Influence of intrinsic sympathomimetic activity and cardioselectivity on beta adrenoceptor blockade.

Dose-response curves for propranolol and oxprenolol were studied in healthy volunteers, with a standardized excercise test and percentage reduction in excercise heart rate (EHR) as the index of drug effect. The dose-response curves obtained were compared with similar curves previously reported for sotalol, practolol, and atenolol with identical experimental methods. Two distinct types of response were identified: in the first, shown by propranolol and sotalol, increasing doses of the beta adrenoceptor-blocking drug continued to produce increasing effects to the limits of the dose levels examined; with the second (oxprenolol and practolol), increasing the dose initially resulted in substantial increase in effect but subsequently larger doses produced almost no increase in effect. Consideration of the additional properties of these beta adrenoceptor-blocking drugs revealed that both practolol and oxprenolol have intrinsic sympathomimetric activity (ISA), whereas propranolol and sotalol do not. In addition, practolol is cardioselective. Further investigation of the possible influence of ISA or cardioselectivity on beta adrenoceptor-blocking activity was undertaken by studying the effects of combinations of drugs on EHR. Sotalol produced greater effect when given 2 hr after sotalol, oxprenolol, practolol, or atenolol. When oxprenolol was given after sotalol or oxprenolol, or practolol was given after sotalol or practolol, there was no further increase in percentage reduction in EHR. When atenolol was given, the combinations of sotalol and atenolol together with two doses either of sotalol or atenolol all induced increases and similar final percentage reductions in EHR. Thus atenolol induces effects like those of sotalol, which are quite different from those of oxprenolol or practolol. The presence or absence of ISA would appear to be the important difference between these two groups of drugs: ISA would, therefore, appear to be demonstrated in man by flattening of the dose-response curves with exercise.     

Celiprolol does not protect against ventricular tachycardia or sudden death in the conscious canine: a comparison with pindolol in assessing the role of intrinsic sympathomimetic activity

The antiarrhythmic and antifibrillatory effects of the beta-1 adrenoceptor antagonist celiprolol were evaluated in a chronic canine model of myocardial infarction and sudden death. Programmed electrical stimulation (PES) was performed in conscious animals 3 to 5 days after a 2-hr occlusion/reperfusion of the left anterior descending coronary artery. Dogs in which PES resulted in a reproducible nonsustaining or sustained ventricular tachycardia (VT) were randomized to receive i.v. celiprolol (3 mg/kg, n = 10) or vehicle (n = 10). PES and measurement of electrophysiologic (parameters were repeated after 30 min and the animals were entered into the sudden death protocol by introducing a 150-microA anodal current to the lumen of the left circumflex coronary artery via a surgically implanted silver wire electrode. Celiprolol failed to prevent the induction of VT, and the outcome of the sudden death protocol did not differ from vehicle with respect to either sudden (within 1 hr of ischemia) or delayed (greater than 1 hr) mortality. VT cycle length and ventricular refractoriness were prolonged (P less than .05) by celiprolol, but other electrophysiologic parameters were unaffected. Heart rate was not altered after drug, but celiprolol antagonized the ischemia-induced increase in rate seen in the vehicle group. Similar electrophysiologic results and mortality data were apparent in a third group of dogs which received pindolol (0.09 mg/kg, n = 8). The failure of both drugs to protect against ischemic ventricular fibrillation in a model in which beta adrenoceptor antagonism has previously proved beneficial may be due in part to related cardiostimulant properties shared by celiprolol and pindolol.     

