Effects of arotinolol on exercise capacity and humoral factors during exercise in normal subjects

Summary A placebo-controlled, double-blind crossover study was undertaken in 10 normal subjects to examine the effects of arotinolol (10 mg bid), a nonselective beta blocker with alpha-blocking activity, on exercise capacity and hormone levels during exercise after a 2-week treatment period. Maximal oxygen uptake (VO₂ max) and blood lactic acid concentration (LA) were measured during progressive exercise testing. An exercise intensity equivalent to 4 mmol/l of LA was used for the constant workload exercise test. Humoral factors were measured after 20 minutes of constant workload exercise. The administration of arotinolol significantly decreased systolic blood pressure and heart rate at rest and during exercise, but diastolic blood pressure did not change. No significant difference was found between arotinolol and placebo with regard to VO₂ max and maximal workload. Plasma renin activity (PRA), aldosterone (PAC), and norepinephrine (NE) levels at rest and during exercise did not differ between the two treatments. In contrast, plasma epinephrine (EN) levels at rest and during exercise were significantly greater with arotinolol. Atrial natriuretic peptide (ANP) at rest did not differ between the two treatments. However, exercise caused a significant increase in ANP after arotinolol treatment. These findings suggest that arotinolol decreases blood pressure and heart rate without affecting exercise capacity.     

Effects of Exercise Therapy Alone and in Combination with a Calcium Channel Blocker or an Angiotensin Receptor Blocker in Hypertensive Patients

We compared the effects of exercise alone and in combination with a calcium channel blocker (amlodipine) or an angiotensin receptor blocker (valsartan) in hypertensive patients. Our results indicated that exercise therapy exerted similar effects on systolic blood pressure whether administered alone or in combination with amlodipine or valsartan; however, diastolic blood pressure decreased significantly when exercise therapy was combined with amlodipine. However, when combined with valsartan, exercise therapy additionally improved the lipid profile of hypertensive patients. Thus, this study enabled the identification of the drugs suitable for combination with exercise therapy in the treatment of hypertensive patients.     

The effects of propranolol on myocardial perfusion and metabolism during acute regional ischaemia

The unique physical properties of the short-lived inert and freely diffusing isotope ^81mkrypton allow a continuous observation to be made of regional myocardial perfusion. Eighteen dogs were anaesthetised and a reversible snare placed on the left anterior descending coronary artery (LAD). ^81mKrypton was used to study regional myocardial perfusion, and myocardial metabolism was assessed using the epicardial ECG and release of creatine kinase activity (CK). Six dogs did not undergo LAD occlusion (“sham operated”); in six other dogs the LAD was occluded (controls), and another six dogs were given propranolol, 0.5 mg/kg, 20 min after LAD occlusion. All the parameters were measured before and for 5 h after LAD occlusion. When compared to controls, dogs treated with propranolol showed significant improvement (p<0.01) in regional myocardial perfusion; smaller loss of electrically active myocardium for any given degree of early ST-segment elevation; and a delay in the release of CK activity from a local coronary vein. These results suggest that propranolol exerts a beneficial effect following the development of acute myocardial infarction.     

Effects of propranolol, atenolol, and chlordesmethyldiazepam on response to mental stress in patients with recent myocardial infarction

Stress testing was carried out by two stressors, mental arithmetic and Sacks-Levy's test in randomized sequence, in 64 male patients with a mean age of 51 +/- 7 years in NYHA Classes I or II within 3 months after acute myocardial infarction. The stress profile was obtained after drug withdrawal by continuous recording of electrocardiogram, frontal electromyogram, and peripheral skin temperature and conductance. Blood pressure was measured each minute by cuff. The patients were subdivided into 4 groups of 16 each and were studied in an identical fashion after a 48-h oral treatment with propranolol 120 mg daily, atenolol 100 mg daily, chlordesmethyldiazepam 2 mg daily, or placebo. During stress, signs of myocardial ischemia or pump failure were not observed; minor arrhythmias were recorded. Cardiovascular activation was observed with significant increments (p less than 0.001) in heart rate, systolic and diastolic blood pressures in all 4 groups for both stressors with a slightly greater effect of mental arithmetic; Sacks' test was more effective on the frontal electromyograph response. Following beta blockade the stress profile of heart rate was significantly lower and flattened. The stress profile of blood pressure was also lower, but the reduction in the increment during stress was not significant. No differences were observed in the effects of the two beta blockers; no significant changes were evident in the stress profile of the noncardiovascular psychophysiologic indexes. Stress profiles were not altered by the benzodiazepine. In conclusion beta-blocker agents seem to be more useful than anxiolytic drugs in preventing cardiovascular activation induced by mental stress in patients with recent myocardial infarction.     

