OBJECTIVES: Investigate the influence of benazepril and amlodipine on the expression of secretin (PZ) and somatostatin (SS) in spontaneously hypertensive rats (SHR). METHODS: Forty-five SHRs (14 weeks old, male) were randomly assigned into 3 groups (=15):SHR group, Benazepril group (which was given benazepril 0.90 mg·kg·d) and Amlodipine group (SHRs were given amlodipine 0.45 mg· kg·d), taking WistarKyoto(WKY) as normal control (=15), meanwhile, rats in SHR group and WKY group were given the same volume of distilled water. After 8 weeks of intervention, the expression of protein and mRNA of PZ in duodenum and SS in sinuses ventriculi was detected by enzyme-linked immunoassay and RT-PCR. RESULTS: After 8 weeks of intervention, compared with the WKY group, the expression of protein and mRNA of PZ in duodenum and SS in sinuses ventriculi was increased significantly in SHR group (<0. 05). Compared with SHR group, the expression of PZ in duodenum and SS in sinuses ventriculi was decreased significantly in Benazepril group and Amlodipine group (<0.05). Compared with Benazepril group, in Amlodipine group the expression of PZ mRNA in duodenum and SS mRNA in sinuses ventriculi was decreased more significantly (<0.05). CONCLUSIONS The regulation disorder of PZ in duodenum and SS in sinuses ventriculi exists in SHR. The antihypertensive effect of benazepril and amlodipine may be realized by regulating the expression of PZ and SS, while the regulation of amlodipine is more obvious than benazepril.
Amlodipine ; pharmacology ; Animals ; Antihypertensive Agents ; pharmacology ; Benzazepines ; pharmacology ; Blood Pressure ; Hypertension ; drug therapy ; Male ; Random Allocation ; Rats ; Rats, Inbred SHR ; Rats, Inbred WKY ; Secretin ; metabolism ; Somatostatin ; metabolism

The aim of the present study was to observe whether dopamine receptor (DR) was involved in the effects of sodium salicylate (SS) on the expressions of N-methyl-D-aspartic acid (NMDA) and γ-aminobutyric acid (GABA) receptors in rat cochlear spiral ganglion neurons (SGNs). Forty-eight hours after primary culture of rat SGNs, immunofluorescence technique was applied to detect expressions of DR1 and DR2, the two subtypes of dopamine receptors. Western blot was performed to assess NMDA receptor NR1 subunit and GABAreceptor subunit α2 (GABRα2) protein expressions in the SGNs after the treatments of SS alone or in combination with DR antagonists. The results demonstrated that: (1) The DR1 and DR2 were expressed in the bodies and axons of the SGN; (2) After the treatment with SS, the surface protein expressions of GABRα2 and NR1 were decreased by 44.69% and 21.57%, respectively, while the total protein expressions showed no significant changes; (3) Neither SS + SCH23390 (DR1 antagonist) group nor SS + Eticlopride (DR2 antagonist) group showed significant differences in GABRα2 and NR1 surface protein expressions compared with the control group. These results suggest that SS regulates the surface GABAand NMDA receptors trafficking on SGN, and the mechanism may involve DR mediation.
Animals ; Benzazepines ; pharmacology ; Cells, Cultured ; Cochlea ; cytology ; Neurons ; drug effects ; Rats ; Receptors, Dopamine ; metabolism ; Receptors, GABA-A ; metabolism ; Receptors, N-Methyl-D-Aspartate ; metabolism ; Sodium Salicylate ; toxicity ; Spiral Ganglion ; drug effects

OBJECTIVETo observe the current status of β-blocker (BB) use and heart rate control in Chinese patients with stable coronary artery disease (SCAD) based on subgroup data of the prospective observational longitudinal registry of patients with stable coronary artery disease (CLARIFY).