Short-term effects of beta-adrenoceptor blocking drugs with and without cardioselectivity and intrinsic sympathomimetic activity on lipoprotein metabolism in hypertriglyceridaemic patients and in normal men

In six patients with hypertriglyceridaemia presenting whilst receiving treatment with beta-adrenoreceptor blocking drugs (mean serum triglycerides 31.2 mmol/l) the half-life (t1/2) of an intravenously administered triglyceride emulsion was 32.8 +/- 7.9 min (mean +/- SEM) on beta-blocker and 22.8 +/- 4.8 min after stopping beta-blocker treatment. In three of these patients subsequent administration of a beta-blocker with intrinsic sympathomimetic activity had no effect on t1/2. In a cross-over trial of placebo, atenolol (beta 1-blocker), propranolol (beta 1- and beta 2-blocker) and pindolol (beta 1- and beta 2-blocker with intrinsic sympathomimetic activity) in 11 normal men t1/2 was 11.8 +/- 0.9, 12.6 +/- 1.1, 14.3 +/- 1.7 and 12.4 +/- 1.1 min respectively. None of the apparent differences achieved statistical significance, but in two men marked increases in t1/2 occurred on propranolol. The concentrations of serum triglycerides and very low density lipoprotein cholesterol in the normal men were, however, increased by beta-blockade, most markedly by pindolol. Serum high density lipoprotein (HDL) cholesterol concentration decreased in normal men on beta-blockers, most clearly on atenolol and propranolol. This decrease was due to a reduction in cholesterol in the HDL2 subfraction. No statistically significant effects on serum low density lipoprotein cholesterol or apolipoprotein B concentrations occurred in the normal men. The doses of atenolol and propranolol used in this study were equipotent as judged by the heart rate response to exercise.     

In vitro and in vivo characterization of intrinsic sympathomimetic activity in normal and heart failure rats

Clinical studies conducted with carvedilol suggest that beta-adrenoceptor antagonism is an effective therapeutic approach to the treatment of heart failure. However, many beta-adrenoceptor antagonists are weak partial agonists and possess significant intrinsic sympathomimetic activity (ISA), which may be problematic in the treatment of heart failure. In the present study, the ISAs of bucindolol, xamoterol, bisoprolol, and carvedilol were evaluated and compared in normal rats [Sprague-Dawley (SD)], in rats with confirmed heart failure [spontaneously hypertensive heart failure (SHHF)], and in isolated neonatal rat cardiomyocytes. At equieffective beta1-adrenolytic doses, the administration of xamoterol and bucindolol produced a prolonged, equieffective, and dose-related increase in heart rate in both pithed SD rats (ED50 = 5 and 40 microgram/kg, respectively) and SHHF rats (ED50 = 6 and 30 microgram/kg, respectively). The maximum effect of both compounds in SHHF rats was approximately 50% of that observed in SD rats. In contrast, carvedilol and bisoprolol had no significant effect on resting heart rate in the pithed SD or SHHF rat. The maximum increase in heart rate elicited by xamoterol and bucindolol was inhibited by treatment with propranolol, carvedilol, and betaxolol (beta1-adrenoceptor antagonist) but not by ICI 118551 (beta2-adrenoceptor antagonist) in neonatal rat. When the beta-adrenoceptor-mediated cAMP response was examined in cardiomyocytes, an identical partial agonist/antagonist response profile was observed for all compounds, demonstrating a strong correlation with the in vivo results. In contrast, GTP-sensitive ligand binding and tissue adenylate cyclase activity were not sensitive methods for detecting beta-adrenoceptor partial agonist activity in the heart. In summary, xamoterol and bucindolol, but not carvedilol and bisoprolol, exhibited direct beta1-adrenoceptor-mediated ISA in normal and heart failure rats.     

Clinical significance of the activity of nitric oxide synthase in patients with leptospirosis

Endotoxin-induced activation of inducible nitric oxide (NO) synthase (iNOS) becomes one of the triggers of the systemic response syndrome (SIRS). Determination of the activity of iNOS reflects the level of NO accumulation and may serve as a prognostically significant test of the severity of a pathological process. A procedure for determining the monocytic activity of iNOS has been developed on the basis of a histochemical reaction to NADPH-diaphorase. iNOS activity was determined in a group of healthy individuals and in 17 patients with leptospirosis. iNOS activity was decreased or absent (mean 0.56 +/- 0.085 c.u.) in patients with a very severe course of the disease and in those with protracted early convalescence. The increased activity of iNOS during early convalescence testifies to the incompleteness of an infectious process.     

