Effects of garden cress, fenugreek and black seed on the pharmacodynamics of metoprolol: an herb-drug interaction study in rats with hypertension.

CONTEXT: Garden cress (GC), fenugreek (FG), and black seed (BS) are traditional herbal medicine for managing hypertension. OBJECTIVE: The effects of the three herbs on the pharmacodynamics of metoprolol tartrate (MT) in hypertensive rats were investigated. MATERIALS AND METHODS: Wistar rats were divided in five groups (n = 6). Group I served as normal control group and Group II (hypertensive control group) had rats treated orally with N-nitro L-arginine methyl ester (L-NAME, 40 mg/kg/day) only. Groups III, IV, and V rats were orally treated with L-NAME (40 mg/kg/day) + GC (300 mg/kg, once daily), L-NAME (40 mg/kg/day) + FG (300 mg/kg, once daily) and L-NAME (40 mg/kg/day) + BS (300 mg/kg, once daily), respectively, for 2 weeks, and on the 14th day, blood pressure and heart rate were recorded using a tail-cuff blood pressure-measuring system. On the 16th day, a single dose of MT (10 mg/kg) was orally administered, and the rats' blood pressure and heart rate were recorded. RESULTS: GC, FG, and BS decreased systolic blood pressure (SBP) by 8.7%, 8.5%, and 8.7%, respectively, in hypertensive rats. A greater decrease in SBP by 14.5%, 14.8%, and 16.1% was observed when hypertensive rats were treated with L-NAME + GC + MT, L-NAME + FG + MT, and L-NAME + BS + MT, respectively. Similarly, hypertensive rats treated with the combination of herbs and MT had significantly lower diastolic blood pressure (DBP) than those treated with herbs alone and those treated with L-NAME alone. CONCLUSIONS: The combination of investigated herbs and MT had a beneficial effect on hypertension. However, the concurrent administration of drugs, particularly those predominantly cleared through CYP450 2D6-catalyzed metabolism, with the three investigated herbs should be considered with caution.

Modulatory properties of cardiac and quercetin glycosides from Dacryodes edulis seeds during L-NAME-induced vascular perturbation.

Background Numerous food wastes have been identified to possess potent bioactive compounds used for the treatment of several diseases. Therefore this study evaluated the potentials of cardiac and quercetin glycosides extracted from Dacryodes edulis seeds to reverse vascular and endothelial damage (VAED). Methods The glycoside composition of the seeds was extracted using standard methods and characterized by gas chromatography. We then recruited rats with L-NAME-induced VAED based on confirmatory biomarkers cardiac troponin (CnT), cellular adhesion molecule (VCAM-1), lipoprotein associated phospholipase A2 (Lp-PLA2), RAAS, VWF, endothelin, eNOx, and homocysteine. Only rats that showed total alterations of all biomarkers were recruited into the respective experimental groups and treated with either metaprolol succinate (met.su) + losartan or glycoside extracts of D. edulis seeds (NPSG). Results Chromatographic isolation of glycosides in the seed showed predominance of artemetin (1.59 mg/100 g), amygdalin (3.68 mg/100 g), digitoxin (19.21 mg/100 g), digoxin (27.23 mg/100 g), avicularin (133.59 mg/100 g), and hyperoside (481.76 mg/100 g). We observed decreased water intake and higher heart beats under vascular damage as the experiment progressed up to the fourth week. The met.su + losartan and H.D NPSG proved effective in restoring troponin, but both doses of NPSG normalized the VCAM-1 and RAAS activities excluding aldosterone and Lp-PLA2. Among the endothelial dysfunction biomarkers, H.D NPSG produced equivalent effects to met.su + losartan towards restoring the eNOx and VWF activities, but showed higher potency in normalizing the endothelin and Hcy levels. Conclusions We thus propose that the synergistic effect of the isolated glycosides from D. edulis shown in our study proved potent enough at high doses in treatment of vascular and endothelial dysfunction.

A High Throughput HPLC-MS/MS Method for Antihypertensive Drugs Determination in Plasma and Its Application on Pharmacokinetic Interaction Study with Shuxuetong Injection in Rats.