Exercise test and glucose homeostasis in rats treated with alloxan during the neonatal period or fed a high calorie diet

Background: Animal models appear well‐suited for studies into the role of exercise in the prevention of non‐insulin‐dependent diabetes mellitus (NIDDM). The aim of the present study was to analyze glucose homeostasis and blood lactate during an exercise swimming test in rats treated with alloxan during the neonatal period and/or fed a high calorie diet from weaning onwards. Methods: Rats were injected with alloxan (200 mg/kg, i.p.) or vehicle (citrate buffer) at 6 days of age. After weaning, rats were divided into four groups and fed either a balanced diet or a high‐caloric diet as follows: C, control group (vehicle + normal diet); A, alloxan‐treated rats fed the normal diet; H, vehicle‐treated rats fed the high‐caloric diet; and HA, alloxan‐treated rats fed the high‐caloric diet. Results: Fasting serum glucose levels were higher in groups A and AH compared with the control group. The Homeostatic Model Assessment index varied in the groups as follows: H>A>HA = C. There were no differences in free fatty acids or blood lactate concentrations during the swim test. Conclusions: Alloxan‐treated rats fed a normal or high‐caloric diet have the potential to be used in studies analyzing the role physical exercise plays in the prevention of NIDDM.     

尼卡地平对低密度脂蛋白氧化及巨噬细胞泡沫化过程中脂质代谢的影响

目的 :观察钙通道阻滞剂尼卡地平对低密度脂蛋白 (LDL)体外氧化以及对小鼠腹腔巨噬细胞泡沫化过程中细胞内脂质代谢两个环节的影响 ,探讨钙通道阻滞剂抗动脉粥样硬化 (AS)的作用机制。方法 :采用Cu2 + 氧化LDL ,动态监测LDL氧化修饰过程中 2 34nm处紫外吸光度及丙二醛 (MDA)含量的变化 ,观察不同浓度尼卡地平 (10 μmol/L、10 0 μmol/L)对体外LDL氧化修饰的抑制作用。收集和培养纯系 6 15小鼠腹腔巨噬细胞 ,将其分成 4组 :①对照组 ,②氧化修饰LDL(ox LDL)组 ,③ox LDL加 10 μmol/L尼卡地平组 ,④ox LDL加 10 0μmol/L尼卡地平组 ,培养 4 8h后 ,分别测定细胞内总胆固醇 (TC)、游离胆固醇 (FC)及胆固醇酯 (CE) ,观察不同浓度尼卡地平对小鼠腹腔巨噬细胞泡沫化过程中细胞内脂质代谢的影响。结果 :①尼卡地平可以降低LDL氧化修饰过程中 2 34nm吸光度峰值 ,明显延长迟滞期 ,使氧化曲线右移 ,且存在剂量效应关系。 10 μmol/L及 10 0μmol/L尼卡地平分别将迟滞期延长33.96 %和 6 9.6 5 % ,与对照组比较差异均有显著性意义 (均P <0 .0 5 )。同时 ,尼卡地平可以减少MDA的生成量 ,10 0 μmol/L尼卡地平抑制MDA生成量更明显 ,MDA减少 2 1%。②ox LDL组细胞内TC、FC及CE较对照组均显著增高 (均P <0 .0 1) ,巨噬     

Comparison of metoprolol with low, middle and high doses of carvedilol in prevention of postinfarction left ventricular remodeling in rats

