rate (HR) and stroke volume. Although RV ejection fraction improved only modestly, there was a significant increase (4% of end diastolic volume) in RV direct flow fraction (P = 0.04), consistent with hemodynamic improvement. Metoprolol administration resulted in a 5-beats/min median decrease in HR (P = 0.01), a 0.37 L/min/m2 median decrease in CI (P = 0.04), and a reduction in time-averaged kinetic energy (KE) in both ventricles (P < 0.01), despite increased RV diastolic E/A KE ratio (P = 0.04). Despite reduced right atrial workload, metoprolol significantly depressed overall cardiac systolic function. Sildenafil, however, increased CI and improved RV function, as quantified by the direct flow fraction. The preterm heart appears dependent on HR but sensitive to RV afterload manipulations.NEW & NOTEWORTHY We assessed the effect of right ventricular afterload reduction with sildenafil and heart rate reduction with metoprolol on cardiac hemodynamics and function in young adults born premature using 4D flow MRI. Metoprolol depressed cardiac function, whereas sildenafil improved cardiac function including right ventricular direct flow fraction by 4D flow, consistent with hemodynamic improvement. This suggests that the preterm heart is dependent on heart rate and sensitive to right ventricular afterload changes.

Metoprolol Impairs ß1-Adrenergic Receptor-Mediated Vasodilation in Rat Cerebral Arteries: Implications for ß-Blocker Therapy.

The practice of prescribing ß-blockers to lower blood pressure and mitigate perioperative cardiovascular events has been questioned because of reports of an increased risk of stroke. The benefit of ß-blocker therapy primarily relies on preventing activation of cardiac ß1-adrenergic receptors (ARs). However, we reported that ß1ARs also mediate vasodilator responses of rat cerebral arteries (CAs), implying that ß-blockers may impair cerebral blood flow under some conditions. Here, we defined the impact of metoprolol (MET), a widely prescribed ß1AR-selective antagonist, on adrenergic-elicited diameter responses of rat CAs ex vivo and in vivo. MET (1-10 µmol/l) prevented ß1AR-mediated increases in diameter elicited by dobutamine in cannulated rat CAs. The ß1AR-mediated dilation elicited by the endogenous adrenergic agonist norepinephrine (NE) was reversed to a sustained constriction by MET. Acute oral administration of MET (30 mg/kg) to rats in doses that attenuated resting heart rate and dobutamine-induced tachycardia also blunted ß1AR-mediated dilation of CAs. In the same animals, NE-induced dilation of CAs was reversed to sustained constriction. Administration of MET for 2 weeks in drinking water (2 mg/ml) or subcutaneously (15 mg/kg per day) also resulted in NE-induced constriction of CAs in vivo. Thus, doses of MET that protect the heart from adrenergic stimulation also prevent ß1AR-mediated dilation of CAs and favor anomalous adrenergic constriction. Our findings raise the possibility that the increased risk of ischemic stroke in patients on ß-blockers relates in part to adrenergic dysregulation of cerebrovascular tone. SIGNIFICANCE STATEMENT: ß-Blocker therapy using second-generation, cardioselective ß-blockers is associated with an increased risk of stroke, but the responsible mechanisms are unclear. Here, we report that either acute or chronic systemic administration of a cardioselective ß-blocker, metoprolol, mitigates adrenergic stimulation of the heart as an intended beneficial action. However, metoprolol concomitantly eliminates vasodilator responses to adrenergic stimuli of rat cerebral arteries in vivo as a potential cause of dysregulated cerebral blood flow predisposing to ischemic stroke.

ß-blockade prevents coronary macro- and microvascular dysfunction induced by a high salt diet and insulin resistance in the Goto-Kakizaki rat.

A high salt intake exacerbates insulin resistance, evoking hypertension due to systemic perivascular inflammation, oxidative-nitrosative stress and endothelial dysfunction. Angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blockers (ARBs) have been shown to abolish inflammation and redox stress but only partially restore endothelial function in mesenteric vessels. We investigated whether sympatho-adrenal overactivation evokes coronary vascular dysfunction when a high salt intake is combined with insulin resistance in male Goto-Kakizaki (GK) and Wistar rats treated with two different classes of ß-blocker or vehicle, utilising synchrotron-based microangiography in vivo. Further, we examined if chronic carvedilol (CAR) treatment preserves nitric oxide (NO)-mediated coronary dilation more than metoprolol (MET). A high salt diet (6% NaCl w/w) exacerbated coronary microvessel endothelial dysfunction and NO-resistance in vehicle-treated GK rats while Wistar rats showed modest impairment. Microvascular dysfunction was associated with elevated expression of myocardial endothelin, inducible NO synthase (NOS) protein and 3-nitrotyrosine (3-NT). Both CAR and MET reduced basal coronary perfusion but restored microvessel endothelium-dependent and -independent dilation indicating a role for sympatho-adrenal overactivation in vehicle-treated rats. While MET treatment reduced myocardial nitrates, only MET treatment completely restored microvessel dilation to dobutamine (DOB) stimulation in the absence of NO and prostanoids (combined inhibition), indicating that MET restored the coronary flow reserve attributable to endothelium-derived hyperpolarisation (EDH). In conclusion, sympatho-adrenal overactivation caused by high salt intake and insulin resistance evoked coronary microvessel endothelial dysfunction and diminished NO sensitivity, which were restored by MET and CAR treatment in spite of ongoing inflammation and oxidative-nitrosative stress presumably caused by uninhibited renin-angiotensin-aldosterone system (RAAS) overactivation.