A high-throughput HPLC-MS/MS method was developed and validated for the determination of four antihypertensive drugs including metoprolol tartrate, hydrochlorothiazide, nifedipine, and valsartan in rat plasma. The Sprague-Dawley rats were randomly divided into three groups: A Group: gastric-administration of metoprolol tartrate, hydrochlorothiazide, nifedipine, or valsartan; B Group: a single intravenous injection of SXT, then dosing as the A group; C Group: daily injection of SXT through the tail vein for 8 consecutive days and dosing as the A group on the eighth day. For metoprolol tartrate and valsartan, blood samples were collected before administration and at time points 0.03, 0.08, 0.17, 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 h from the fossa orbitalis vein. For hydrochlorothiazide and nifedipine, the time points were 0, 0.08, 0.17, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, and 24 h. The plasma samples containing different individual antihypertensive drug were mixed and prepared by protein precipitation with methanol. The chromatographic separation was performed on an Agilent Eclipse Plus C18 column (2.1 mm×100 mm, 3.5 µm) using gradient elution with mobile phase consisting of acetonitrile and water (containing 0.1% formic acid). The flow rate was 0.3 mL/min. The detection was accomplished on a tandem mass spectrometer with an electrospray ionization (ESI) source by multiple reaction monitoring (MRM) in both positive and negative modes. The method was successfully applied to a pharmacokinetic interaction study of Shuxuetong injection on the antihypertensive drugs. The results suggested that SXT could increase the total amount of metoprolol tartrate and nifedipine in plasma and showed little influence on the pharmacokinetic behaviors of hydrochlorothiazide and valsartan.

Multi-dry-electrode plate sensor for non-invasive electrocardiogram and heart rate monitoring for the assessment of drug responses in freely behaving mice.

Monitoring of electrocardiogram (ECG) and heart rate (HR) is essential in a wide range of experiments. For conscious animal studies, telemetry is the preferred approach; however, it requires 1-3 weeks of recovery after surgical device-implantation. The present paper describes a novel multi-dry-electrode plate (MDEP) sensor system to monitor ECG/HR in freely behaving mice without the need for surgery for device/electrode implantation. The MDEP sensor is a rectangular plate with 15 gold-plated stripe pattern electrodes, on which a mouse can walk around freely, and detects ECG whenever ≥2 paws (footpads) come in contact with the electrodes. Here we show that the MDEP sensor detected distinct QRS complexes which, were fragmented due to locomotion and insufficient perspiration on the footpads. Nonetheless, the HR calculated from the QRS complexes were similar to the HR calculated from R-R intervals simultaneously recorded from lead-II ECG (difference = 0.0 ±â€¯0.16 ms) as part of the validation exercise. Also, the archetypal responses to isoproterenol and metoprolol injections were successfully detected as a significantly elevation (+151 ±â€¯15 bpm) and reduction (-77 ±â€¯6 bpm) in HR, respectively, compared to vehicle at 20-60 min postdose. Conversely, the P wave was rarely identifiable unless signal averaging was undertaken. These results indicate a potential utility for the MDEP-sensor system for cardiac pharmacological studies. In addition, signal averaging appeared to be effective for detection of ECG intervals such as PR and QT, although the QT cannot be measured in the mouse heart as there is no T wave.

Targeting multiple pathways reduces renal and cardiac fibrosis in rats with subtotal nephrectomy followed by coronary ligation.

AIM: Multiple interacting pathways contribute to progression of renal and cardiac damage in chronic kidney disease followed by chronic heart failure (renocardiac syndrome). We hypothesized that simultaneous pharmacological modulation of critical pathways implicated in renocardiac syndrome would effectively reduce fibrosis in and preserve function of heart and kidney. METHODS: Rats were subjected to subtotal nephrectomy followed 9 weeks later by coronary artery ligation. From week 11 until week 16, rats received vehicle or losartan, or a combination of the NF-kB inhibitor PDTC, the NO donor molsidomine and superoxide dismutase mimetic tempol, or a combination of all four of these plus metoprolol together. At week 16, renal and cardiac structure, function and gene expression were assessed. RESULTS: Individual and combined treatments were similarly effective in limiting cardiac fibrosis and further decline in systolic function. Combined treatment with all five drugs reduced renal fibrosis and CTGF gene expression more effectively than other strategies. Combining all five drugs reduced heart rate, inotropy and mean arterial pressure (MAP). CONCLUSION: Thus, in our model of chronic renocardiac syndrome, combined treatments similarly decreased cardiac fibrosis and stabilized systolic function as losartan alone, perhaps suggesting a dominant role for a single factor such as angiotensin II type 1 (AT1) receptor activation or inflammation in the network of aberrant systems in the heart. However, tubulointerstitial fibrosis was most effectively reduced by a five-drug regimen, pointing to additive effects of multiple pathophysiological pathways in the kidney.