The dose-related beneficial effects of carvedilol on survival in heart failure have been verified, however, the effects on left ventricular remodeling (LVRM) after acute myocardial infarction (AMI) have not been defined. This experiment was designed to compare the effects of low, middle, and high doses of carvedilol (LD-car, MD-car, and HD-car) with metoprolol (Meto) in preventing postinfarction LVRM in rats. After the left coronary artery was ligated, 177 surviving female SD rats were randomized to: (1) AMI (n = 35), (2) LD-car (0.1 mg x kg(-1) x d(-1), n = 35), (3) MD-car (1 mg x kg(-1) x d(-1), n = 35), (4) HD-car (10 mg x kg(-1) x d(-1), n = 37) and (5) Meto (2 mg x kg(-1) x d(-1), n = 35) groups. A sham-operated group (n = 16) was also randomly selected. Gastric gavage therapy lasted for 4 weeks. After hemodynamic studies, the rat hearts were fixed and pathologically analyzed. After exclusion of rats which died or had an infarct size < 35% or > 55%, complete data were obtained in 69 rats, comprising AMI (n = 11), LD-car (n = 11), MD-car (n = 12), HD-car (n = 12), Meto (n = 11) and sham (n = 12) groups. There were no significant differences in MI size among the five AMI groups (44.5-46.3%, all P > 0.05). Compared with the sham group, left ventricular (LV) end-diastolic pressure (LVEDP), volume (LVV), weight (LVW) and septal thickness (STh) were all significantly increased, while +/- dp/dt was significantly decreased in the AMI group (all P < 0.001). Compared with the AMI group, heart rate was significantly decreased in all except the LD-car treatment groups (P < 0.05-0.01); LVEDP, LVV, LVW, and STh in the four treatment groups were also significantly decreased (P < 0.05-0.001) except LVW and STh in the Meto group (both P > 0.05)(LVEDP: 14.5 +/- 4.6, 12.1 +/- 2.4, 7.7 +/- 1.9 and 13.0 +/- 6.7 mmHg vs 24.1 +/- 5.2 mmHg; LVV: 0.82 +/- 0.1, 0.79 +/- 0.1, 0.72 +/- 0.1 and 0.72 +/- 0.1 mL vs 0.92 +/- 0.1 mL; LVW: 666 +/- 57, 622 +/- 70, 589 +/- 57 and 699 +/- 78 mg vs 730 +/- 79 mg; STh: 1.14 +/- 0.12, 1.18 +/- 0.21, 1.19 +/- 0.15 and 1.35 +/- 0.20 mm vs 1.33 +/- 0.29 mm; P < 0.05-0.001); while +/- dp/dt was significantly increased in each therapy group (P < 0.05-0.001). There were dose-effect relations in LVEDP and LVV in the carvedilol groups. The results indicate that low, middle and high dose carvedilol has dose-related effects in the prevention of postinfarction LVRM with respect to volume expansion and segmental hypertrophy in rats, while metoprolol prevents only LV dilatation but not hypertrophy.     

Comparison of reducing epicardial fat by exercise,diet or bariatric surgery weight loss strategies: a systematic review and meta‐analysis

The objectives were to determine whether epicardial fat (EAT) is subject to modification, and whether various strategies accomplish this end point and the relationship between weight loss and EAT. A systematic review of the literature following meta‐analysis guidelines was conducted using the search strategy ‘epicardial fat’ OR ‘epicardial adipose tissue’ AND ‘diet’ OR ‘exercise’ OR ‘bariatric surgery (BS)’ OR ‘change in body weight’ limited to humans. Eleven articles were identified with 12 intervention approaches of which eight studies showed a statistically significant reduction in EAT. A random‐effects meta‐analysis suggests an overall significant reduction of 1.12 standardized units (95% CI = [?1.71, ?0.54], P value < 0.01). While there is a large amount of heterogeneity across study groups, a substantial amount of this variability can be accounted for by considering intervention type and change in body mass index (BMI). These variables were incorporated into a random‐effects meta‐regression model. Using this analysis, significant EAT reduction occurred with diet and BS but not with exercise. BMI reductions correlated significantly with EAT reductions for diet‐based interventions, i.e. for some but not all interventions. In conclusion, EAT, a factor that is significantly associated with coronary artery disease, can be modified. The type of intervention, in addition to the amount of weight loss achieved, is predictive of the amount of EAT reduction.     