METHODSThe CLARIFY study is an international prospective observational registry of outpatients with SCAD. From November 2009 to July 2010, patients with SCAD were enrolled, and demographic information, clinical indicators, medication and blood flow reconstruction were collected. Patients were divided in three mutually exclusive categories by baseline pulse palpation heart rate(HR)≤60 beats per minute (bpm)(n=397), 61-69 bpm(n=782), and ≥70 bpm(n=1 443). The patients were also divided into taking BB or not taking BB groups. The aim of present study is to describe and analyze the current status and factors related to the HR control and BB use in the Chinese subgroup of CLARIFY.

RESULTSA total of 2 622 patients were enrolled from 56 centers across China. The mean age was (63.6±10.3) years old with 75.6% (1 983) male patients, 55.0% (1 443) patients had HR≥70 bpm. Mean HR measure by electrocardiogram(ECG) was (69.4±10.2)bpm, 50.9% (1 334 cases) patients had myocardial infarction(MI) history. A total of 21.9%(575 cases) patients had anginal symptoms; coronary angiography was performed in 88.8%(2 327 cases) of the patients. 76.2%(1 997 cases) patients were treated with BB (any molecule and any dose), 2.7% (70 cases) with digoxin or derivatives, 3.9% (103 cases) with verapamil or diltiazem, and 1.8% (47 cases) with amiodarone or dronedarone and 0.1%(2 cases) received ivabradine. BB use was similar among 3 HR groups(P>0.05). The independent risk factors associated with HR≥70 bpm were diabetes(OR=1.31), current smoker(OR=1.57), chronic heart failure(CHF) with NYHA Ⅲ (OR=2.13) and increased diastolic blood pressure (OR=1.30). Conversely, high physical activity (OR=0.61), former smoker (OR=0.76) and history of percutaneous coronary intervention(PCI, OR=0.80) were associated with lower risk of HR≥70 bpm (all P<0.05). The independent risk factors associated with non-BB use were older age (OR=1.11, 95%CI 1.01-1.47, P=0.005), lower diastolic blood pressure (OR=1.47, 95%CI 1.32-1.68, P=0.012), no history of MI (OR=1.86, 95%CI 1.43-2.44, P<0.001) or PCI (OR=1.94, 95%CI 1.55-3.73, P<0.001), asthma/chronic obstructive pulmonary disease (OR=1.32, 95%CI 1.15-1.99, P<0.001).

CONCLUSIONSA total of 76.2% Chinese SCAD patients received BB medication but more than half of them did not reach the optimal HR. Clinical characteristics including diabetes, current smoker, CHF, increased diastolic blood pressure and no PCI were associated with poorly controlled HR(≥70 bpm). More efforts including adjusting the type and dose of heart rate lowering drugs are needed to achieve optimal HR control in Chinese SCAD patients. Clinical Trail Registry International Standard Randomized Controlled Trial, ISRCTN43070564.

Adrenergic beta-Antagonists ; Angina Pectoris ; Benzazepines ; Blood Pressure ; Coronary Angiography ; Coronary Artery Disease ; Electrocardiography ; Female ; Heart Failure ; Heart Rate ; Humans ; Male ; Middle Aged ; Myocardial Infarction ; Outpatients ; Percutaneous Coronary Intervention ; Prospective Studies ; Registries ; Risk Factors

OBJECTIVETo study the effects of low concentration dopamine(DA) on hydrogen peroxide-induced apoptosis in cultured rat cardiomyocytes as well as the possible molecular mechanisms.

METHODSCultured neonatal rat cardiomyocytes were randomly divided into the following groups: control group (control), hydrogen peroxide group (H2O2), pretreated with low concentration dopamine ( DA + H2O2), dopamine receptor l(DR1) antagonist group (DR1 + DA + H2O2), dopamine receptor 2(DR2) antagonist group (DR2 + DA + H2O2). The cell apoptosis was then assessed by MTT and flow cytometry. The cellular ultrastructure changes were observed by transmission electron micro- scope. The activity of lactate dehydrogenase(LDH )and superoxide dismutase (SOD) in cell medium was analyzed by colorimetry. The protein expressions of Cytochrone c, Caspase 3 and Caspase 9 were obtained by Western blot.