Pharmaceutical Metabolism in Fish: Using a 3-D Hepatic In Vitro Model to Assess Clearance.

At high internal doses, pharmaceuticals have the potential for inducing biological/pharmacological effects in fish. One particular concern for the environment is their potential to bioaccumulate and reach pharmacological levels; the study of these implications for environmental risk assessment has therefore gained increasing attention. To avoid unnecessary testing on animals, in vitro methods for assessment of xenobiotic metabolism could aid in the ecotoxicological evaluation. Here we report the use of a 3-D in vitro liver organoid culture system (spheroids) derived from rainbow trout to measure the metabolism of seven pharmaceuticals using a substrate depletion assay. Of the pharmaceuticals tested, propranolol, diclofenac and phenylbutazone were metabolised by trout liver spheroids; atenolol, metoprolol, diazepam and carbamazepine were not. Substrate depletion kinetics data was used to estimate intrinsic hepatic clearance by this spheroid model, which was similar for diclofenac and approximately 5 fold higher for propranolol when compared to trout liver microsomal fraction (S9) data. These results suggest that liver spheroids could be used as a relevant and metabolically competent in vitro model with which to measure the biotransformation of pharmaceuticals in fish; and propranolol acts as a reproducible positive control.

Cost-effectiveness of nitrendipine and hydrochlorothiazide or metoprolol to treat hypertension in rural community health centers in China.

OBJECTIVES: The objective of this article is to compare blood pressure (BP)-lowing effects of nitrendipine and hydrochlorothiazide and nitrendipine and metoprolol, and estimate the economic effect of these therapies on hypertension. METHODS: Outpatients (N = 793) 18-70 years of age with stage 2 or severe hypertension (SBP ≥ 160 mmHg and/or DBP ≥ 100 mmHg) were recruited from four randomly selected rural community health centers in Beijing and Jilin. After drug wash out, they were randomly divided into nitrendipine and hydrochlorothiazide group or nitrendipine and metoprolol group. The costs of drug treatment for hypertension were calculated and general estimation, whereas effectiveness was measured as a reduction in SBP and DBP at the end of a 24-week study period. RESULTS: Overall, 623 patients were eligible for the study and after a 24-week follow-up, SBP and DBP were 131.2/82.2 mmHg for the nitrendipine and hydrochlorothiazide group and 131.4/82.9 mmHg for the nitrendipine and metoprolol group and these were not significantly different (P = 0.7974 SBP and P = 0.1166 DBP). Comparing with nitrendipine and metoprolol, the cost of nitrendipine and hydrochlorothiazide was less, and its effectiveness was similar. The cost/effect ratio (US$/mmHg) was 1.4 for SBP and 2.8 for DBP for the nitrendipine and hydrochlorothiazide group, and 1.9 and 3.8 for the nitrendipine and metoprolol group's SBP and DBP values, respectively. The incremental cost per patient for achieving target BP was 5.1. Adverse events were mild or moderate and there were no differences between treatment groups. CONCLUSION: Treating hypertension with nitrendipine and hydrochlorothiazide was cost-effective than nitrendipine and metoprolol, and these data will allow more reasonable and efficient allocation of limited resources in low-income countries.

Promising approach for the preclinical assessment of cardiac risks using left ventricular pressure-volume loop analyses in anesthetized monkeys.