Effects of olmesartan and enalapril at low or high doses on cardiac, renal and vascular interstitial matrix in spontaneously hypertensive rats

We have evaluated the effects of different doses of an angiotensin-converting enzyme (ACE) inhibitor, enalapril (ENA) and of an angiotensin II type 1 receptor blocker olmesartan (OLM), on extracellular matrix of the heart, kidney, aorta and mesenteric artery of spontaneously hypertensive rats (SHR). Forty SHR and eight Wistar-Kyoto controls (WKY) were included in the study. Eight SHR were treated with high-dose OLM 15 mg/kg per day, eight with high-dose ENA 25 mg/kg per day, eight with low-dose OLM 1 mg/kg per day and eight with low-dose ENA (2 mg/kg per day). Eight SHR and eight WKY were kept untreated as controls. Treatment was from age 4 to 12 weeks. Systolic blood pressure (SBP) was measured non-invasively every week. The left ventricular weight to body weight (RLVM) was measured, and the cardiac, aortic and glomerular interstitial collagen content was evaluated using Sirius red staining and image analysis. Mesenteric small arteries were dissected and mounted on a micromyograph, and the media:lumen ratio (M/L) was calculated. Collagen subtypes were evaluated by polarized light microscopy. The SHR treated with high-dose OLM or ENA showed a normalization of SBP. The RLVM was significantly increased in untreated SHR compared with untreated WKY, whereas significantly lower values were observed in the groups of SHR treated with high-dose OLM or ENA. A significant increase in cardiac and glomerular collagen content was observed in untreated SHR. Both high- or low-dose OLM and ENA normalized collagen content in the heart and the kidney. Both high-dose OLM and high-dose ENA normalized M/L ratio; however, OLM proved to be more effective than ENA in normalizing collagen pattern. In fact, aortic collagen content was normalized by both high-dose and low-dose OLM, but only by high-dose ENA. In conclusion, both OLM and ENA were significantly and equally effective in the prevention of cardiac and renal damage in SHR, whereas OLM was more effective than ENA in terms of effects on vascular extracellular matrix.     

A controlled trial of a high fibre,low fat and low sodium diet for mild hypertension in type 2 (non-insulin-dependent) diabetic patients

Summary Fifty hypertensive Type 2 (non-insulin-dependent) diabetic patients were allocated, in a controlled trial, to a treatment diet of high fibre, low fat and low sodium composition, or to a control diet by the hospital dietitian. After 3 months treatment, the modified diet-treated group showed a highly significant reduction in mean systolic (180.5±19.0 to 165.0±20.7 mmHg) and diastolic blood pressure (96.6±9.3 to 88.0±10.5 mmHg), accompanied by significant reductions in urinary sodium excretion (183.0±62.1 to 121.7+ 65.8 mmol/day) glycosylated haemoglobin (12.4±3.1 to 10.5±2.9%), weight (74.6s±13.5 to 71.7±12.1 kg) and serum triglyceride levels (p<0.05). The mean values of diastolic pressure (p<0.01), urinary sodium/potassium ratio (p< 0.001), urinary potassium (p<0.01) was significantly reduced at 3 months compared to control. No changes in serum HDL-cholesterol levels were observed. The number of patients with normal blood pressure at 3 months was greater in the modified diet-treated group (ten versus five). Treatment of mild hypertension in diabetic subjects with this form of dietary regimen has a hypotensive response, with improvement in glycaemic control and no side effects. This modified diet may be an attractive alternative to anti-hypertensive drug therapy as a first line treatment.     