RESULTSCompared with hydrogen peroxide group, low concentration dopamine(10 µmol/L) decreased the apoptosis rate and the expression of protein of apoptosis related protein, enhanced SOD activity, decreased LDH activity. DR1 antagonist SCH-23390 treatment inhibited dopamine induced cardiac protective effect. DR2 antagonist haloperido treatment had no changes compared with dopamine group.

CONCLUSIONAbove findings indicate that low concentration dopanine inhibits apoptosis induced by hydrogen peroxide in neonatal rat cardiomyocytes, which is partly associated with the activation of DR1.

Animals ; Apoptosis ; Benzazepines ; Caspase 3 ; metabolism ; Caspase 9 ; metabolism ; Cells, Cultured ; Dopamine ; pharmacology ; Hydrogen Peroxide ; L-Lactate Dehydrogenase ; metabolism ; Myocytes, Cardiac ; drug effects ; Rats ; Rats, Wistar ; Receptors, Dopamine D1 ; metabolism ; Superoxide Dismutase ; metabolism

This study aims to develop a liquid chromatography with tandem mass spectrometry (LC-MS/MS) method for the simultaneous determination of ivabradine and N-demethylivabradine in human plasma, and investigate effects of stable isotope labeled (SIL) internal standard (IS) on ivabradine. The analytes and IS were extracted from plasma by protein precipitation with acetonitrile, and chromatographied on a Capcell PAK C18 (100 mm x 4.6 mm, 5 μm) column using a mobile phase of methanol and 5 mmol x L(-1) ammonium acetate. Multiple reaction monitoring with electrospray ionization (ESI) was used in the positive mode for mass spectrometric detection. The effect of ivabradine isotope peak [M+H+3] + on IS and the effect of SIL IS purity on ivabradine were evaluated. An appropriate concentration of SIL IS was chosen to permit method selectivity and linearity of the assay over the required range. The standard curves were demonstrated to be linear in the range of 0.100 to 60.0 ng x mL(-1) for ivabradine, and 0.050 0 to 20.0 ng x mL(-1) for N-demethylivabradine. The intra and inter day precision and accuracy were within the acceptable limits for all concentrations. Besides, the interaction between IS and ivabradine did not impact the determination of analytes. This method was successfully applied to a pharmacokinetic study of hydrogen sulfate ivabradine sustained release tablets on Chinese healthy volunteers.
Benzazepines ; blood ; Chromatography, High Pressure Liquid ; Delayed-Action Preparations ; Humans ; Isotope Labeling ; standards ; Reference Standards ; Reproducibility of Results ; Sensitivity and Specificity ; Spectrometry, Mass, Electrospray Ionization ; Tablets ; Tandem Mass Spectrometry

The study aims to develop a rapid, sensitive and specified method of liquid chromatography with heated electrospray ionization tandem mass spectrometry (LC-HESI/MS/MS) for simultaneous determination of amlodipine, benazepril and benazeprilat in human plasma using amlodipine-d4 and ubenimex as internal standards (ISs). Selected reaction monitoring (SRM) with heated electrospray ionization (HESI) was used in the positive mode for mass spectrometric detection. Analytes and ISs were extracted from plasma by simple protein precipitation. The reconstituted samples were chromatographed on a C18 (100 mm x 4.6 mm, 5 microm) column with mixture of methanol-acetonitrile-5 mmol.L- ammonium acetate-formic acid (30 : 30 : 40 : 0.1) as mobile phase at a flow rate of 0.6 mL.min-1. The standard curves were demonstrated to be linear in the range of 0.02 to 6.00 ng.mL-1 for amlodipine, 0.2 to 1,500 ng.mL-1 for benazepril and benazeprilat with r2>0.99 for each analyte. The lower limit of quantitation was identifiable and reproducible at 0.02, 0.2 and 0.2 ng mL-1 for amlodipine, benazepril and benazeprilat, respectively. The intra-day and inter-day precision and accuracy results were within the acceptable limit across all concentrations. The plasma samples were stable after four freeze-thaw cycles and being stored for 93 days at -20 degrees C. The method was applied to a pharmacokinetic study of a fixed-dose combination of amlodipine and benazepril on Chinese healthy volunteers.
Administration, Oral ; Amlodipine ; administration & dosage ; blood ; Benzazepines ; administration & dosage ; blood ; Chromatography, Liquid ; Humans ; Sensitivity and Specificity ; Spectrometry, Mass, Electrospray Ionization ; Tandem Mass Spectrometry