INTRODUCTION: Load-independent cardiac parameters obtained from the ventricular pressure-volume relationship are recognized as gold standard indexes for evaluating cardiac inotropy. In this study, for better analyses of cardiac risks, load-independent pressure-volume loop parameters were assessed in addition to load-dependent inotropic, hemodynamic and electrocardiographic changes in isoflurane-anesthetized monkeys. METHODS: The animals were given milrinone (a PDE 3 inhibitor), metoprolol (a ß-blocker), or dl-sotalol (a ß+IKr blocker) intravenously over 10min at two dose levels including clinically relevant doses (n=5/drug). RESULTS: Milrinone and metoprolol produced positive and negative inotropy, respectively. These effects were detected as changes in the slope of the preload-recruitable stroke work, which is a load-independent inotropic parameter. However, dl-sotalol did not alter the slope of the preload-recruitable stroke work. That means dl-sotalol produced no inotropy, although it decreased load-dependent inotropic parameters, including maximal upstroke velocity of left ventricular pressure, attributable to decreased heart rate and blood pressure. Other typical pharmacological effects of the compounds tested were also detected. Both ß-blockers produced PR prolongation, decreased left ventricular end-systolic pressure, increased left ventricular end-diastolic pressure, and increased maximal descending velocity of left ventricular pressure and time constant for isovolumic relaxation. dl-Sotalol also prolonged heart-rate-corrected QT interval. Milrinone induced reflex tachycardia, PR shortening, and decreased left ventricular end-diastolic pressure. DISCUSSION: The overall assessment by not only load-dependent inotropic parameters but also load-independent parameters obtained from the ventricular pressure-volume loop analysis using monkeys can provide further appropriate information for the assessment of drug-induced cardiac risks.

Lotus leaf alkaloid fraction can strongly inhibit CYP2D6 isoenzyme activity.

ETHNOPHARMACOLOGICAL RELEVANCE: The Chinese herbal medicine He-Ye, the leaves of the lotus (Nelumbo nucifera) plant, is traditionally used in China for the treatment of sunstroke, thirst, diarrhea, and fever. Currently, the leaf is used not only as an herbal tea to reduce lipid level and control body weight, but also as a major ingredient in some lipid-lowering Chinese patented medicines. Our previous study demonstrated that the alkaloid fraction (AF) of the herb has a strong inhibitory effect on CYP2D6 isoenzyme activity in vitro. The present study aims to further verify this activity using the in vivo rat model and to explore the inhibitory mechanism on CYP2D6 using human liver microsomes (HLMs). MATERIALS AND METHODS: After a continuous 7-d oral dose of AF (50mg/kg) or a vehicle, Sprague Dawley rats received a single intravenous dose of dextromethorphan or metoprolol. Blood samples were collected at various time points, and the plasma concentrations of the relevant metabolites dextrorphan and hydroxymetoprolol were assayed by LC-MS/MS for evaluating the effect of AF on their pharmacokinetics and CYP2D6 activity. Dextromethorphan as a probe at different concentrations was incubated with HLMs in an incubation buffer system, in the presence or absence of AF at different concentrations. After incubation, the produced metabolite was assayed. RESULTS: After being pretreated with AF in rats, the plasma concentrations of dextrorphan and hydroxymetoprolol significantly decreased, with Cmax going from 79.44 to 29.96 and 151.18 to 83.39hng/mL (P<0.05), AUCall from 167.27 to 62.25 and 347.68 to 223.24hng/mL (P<0.05), and AUCinf from 183.39 to 84.76 and 350.59 to 234.57hng/mL (P<0.05), respectively, in comparison with those of untreated rats. The t1/2 of hydroxymetoprolol significantly increased from 1.14 to 1.99h (P<0.05). The in vitro incubation test showed that AF competitively inhibited the CYP2D6, with apparent Ki value of 0.64µg/mL. CONCLUSIONS: AF can strongly inhibit the activity of CYP2D6 enzyme, as confirmed by in vivo and in vitro models. Possible drug interactions may occur between AF and other medications metabolized by CYP2D6. Thus, caution should be paid when the lotus leaf and its preparations are concurrently administered with conventional medicines.

Osteogenic actions of metoprolol in an ovariectomized rat model of menopause.