Comparison of serum cholesterol in children fed high,moderate, or low cholesterol milk diets during neonatal period

The long-term effects of milk diets in infancy on the blood serum cholesterol concentrations were studied in 97 school children 7–12 yr of age. Detailed histories were available for these children with respect to their diets during infancy. The major criterion for inclusion in the study was milk (human milk, cow's milk, or commercial formula) as the exclusive source of diet cholesterol during the first 3 mo of life. Fasting blood cholesterol and triglycerides were measured in these 97 school children, and the current diets of 29 of the 97 were evaluated for daily cholesterol intake. A 7-day diet diary was recorded, the food intake was measured and analyzed for nutrients, and validity of the diets was verified by determination of urinary nitrogen excretion. Results of the study showed that the school children fed a low cholesterol formula during infancy had a mean serum cholesterol value 7–12 yr later that was lower than the mean values of the groups fed greater amounts of cholesterol in infancy. Analysis of current diets of 29 of the 97 school children showed that their current dietary intake of cholesterol did low. Dietary intake of cholesterol did not have a noticeable effect on the serum cholesterol levels of the 29 children.     

Promotive action of acylated ascorbate on cellular DNA synthesis and growth at low doses in contrast to inhibitory action at high doses or upon combination with hyperthermia

Effects of 6-O-palmitoyl ascorbate (ascorbate) developed to increase the antitumour activity of ascorbic acid on DNA synthesis and proliferation of Ehrlich ascites tumour cells were investigated. Treatment of the cells with the acylated ascorbate at 25–50 M for 1 h resulted in no effect on DNA synthesis, assayed by pulse incorporation of [³H]thymidine after a culture period of 20 h, but led to 49%–87% enhanced DNA synthesis after 4 days, suggesting that long-term culture is required for promotion by ascorbate to occur. At a dose as high as 75 M acylated ascorbate, however, cellular DNA synthesis was 64% inhibited after 20 h and 99% after 4 days. The results suggest that acylated ascorbate exhibits a dual action on DNA synthesis: promotion at low doses and inhibition at high doses, both of which are potentiated in a time-dependent manner. In contrast to the above-mentioned results at 37°C, acylated ascorbate at 25–75 M inhibited but did not promote DNA synthesis at 42°C whatever the culture period. Similar results were exhibited when proliferation of cells cultured for a long period was investigated. At 37°C, 50M acylated ascorbate increased the number of the cells to 3.6 times the control values after 8 days and to 1.9 times after 11 days; in contrast, a 75-M dose decreased the cell number considerably. Combination with hyperthermia (42°C) suppressed the increase and cell growth was completely inhibited at 75M.Abbreviation 6 Pam-ascorbate 6-O-palmitoyl ascorbate     

Extent of beta1- and beta2-receptor occupancy in plasma assesses the antagonist activity of metoprolol,pindolol, and propranolol in the elderly

Summary We estimated antagonist activity of metoprolol, pindolol, and propranolol in elderly cardiovascular patients by determining the extent to which the drugs occupied rabbit lung beta₁- and rat reticulocyte beta₂-adrenoceptors in plasma samples during drug treatment. The randomized, double-blind, crossover study was carried out by administering twice daily 100 mg metoprolol, 5 mg pindolol, and 80 mg propranolol for 7 days to 20 hypertensive subjects with a mean age of about 70 years. A 2-week interval was kept between administration of the different regimens. Receptor occupancy was measured at 1 hour before and 2 hours after administration of the last dose of each regimen by adding rabbit lung beta₁- and rat reticulocyte beta₂-receptors to plasma samples and by labeling the receptors with a radiolabeled beta-antagonist, (–)-[³H]CGP-12177. The results and conclusions were the following: (a) The extent to which metoprolol, pindolol, and propranolol occupied rabbit lung beta₁-and rat reticulocyte beta₂-adrenoceptors in plasma samples estimated accurately the intensity of beta-receptor antagonism in the patients who did not tolerate physiological and pharmacological tests measuring the degree of beta₁- and beta₂-adrenoceptor blockade. (b) The mean beta₁- and beta₂-receptor occupancy of pindolol and propranolol varied between 76% and 99% during the treatments. The mean beta₁-receptor occupancy of the metoprolol regimen varied between 54% and 92%, and its beta₂-receptor occupancy varied between 6% and 38%. Thus the antagonist activity of the metoprolol regimen differed significantly from that of the other regimens (ANOVA for repeated measures, p<0.05 and 0.001, for the beta₁- and beta₂-occupancy, respectively). (c) The extent of beta₁- and beta₂-receptor occupancy in plasma samples was in conformity with the literature on the intensity, selectivity, and duration of beta-blockade after similar drug doses. (d) The data on the receptor occupancy of beta-blocking drugs in plasma samples appear to be valuable in analyzing their effects, and it may be a method for optimizing drug therapy for aged cardiovascular patients.     