病毒性肝炎患者血清胆碱酯酶、凝血酶原活动度检测的临床意义

目的　研究血清胆碱酯酶 (CHE)、凝血酶原活动度 (PTA)与病毒性肝炎临床分型、病情及预后之间的关系。方法　分别采用酶速率法和比浊法测定 16 0例急性病毒性肝炎、慢性病毒性肝炎 (轻度、中度、重度 )、肝炎肝硬化患者血CHE和PTA ,其中 2 3例行肝穿病理诊断。结果　急性病毒性肝炎组CHE和PTA下降率分别为 0 .0 0 %和8.82 % ,急性病毒性肝炎组、慢性病毒性肝炎组、肝炎肝硬化组中CHE和PTA依次降低 (P <0 .0 1) ,且二者之间相关系数为 0 .75 2 (P <0 .0 1) ;12例血清CHE低于 1kU/L和PTA低于 2 0 %的肝硬化患者中 10例死亡 ,病死率为83.33% ,明显增高 (P<0 .0 1)。结论　血清CHE和PTA不能作为急性肝损伤指标 ,却是反映肝脏疾病慢性化、肝脏储备功能和再生功能的良好指标 ,与病情及预后有关     

The effect of pindolol on plasma renin activity in patients with essential hypertension

Twenty-two patients with essential hypertension were treated for 3 months with pindolol, and blood pressure and plasma renin activity were measured at rest and after stimulation (upright posture stimulation and insulin induced hypoglycaemia stimulation). Beta-receptor blockade produced a significant decrease in systolic and diastolic blood pressure. After treatment with pindolol the plasma renin activity was significantly lower. Under conditions of renin stimulation such as orthostasis and insulin produced hypoglycaemia, plasma renin activity was significantly lower in treated patients. There was no correlation between the fall of plasma renin activity and the decrease of blood pressure. Renin suppression is probably only one of the factors involved in the reduction in the blood pressure in these patients.     

An AT-II blocker in patients with type II diabetes and arterial hypertension

The subjects of the study were 30 patients with type II diabetes mellitus and mild or moderate arterial hypertension. Clinical-and-hemodinamic organoprotective effects of eprosartan, a new angiotensin II blocker, was evaluated in these patients within 16 weeks. The study found a good hypotensive effect of monotherapy with eprosartan in a mean therapeutic dose of 600 mg/day--the target blood pressure levels were achieved in 63.3% of the patients. Fasting insulin level and insulin resistance decreased, which improved hydrocarbonate and lipid exchange parameters. Eprosartan was significantly effective as an organoprotective agent: the patients displayed improvement of eye ground vessel condition, decrease of microalbuminuria, improvement of cardiodynamic parameters i.e. decrease of the thickness of left ventricular (LV) back wall and intravenricular septum, as well as reduction of myocardial mass index. 70% of the patients demonstrated improvement of LV diastolic function.     

Comparative studies of the activity of ciclacillin and dicloxacillin.

The penicillins ciclacillin and dicloxacillin demonstrate marked similarities in biological activity but, as far as can be determined, differ substantially in respect to the degree of protein binding, which is relatively low for ciclacillin and relatively high for dicloxacillin. In mice infected with Staphylococcus aureus Smith, ciclacillin is considerably more active than dicloxacillin, although both drugs are similarly effective in vitro and similarly absorbed and eliminated in vivo. The high degree of protein binding exhibited by dicloxacillin could therefore very probably explain its relatively low chemotherapeutic activity. Moreover, the in vitro and in vivo findings of the study are inconsistent with the tenets of the tau/2 thesis.     