OBJECTIVE: Osteoporosis and hypertension are age-related chronic diseases with increased morbidity rates among postmenopausal women. Clinical epidemiological investigations have demonstrated that hypertensive patients treated with ß1-selective ß-blockers have a higher bone mineral density (BMD) and lower fracture risk. Nevertheless, no fundamental studies have examined the relationships between ß1-selective ß-blockers and these effects. The present study explored the effects and mechanisms of metoprolol in the in vitro treatment of osteoblasts and the in vivo treatment of ovariectomy-induced osteoporosis in rats. METHODS: Primary osteoblasts were obtained by digestion of the cranial bones of 24-hour-old Sprague-Dawley rats. After metoprolol treatment, cell proliferation and differentiation capacities were assessed at the corresponding time points. In addition, 3-month-old female Sprague-Dawley rats (200-220 g) were divided into a sham-operated group (n = 8) and three ovariectomized (OVX) (bilateral removal of ovaries) groups as follows: vehicle (OVX; n = 8), low-dose metoprolol (L-M, oral, 120 mg/kg/d; n = 8), and high-dose metoprolol (H-M, oral, 240 mg/kg/d; n = 8). After 12 weeks of metoprolol treatment, BMD, microarchitecture, and biomechanical properties were evaluated. RESULTS: The results indicated that the treatments with 0.01 to 0.1 µM metoprolol increased osteoblast proliferation, alkaline phosphatase activity, and calcium mineralization, and promoted the expression of osteogenic genes. The in vivo study indicated that administration of metoprolol to OVX rats resulted in maintenance of the BMDs of the L4 vertebrae. Moreover, amelioration of trabecular microarchitecture deterioration and preservation of bone biomechanical properties were detected in the trabecular bones of the OVX rats. CONCLUSIONS: Our findings indicate that metoprolol prevents estrogen deficiency-induced bone loss by increasing the number and enhancing the biological functions of osteoblasts, implying its potential use as an alternative treatment for postmenopausal osteoporosis in hypertensive patients.

Atomic force microscopy combined with human pluripotent stem cell derived cardiomyocytes for biomechanical sensing.

Cardiomyocyte contraction and relaxation are important parameters of cardiac function altered in many heart pathologies. Biosensing of these parameters represents an important tool in drug development and disease modeling. Human embryonic stem cells and especially patient specific induced pluripotent stem cell-derived cardiomyocytes are well established as cardiac disease model.. Here, a live stem cell derived embryoid body (EB) based cardiac cell syncytium served as a biorecognition element coupled to the microcantilever probe from atomic force microscope thus providing reliable micromechanical cellular biosensor suitable for whole-day testing. The biosensor was optimized regarding the type of cantilever, temperature and exchange of media; in combination with standardized protocol, it allowed testing of compounds and conditions affecting the biomechanical properties of EB. The studied effectors included calcium , drugs modulating the catecholaminergic fight-or-flight stress response such as the beta-adrenergic blocker metoprolol and the beta-adrenergic agonist isoproterenol. Arrhythmogenic effects were studied using caffeine. Furthermore, with EBs originating from patient's stem cells, this biosensor can help to characterize heart diseases such as dystrophies.

In Vitro CYP2D Inhibitory Effect and Influence on Pharmacokinetics and Pharmacodynamic Parameters of Metoprolol Succinate by Terminalia arjuna in Rats.

BACKGROUND: Terminalia arjuna Wight & Arn. (Combretaceae) is a tree having an extensive medicinal potential in cardiovascular disorders. T. arjuna bark extract has been reported to play a significant role as a cardiac stimulant for its beneficial effects in angina. Herb - drug interactions (HDI) are one of the most important clinical concerns in the concomitant consumption of herbs and prescription drugs. Our study was to investigate the in vitro CYP2D inhibition potential of Terminalia arjuna (T. arjuna) extracts in rat liver microsomes and to study the influence of aqueous bark extract of T. arjuna on the oral pharmacokinetics and pharmacodynamics of metoprolol succinate in rats. METHODS: The CYP2D inhibition potential of herbal extracts of T. arjuna was investigated in rat liver microsomes. Pharmacokinetic-pharmacodynamic interaction of aqueous extract of T. arjuna with metoprolol succinate was investigated in rats. RESULTS: The ethyl acetate, alcoholic & aqueous bark extracts of T. arjuna showed potent reversible non-competitive inhibition CYP2D enzyme in rat liver microsomes with IC50 values less than 40 µg/mL. Arjunic acid, arjunetin and arjungenin did not show significant inhibition of CYP2D enzyme in rat liver microsomes. Pharmacokinetic studies showed that aqueous bark extract of T. arjuna led to a significant reduction (P < 0.05) in AUC0-24h and Cmax of metoprolol succinate in rats, when co-administered. Pharmacodynamic studies reveal a significant reduction in therapeutic activity of metoprolol succinate on co-administration with aqueous bark extract of T. arjuna. CONCLUSION: Based on our in vitro and in vivo findings and until further clinical drug interaction experiments are conducted, the co-administration of drugs, especially those primarily cleared via CYP2D catalyzed metabolism, with T. arjuna extracts should be done with caution.