Speeding up beta-blockade prior to coronary CT angiography: can we predict the dose of intravenous metoprolol required to achieve target heart rate in a given patient?

AIM: To evaluate the use and safety of intravenous (IV) metoprolol in a cohort of patients undergoing coronary computed tomographic angiography (CCTA) at a university hospital, and in particular, to establish if the minimum dose required to achieve the target heart rate (HR) in a given patient can be predicted from the baseline HR. MATERIALS AND METHODS: Patients undergoing CCTA at a tertiary centre between January 2015 and May 2018, with baseline HR ≥60 bpm requiring IV metoprolol, were identified retrospectively from the database. Patients with a contraindication to beta-blockade or an indication for CCTA other than coronary disease were excluded. HR at baseline and at the time of scanning were recorded, together with the total dose of IV metoprolol administered. RESULTS: Of 625 patients identified, 330 (52.8%) achieved HR ≤60 with IV metoprolol. Patients who achieved target HR had lower baseline HR. They received a lower radiation exposure due to tight prospective gating and a lower tube voltage. The lower quartile dose of metoprolol administered was 5 mg for patients with baseline HR <65 beats per minute (bpm), but 10 mg for HR 65-74 bpm, and ≥20 mg for higher HRs. There were no cases of symptomatic bradycardia/hypotension. CONCLUSION: Patients with a resting HR of ≥60 bpm can reasonably be given an initial minimum dose of 5-20 mg metoprolol IV before CCTA, with additional doses as required.

Evaluation of metoprolol versus diltiazem for rate control of atrial fibrillation in the emergency department.

OBJECTIVE: The purpose of this study was to compare the effectiveness and safety of the metoprolol and diltiazem administration in the Emergency Department (ED) for rate control of supraventricular tachycardia. METHODS: This was a retrospective cohort study of adult patients who presented to the ED with ventricular rates ≥120 beats per minute (bpm) and who received bolus doses of either intravenous metoprolol or intravenous diltiazem. The primary outcome was achievement of rate control, defined as heart rate < 110 bpm, at two hours after administration of the last bolus dose of metoprolol or diltiazem. Safety outcomes included occurrence of hypotension, defined as systolic blood pressure < 90 mmHg or diastolic blood pressure < 60 mmHg, and bradycardia, defined as heart rate < 60 bpm. RESULTS: There were 166 patients receiving metoprolol and 183 patients receiving diltiazem included in the study. The primary outcome, rate control at two hours after the last bolus dose of metoprolol or diltiazem was similar between the two groups (45.8% vs 42.6%, p = 0.590, respectively). The percentage of patients achieving rate control was also similar (47.0% vs 41.6%, p = 0.333) at one hour. At 0.5 h HR had a significantly greater numerical (diltiazem: 29.3 ± 23.1 bpm vs metoprolol: 21.8 ± 18.9 bpm, p = 0.012) and percent decrease (21.1% vs 15.94%, p = 0.014) in the diltiazem group compared to metoprolol. There was no significant difference in occurrence of bradycardia in the two groups (diltiazem: 3.83% vs metoprolol: 1.2%, p = 0.179). More patients in the diltiazem group compared to the metoprolol group experienced hypotension (39.3% vs 23.5%, p = 0.002). The difference in systolic hypotension events was not significantly different (9.29% vs 5.42%, p = 0.221), while the difference in diastolic hypotension events was significantly different (37.7% vs 22.3%, p = 0.002). CONCLUSION: There was no difference in acute rate control effectiveness two hours after the last bolus dose of diltiazem and metoprolol for supraventricular tachycardias. There was a significantly higher occurrence of hypotension in the diltiazem group which was driven by higher rates of diastolic blood pressures less than 60 mmHg.