Effect of beta blockade with and without sympathomimetic activity (ISA) on sympathovagal balance and baroreflex sensitivity

Beta blockers increase heart rate variability (HRV) and improve survival in coronary artery disease (CAD). The benefit of beta blockers with intrinsic sympathomimetic activity (ISA) in CAD still remains a matter of debate, and their effect on HRV has not yet been investigated. Therefore, we measured HRV, systolic blood pressure variability (BPV) and baroreflex sensitivity (BRS) under propranolol (PROP, without ISA, 160 mg q.d.), pindolol (PIN, with potent ISA, 15 mg q.d.) and placebo (PLA, q.d.) in 30 healthy subjects, aged 21–39 years, during controlled frequency breathing (0·30 Hz) in supine and tilt positions. PROP increased HRV in the high-frequency (0·15–0·40 Hz) band (PROP 7·4 ± 1·0; PLA 6·9 ± 1·4; PIN 6·8 ± 1·0 ln MI²; P = 0·003), decreased BPV in the low-frequency band (at 0·1 Hz, Mayer waves) (PROP 0·6 ± 0·7; PLA 1·3 ± 1·1; PIN 1·2 ± 1·2 ln mmHg²; P = 0·001) and enhanced BRS (PROP 14·6 ± 9·5; PLA 8·0 ± 6·8; PIN 8·7 ± 6·8 ms mmHg^?1; P = 0·001) in the supine position. After passive tilt, PROP decreased HRV in the low-frequency band (PROP 6·1 ± 0·9; PLA 6·5 ± 1·1; PIN 6·9 ± 0·7 ln MI²; P<0·001) and decreased Mayer waves (PROP 1·8 ± 0·8; PLA 2·4 ± 1·0; PIN 2·7 ± 0·8 ln mm Hg²; P<0·001). PIN increased the low-frequency HRV response, which is induced by passive tilt (PIN + 0·9 ± 1·0; PLA + 0·3 ± 1·3, PROP + 0·3 ± 1·0 ln MI²; P = 0·026). Our results prove that beta-adrenergic blockade with potent ISA does not increase HRV, has no beneficial effect on autonomic balance and even exaggerates sympathetic responses to passive tilt.     

Challenges of beta blocker therapy in chronic heart failure: the story continues.

Beta blockers are underused and underprescribed in patients with chronic heart failure. This may be due to poor patient knowledge about their condition, pharmacological treatment and self-care management in case of deterioration. Nurse specialist has a decisive role in implementation of evidence based management which can have effects beyond patient care.     

Effect of β-blocking agents with and without intrinsic sympathomimetic activity on work efficiency in healthy men

Summary. In order to evaluate the effect of β-blocking agents with and without intrinsic sympathomimetic activity (ISA) on work efficiency in healthy subjects, we studied the haemodynamic and gas exchange parameters, as well as blood lactate concentrations, during a graded maximal bicycle exercise test performed after perorally given propranolol (PRO) and pindolol (PIN) in seven healthy men. The medications (PRO: 80 mg X 2/day, PIN: 10 mg X 2/day, for seven days) were given in a placebo (PLA) controlled, double-blind, randomized, cross-over fashion. Both the drugs reduced heart rate and blood pressure during exercise equally compared with the placebo. The oxygen uptake at submaximal work loads, as well as at the maximum, was constantly and equally reduced by PRO and PIN compared with PLA. The anaerobic threshold was reached at a slightly lower oxygen uptake for both the drugs compared with the placebo (P < 0.05). No significant difference was, however, observed in the work levels at which the ventilatory anaerobic threshold was reached. Moreover, the gross efficiency, i.e. the amount of work performed at a certain energy consumption level (aerobic+anaerobic), was increased by both PRO (26.7 ± 0.5%, P < 0.02 vs PLA: 24–7 ± 0.5%) and PIN (26.5 ± 0–5%, P < 0.05 vs PLA) at a submaximal work load of 240 W. The results indicate that β-blocking agents propranolol and pindolol slightly and equally reduce maximal work performance, but increase the efficiency of submaximal work in a way that a certain amount of external work can be done with smaller consumption of oxygen. These findings may contribute to the benefit of β-blocking agents in patients with coronary heart disease.     

Glutathione peroxidase activity and serum selenium concentration in intrinsic asthmatic patients.