Effect of ethanolic extract of Cyperus rotundus L. against isoprenaline induced cardiotoxicity.

Interruption of blood supply to the heart results in acute myocardial infarction (AMI), and further damages the heart muscles. Available drugs for the treatment MI have one or other side effects, and there is a need for development of better alternative drugs from herbal sources. Here, we evaluated cardioprotective effect of Cyperus rotundus on isoprenaline- induced myocardial infarction. Thirty five Wistar rats, aged 60-100 days with body wt. 150-200 g, pretreated with ethanolic extract of Cyperus rotundus L. (@ 250 and 500 mg/kg body wt.) orally before induction of myocardial necrosis by administrating isoprenaline (85 mg/kg, s.c.) on 19th and 20th day of the pretreatment period. The treated rats were examined for gross functioning of heart, heart weight/body wt. Ratio, and also observed histopathologically. Further, activities of various cardiac enzymes such as aspartate transaminase, alanine transaminase, creatinine kinase-myoglobulin, lactate dehydrogenase, and the gold marker troponin-I were also determined. The levels altered by isoproterenol were found to be restored significantly by the test extracts especially at higher dose. Biochemical observations viz., serum ALT (P <0.0001), AST (P <0.0001), creatine kinase-myoglobulin (CK-MB) (P <0.0001), LDH (P <0.0001) demonstrated significant cardioprotective activity of the ethanolic extract of C. rotundus (500 mg/kg body wt.), against isoprenaline induced myocardial infarction. These results were also substantiated by physical parameters and histopathological observations. All these results were comparable with that of two standard drugs metoprolol (10 mg/kg/day), ramipril (3 mg/kg/day) as well as polyherbal formulation Abana (50 mg/kg/day).

Combination Treatment With Antihypertensive Agents Enhances the Effect of Qiliqiangxin on Chronic Pressure Overload-induced Cardiac Hypertrophy and Remodeling in Male Mice.

We previously showed that Qiliqiangxin (QL) capsules could ameliorate cardiac hypertrophy and remodeling in a mouse model of pressure overload. Here, we compared the effects of QL alone with those of QL combined with the following 3 types of antihypertensive drugs on cardiac remodeling and dysfunction induced by pressure overload for 4 weeks in mice: an angiotensin II type 1 receptor (AT1-R) blocker (ARB), an angiotensin-converting enzyme inhibitor (ACEI), and a ß-adrenergic receptor (ß-AR) blocker (BB). Adult male mice (C57B/L6) were subjected to either transverse aortic constriction or sham operation for 4 weeks, and the drugs (or saline) were orally administered through gastric tubes. Cardiac function and remodeling were evaluated through echocardiography, catheterization, histology, and analysis of hypertrophic gene expression. Cardiomyocyte apoptosis and autophagy, AT1-R and ß1-AR expression, and cell proliferation-related molecules were also examined. Although pressure overload-induced cardiac remodeling and dysfunction, hypertrophic gene reprogramming, AT1-R and ß1-AR expression, and ERK phosphorylation were significantly attenuated by QL alone, QL + ARB, QL + ACEI, and QL + BB, the attenuation was stronger in the combination treatment groups. Moreover, apoptosis was reduced to a larger extent by each combination treatment than by QL alone, whereas autophagy was more strongly attenuated by either QL + ARB or QL + ACEI. None of the treatments significantly upregulated ErbB2 or ErbB4 phosphorylation, and none significantly downregulated C/EBPß expression. Therefore, the effects of QL on chronic pressure overload-induced cardiac remodeling may be significantly increased when QL is combined with an ARB, an ACEI, or a BB.

Bilayer mucoadhesive microparticles for the delivery of metoprolol succinate: Formulation and evaluation.