BACKGROUNDCombination therapy is an effective method to reduce the blood pressure (BP) for patients with hypertension. This study was performed to evaluate the efficacy and safety of benazepril/lercanidipine compared with benazepril alone in patients with mild-to-moderate hypertension.

METHODSOne hundred and eighty-one patients with mild-to-moderate primary hypertension were assigned in this randomized, single-blind, parallel-group study and were randomly divided into group A (benazepril 10 mg/lercanidipine 10 mg) and group B (benazepril 10 mg) for 8 weeks. At 4 weeks, the dosage of Benazepril was titrated up to 20 mg if the diastolic blood pressure (DBP) remained ≥ 90 mmHg. BP control and side effects were evaluated at the end of 1, 4 and 8 weeks.

RESULTSThe baseline characteristics of the two groups were similar. The BP in both groups decreased from the baseline (P < 0.05). At the end of 4 and 8 weeks, Benazepril/Lercanidipine produced greater BP reduction than Benazepril alone (P < 0.05). The comparison of the rate of BP control for the benazepril/lercanidipine and benazepril groups at the end of 1, 4, and 8 weeks were 41.2% vs. 37.6% (P > 0.05), 67.1% vs. 44.7% (P < 0.05), and 71.8% vs. 45.9% (P < 0.05). There was no significant difference of side effects between the two groups.

CONCLUSIONThe benazepril/lercanidipine combination is more effective in reducing BP than benazepril alone, while it does not increase the incidence of side effects.

Aged ; Angiotensin-Converting Enzyme Inhibitors ; therapeutic use ; Benzazepines ; administration & dosage ; adverse effects ; therapeutic use ; Blood Pressure ; drug effects ; Calcium Channel Blockers ; administration & dosage ; Dihydropyridines ; administration & dosage ; adverse effects ; Drug Therapy, Combination ; Female ; Humans ; Hypertension ; drug therapy ; Male ; Middle Aged ; Single-Blind Method

This study investigated the effects of benazepril administered in the morning or evening on the diurnal variation of renin-angiotensin-aldosterone system (RAAS) and clock genes in the kidney. The male Wistar rat models of 5/6 subtotal nephrectomy (STNx) were established. Animals were randomly divided into 4 groups: sham STNx group (control), STNx group, morning benazepril group (MB) and evening benazepril group (EB). Benazepril was intragastrically administered at a dose of 10 mg/kg/day at 07:00 and 19:00 in the MB group and EB group respectively for 12 weeks. All the animals were synchronized to the light:dark cycle of 12:12 for 12 weeks. Systolic blood pressure (SBP), 24-h urinary protein excretion and renal function were measured at 11 weeks. Blood samples and kidneys were collected every 4 h throughout a day to detect the expression pattern of renin activity (RA), angiotensin II (AngII) and aldosterone (Ald) by radioimmunoassay (RIA) and the mRNA expression profile of clock genes (bmal1, dbp and per2) by real-time PCR at 12 weeks. Our results showed that no significant differences were noted in the SBP, 24-h urine protein excretion and renal function between the MB and EB groups. There were no significant differences in average Ald and RA content of a day between the MB group and EB group. The expression peak of bmal1 mRNA was phase-delayed by 4 to 8 h, and the diurnal variation of per2 and dbp mRNA diminished in the MB and EB groups compared with the control and STNx groups. It was concluded when the similar SBP reduction, RAAS inhibition and clock gene profile were achieved with optimal dose of benazepril, morning versus evening dosing of benazepril has the same renoprotection effects.
Animals ; Antihypertensive Agents ; administration & dosage ; Benzazepines ; administration & dosage ; CLOCK Proteins ; metabolism ; Circadian Rhythm ; Drug Chronotherapy ; Gene Expression Profiling ; Hypertension, Renal ; drug therapy ; physiopathology ; Kidney ; drug effects ; physiopathology ; surgery ; Male ; Nephrectomy ; Rats ; Rats, Wistar ; Renin-Angiotensin System ; drug effects ; Treatment Outcome