Serum glutathione peroxidase (GSH-Px) activity and selenium concentration were compared in intrinsic asthmatic patients and non-asthmatic control subjects. Serum GSH-Px activity and selenium concentration were assessed in 46 asthmatic patients and 75 age- and sex-matched non-asthmatic subjects by spectrophotometric assay. Mean serum GSH-Px activity was lower in intrinsic asthmatic subjects (9.4 +/- 2.6 pmol NADPH oxidized/min/g of protein) than in non-asthmatic subjects (16.3 +/- 2.9 pmol NADPH oxidized/min/g of protein). Mean serum selenium was lower in intrinsic asthmatic subjects (1.15 +/- 0.23 microM) than in non-asthmatic subjects (1.98 +/- 0.27 microM). Asthmatic patients have significantly lower concentration of selenium and GSH-Px activity measured in serum.     

慢性乙型肝炎患者血清转化生长因子β1检测的临床意义

目的评价慢性乙型病毒性肝炎(CHB)患者血清转化生长因子β1(TGF-β1)测定的临床意义.方法采用酶联免疫吸附测定法测定56例慢性乙型病毒性肝炎及肝硬化患者血清TGF-β1水平,并检测肝功能、肝纤维化指标、门静脉及脾静脉内径;以健康人20例为对照,并对患者组经3个月的常规护肝治疗后比较其症状、肝功能、肝纤维化的改善程度.结果随着患者病情的加重和肝纤维化的进展,血清TGF-β1水平随之上升,即对照组<慢性肝炎轻度<慢性肝炎中度<慢性肝炎重度<肝硬化(P< 0.01);患者组血清TGF-β1与血清总胆红素(TBIL)、透明质酸(HA)、层黏连蛋白(LN)、Ⅲ型前胶原氨基端肽(PⅢNP)、IV型胶原(CIV)、脾门静脉内径呈正相关(P< 0.01),与血清白蛋白(ALB)呈负相关(P< 0.01);经3个月常规护肝治疗后,患者丙氨酸转氨酶(ALT)、HA、PⅢNP改善程度与血清TGF-β1呈负相关.结论 TGF-β1密切参与CHB肝细胞破坏和肝纤维化的病理过程,测定患者血清TGF-β1可反映CHB患者肝细胞损害和肝纤维化程度,并能提示预后,对临床有较高的应用价值.     

肝源性糖尿病患者胰岛β细胞功能和胰岛素抵抗及临床意义

目的探讨肝源性糖尿病患者胰岛β细胞功能和胰岛素抵抗的特征。方法对肝源性糖尿病(HD)26例,2型糖尿病(T2DM)30例,正常对照(NC)22例,行口服葡萄糖耐量试验,测定0 min、30 min、60 min、120 min、180 min血糖及胰岛素水平。计算稳态模式评估法的胰岛β细胞基础分泌指数(HOMA-β)、早相胰岛素分泌指数(△I30/△G30)、晚相胰岛素分泌指数(AUCI30-120/AUCG30-120),评估胰岛β细胞功能;计算空腹血糖与空腹胰岛素比值(PFG/FINS)、稳态模式评估法的胰岛抵抗指数(HOMA-IR)、肝脏胰岛素抵抗指数(HIR)及Matsuda指数(MSI),评估胰岛素抵抗。结果 HD组的HOMA-β和AUCI30-120/AUCG30-120高于T2DM组(P<0.05),与NC组无差异(P>0.05);HD组和T2DM组的△I30/△G30低于NC组(P<0.05),HD组和T2DM组无差异(P>0.05);HD组和NC组的PFG/FINS低于T2DM组(P<0.05),HD组和NC组的PFG/FINS和HOMA-IR无差异(P>0.05);HD组和T2DM组的HIR高于NC组(P<0.05),HD组和T2DM组无差异(P>0.05);HD组和T2DM组的MSI低于NC组(P<0.05),HD组和T2DM组无差异(P>0.05)。结论 HD患者基础胰岛素分泌接近正常人,以早相胰岛素分泌损害及餐后胰岛素抵抗为主。