Metoprolol succinate is a very potent drug for the treatment of hypertension but suffers from poor bioavailability due to its erratic absorption in lower GI tract. Therefore, in the present study, it was hypothesized that by formulating mucoadhesive particles, the residence time in the GIT and release of drug may be prolonged that will enhance the bioavailability of metoprolol succinate. Metoprolol succinate loaded chitosan microparticles were prepared by ionic gelation method. The optimized microparticles were coated with sodium alginate to form a layer over chitosan microparticles to increase the mucoadhesive strength and to release the drug in controlled manner. Coated and uncoated microparticles were evaluated for particle size, zeta potential, morphology, entrapment efficiency, drug loading and in vitro drug release. The coated microparticles showed comparatively less drug release in the 0.1 N HCl while sustained release in PBS (pH 6.8) as compared to uncoated microparticles. The in vivo study on albino rats demonstrated an increase in bioavailability of the coated microparticles as compared to marketed formulation. From the study it can be concluded that alginate coated chitosan microparticles could be a useful carrier for the oral delivery of metoprolol succinate.

"Qufeng Tongluo" acupuncture prevents the progression of glomerulonephritis by decreasing renal sympathetic nerve activity.

ETHNOPHARMACOLOGICAL RELEVANCE: Although the exact mechanism(s) underlying acupuncture remain unknown, acupuncture and acupuncture-like somatic nerve stimulation have been used to treat different kidney diseases and several complications related to them.The aim of this preliminary study was to assess the effectiveness of acupuncture on glomerulonephritis (GN) according to the theory of "Wind-hided renal collaterals" previously proposed. MATERIAL AND METHODS: We used a New Zealand white rabbit model of cationized bovine serum albumin (cBSA)-induced glomerulonephritis and then administered them metoprolol, irbesartan or acupuncture to evaluate the effectiveness of acupuncture treatment and preliminarily explore its potential mechanism. RESULTS: After immunization, our results showed that compared to the cBSA+MET and cBSA+IRB medication groups, "Qufeng Tongluo" significantly lowered parameters of renal function and improved podocyte injury in the 3rd, 6th and 8th weeks of treatment. Moreover, acupuncture increased the protein expression of phosphorylated ERK1/2. CONCLUSIONS: Our study suggests that a potential mechanism by which acupuncture has an antihypertensive effect and can significantly halt deteriorating renal function due to cBSA GN might be mediated by inhibiting the Erk1/2 MAPK pathway to reduce renal sympathetic nerve activity (RSNA).

Shengxian decoction in chronic heart failure treatment and synergistic property of Platycodonis Radix: a metabolomic approach and its application.

Shengxian Decoction (SXT), a classic Traditional Chinese Medicine (TCM) prescription, consists of five TCMs: Astragali Radix, Anemarrhenae Rhizoma, Bupleuri Radix, Platycodonis Radix (PG), and Cimicifugae Rhizoma. SXT has been demonstrated to show good therapeutic effects on the cardiovascular system. A metabolomic approach was applied to study its therapeutic mechanisms and the synergistic properties of PG. UPLC-Q-TOF/MS based metabolomic profiling was adopted to assess the intervention effects of SXT, SXT-PG (SXT lacking PG) and PG, on chronic heart failure (CHF) rats. Betaloc was used as a positive control drug. A supervised discriminant technique (PLS-DA) was used to visualize the difference in global metabolic profiles within all experimental groups. Some significantly changed metabolites, such as carnitines, long-chain fatty acids and sphinganines, were identified, and the biochemical alterations of these were related to the disturbance in serum metabolic profiling of CHF rats. Furthermore, the metabolomics study demonstrated that the administration of SXT, but neither SXT-PG or PG alone, gave satisfactory curative effects on CHF through partially regulating the perturbed metabolic pathways. These observations were demonstrated by histopathological, electrocardiogram and serum enzymatic investigations. All these results supported the TCM theory that PG possesses synergistic properties which promote the synergized herbs in SXT in CHF rats. Overall, this paper demonstrates that metabolomics offers opportunities to understand the therapeutic mechanisms and synergistic properties of TCM.

Cardiac contractility modulation increases action potential duration dispersion and decreases ventricular fibrillation threshold via ß1-adrenoceptor activation in the crystalloid perfused normal rabbit heart.