小剂量左旋氨氯地平、替米沙坦和氢氯噻嗪同时或不同时给药对杓型高血压的影响

目的 探讨小剂量左旋氨氯地平、替米沙坦及氢氯噻嗪同时或不同时给药对杓型高血压的影响.方法 选择我院门诊及住院杓型高血压患者272例（收缩压＜ 180 mm Hg,舒张压91～109 mm Hg）,年龄＞45岁,男性179例,女性93例.随机分为两组：Ⅰ组（不同时给药组,135例）晨服替米沙坦40 mg和氢氯噻嗪10 mg,晚服左旋氨氯地平2.5 mg;Ⅱ组（同时给药组,137例）以上三种药物均晨服（剂量同Ⅰ组）.两组基线资料均衡可比.所有病例治疗前及治疗8周后进行动态血压监测.结果 治疗8周后,Ⅰ组和Ⅱ组的24h收缩压/舒张压均较治疗前降低[（128.64± 12.76）mm Hg/（82.46±7.18）mm Hg比（144.36±15.86）mm Hg/（92.34±7.86）mm Hg,P＜0.01,（127.54±13.06）mm Hg/（81.92±7.28）mm Hg比（143.68±15.58）mm Hg/（92.52±7.64）mm Hg,P＜0.01],两组间降低幅度差异无统计学意义（P＞0.05）;夜间收缩压/舒张压较治疗前降低[（134.28 ±13.36）mm Hg/（82.76±6.84）mm Hg比（116.42±12.14）mm Hg/（70.18±6.28）mm Hg,P＜0.01,（134.46±13.58）mm Hg/（82.48±6.72）mm Hg比（118.18±12.18）mm Hg/（71.82±6.86）mm Hg,P＜0.01],降低幅度差异无统计学意义（P＞0.05）.Ⅰ组治疗后收缩压昼夜差值高于治疗前[（21.10±4.88）mm Hg比（17.32±4.26）mm Hg,P＜0.05];Ⅱ组差异无统计学意义（P＞0.05）.治疗后Ⅰ组收缩压昼夜差值高于Ⅱ组[（21.10±4.88）mm Hg和（18.04±4.26）mm Hg,两组比较差异有统计学意义（P＜0.05）].结论 对于杓型高血压患者,小剂量左旋氨氯地平、替米沙坦和氢氯噻嗪无论同时或不同时给药均能有效地控制24h、日间和夜间血压,而同时一次给药患者的依从性会更好,还能减少深杓型血压的发生.     

Onset and reversibility of changes in secretory function and composition of isolated rat pancreatic islets following long-term administration of high or low tolbutamide doses

Chronic administration of a high tolbutamide dose to rats induces islet hypertrophy associated with a decreased insulin content per islet and with a diminished insulin release in response to a glucose or leucine stimulus. These changes are reversible after discontinuation of tolbutamide. Chronic administration of a low tolbutamide dose (effective dose 30%) has no effect on islet size, on insulin content per islet, or on leucine-induced insulin release. In contrast, the glucose-induced insulin release is impaired. However, glucose-induced insulin release is normal in the presence of glucagon (5 μg/ml) or theophylline (5 mM). Since islet hypertrophy occurs following admin-istration of high tolbutamide doses only and is associated with hypofunction rather than with hyperfunction, it seems hardly conceivable that the therapeutic principle of tolbutamide is based on a beta-cytotrophic effect. B-cell hypofunction seems to be due to at least three factors: the decrease in the insulin content per islet, an impairment in secretory signal recognition, and an interference with the process of signal transmission.