Obesity is associated with a reduction in life expectancy and an increase in mortality from cardiovascular diseases, cancer, and other causes. The U.S. Preventive Service Task Force (USPSTF) recommends screening all adults for obesity. Clinicians should offer or refer patients with a body mass index of 30 kg/m2 or higher to intensive, multicomponent behavioral interventions. Behavioral interventions can lead to a moderate weight loss and improvement in blood sugar and other risk factors for cardiovascular disease. Behavioral interventions decreased the incidence of diabetes diagnosis by about 50% over 2 to 3 years. Orlistat, phentermine, diethylpropion, phendimetrazine, mazindol have been approved as anti-obesity drugs by Korea Food and Drug Administration. The U.S. Food and Drug Administration approved lorcaserin and phentermine plus topiramate combination for treatment of obesity in 2012.
Adult ; Advisory Committees ; Anti-Obesity Agents ; Benzazepines ; Blood Glucose ; Body Mass Index ; Cardiovascular Diseases ; Diethylpropion ; Fructose ; Humans ; Incidence ; Korea ; Lactones ; Life Expectancy ; Mass Screening ; Mazindol ; Morpholines ; Obesity ; Phentermine ; Risk Factors ; United States Food and Drug Administration ; Weight Loss

Neuropeptide Y (NPY), a sympathetic neurotransmitter, is highly associated with baroreflex dysfunction and multiple cardiac diseases such as diabetic myocardiopathy. In the present study, we aimed to explore the role of peripheral NPY Y1 receptor (Y1R) and Y2 receptor (Y2R), which are dominantly present in peripheral cardiovascular control, in baroreflex sensitivity (BRS) of streptozotocin (STZ)-induced diabetic rats. Peripheral Y1R and Y2R were antagonized by specific antagonists (BIBP 3226 and BIIE 0246, respectively) from subcutaneously implanted ALZET mini-osmotic pump in STZ-induced diabetic rats for 4 weeks. Then baseline systolic blood pressure, heart rate, cardiac function, BRS, plasma NPY and lipid levels were evaluated. We found that STZ led to increased plasma NPY and lipid level. And the STZ-increased lipid levels were reduced by BIBP 3226 and BIIE 0246. BIBP 3226 ameliorated the aberrant BRS, but had little effect on the impaired cardiac function of the STZ rats. BIIE 0246 alleviated sodium nitroprusside (SNP)-induced but not phenylephrine (PE)-induced aberrant baroreflex control of heart rate in the STZ rats. In addition, BIIE 0246 alleviated the bradycardia, but further impaired cardiac contractility in the STZ rats. These results suggest that peripheral Y1R and Y2R play different roles in STZ-induced impairment of BRS.
Animals ; Arginine ; analogs & derivatives ; pharmacology ; Baroreflex ; Benzazepines ; pharmacology ; Blood Pressure ; Bradycardia ; Diabetes Mellitus, Experimental ; drug therapy ; physiopathology ; Heart Rate ; Myocardial Contraction ; Neuropeptide Y ; blood ; Rats ; Receptors, Neuropeptide Y ; antagonists & inhibitors ; Streptozocin