BACKGROUND/OBJECTIVES: Cardiac contractility modulation (CCM) is a new treatment being developed for heart failure (HF) involving application of electrical current during the absolute refractory period. We have previously shown that CCM increases ventricular force through ß1-adrenoceptor activation in the whole heart, a potential pro-arrhythmic mechanism. This study aimed to investigate the effect of CCM on ventricular fibrillation susceptibility. METHODS: Experiments were conducted in isolated New Zealand white rabbit hearts (2.0-2.5 kg, n=25). The effects of CCM (± 20 mA, 10 ms phase duration) on the left ventricular basal and apical monophasic action potential duration (MAPD) were assessed during constant pacing (200 bpm). Ventricular fibrillation threshold (VFT) was defined as the minimum current required to induce sustained VF with rapid pacing (30 × 30 ms). Protocols were repeated during perfusion of the ß1-adrenoceptor antagonist metoprolol (1.8 µM). In separate hearts, the dynamic and spatial electrophysiological effects of CCM were assessed using optical mapping with di-4-ANEPPS. RESULTS: CCM significantly shortened MAPD close to the stimulation site (Basal: 102 ± 5 [CCM] vs. 131 ± 6 [Control] ms, P<0.001). VFT was reduced during CCM (2.6 ± 0.6 [CCM] vs. 6.1 ± 0.8 [Control] mA, P<0.01) and was correlated (r(2)=0.40, P<0.01) with increased MAPD dispersion (26 ± 4 [CCM] vs. 5 ± 1 [Control] ms, P<0.01) (n=8). Optical mapping revealed greater spread of CCM induced MAPD shortening during basal vs. apical stimulation. CCM effects were abolished by metoprolol and exogenous acetylcholine. No evidence for direct electrotonic modulation of APD was found, with APD adaptation occurring secondary to adrenergic stimulation. CONCLUSIONS: CCM decreases VFT in a manner associated with increased MAPD dispersion in the crystalloid perfused normal rabbit heart.

Effect of Xinjikang on left ventricular hypertrophy remodeling in hypertensive rats.

OBJECTIVE: To investigate the effects of Xinjikang on the left ventricular hypertrophy remodeling and myocardial activity in hypertension. METHODS: Sixty Wistar rats were randomly divided into four groups. The pressure-loaded left ventricular hypertrophy model was established with abdominal aorta ligation method. Rats in A and B groups were intragastrically administered with physiological saline, while C and D groups were administered with Xinjikang and metoprolol, respectively. The changes in blood pressure, E/A ratio, myocardial pathological morphology, myocardial lipoperoxides and superoxide dismustase activity in four groups were observed and compared before and after treatment. RESULTS: There were statistically significant differences in E/A ratio between C group after treatment and model group (P<0.05), while no difference was observed between A and D groups (P>0.05); after treatment the myocardial lipoperoxides and superoxide dismustase contents in C and D groups were improved significantly compared with model group (P<0.05). CONCLUSIONS: Xinjikang can improve myocardial injury, restore myocardial parenchyma and myocardial interstitial remodeling functions in hypertensive rats with the left ventricular hypertrophy.

An evaluation of the effects of nonselective and cardioselective ß-blockers on wound healing in Sprague Dawley rats.

OBJECTIVES: To investigate the effect of a nonselective ß-blocker (propranolol) and cardioselective ß-blocker (metoprolol) on wound healing in rats using incision and excision wound models and to compare the effect of these drugs on wound healing. MATERIALS AND METHODS: Propranolol and metoprolol were given orally. Sprague Dawley rats of either sex were used. Incision and excision wound models were used to evaluate the wound-healing activity. Effects of metoprolol and propranolol on tensile strength, period of epithelialization, and hydroxyproline content were observed. Histological analysis was done to see collagen deposition and inflammatory infiltrate. STATISTICAL ANALYSIS USED: The data was subjected to analysis of variance (ANOVA) followed by Scheffe's test. P < 0.05 was considered to be statistically significant. Statistical analysis was done using SPSS software version 15.0. RESULTS: Administration of propranolol or metoprolol was shown to decrease tensile strength, delay wound contraction and re-epithelialization, increase inflammatory infiltrate, and reduce collagen density and hydroxyproline levels. CONCLUSIONS: The results suggest that nonselective and cardioselective ß-blockers delay wound healing and these effects are mediated by ß1-receptors.