Comparison of beta-adrenoceptor selectivity of acebutolol and its metabolite diacetolol with metoprolol and propranolol in normal man

Summary 1. The beta-adrenergic selectivity of diacetolol, the major metabolite of acebutolol, has been compared with that of acebutolol, metoprolol and propranolol in 11 normal subjects.2. Bronchial and cardiac beta-adrenoceptor blockade were assessed on separate occasions after diacetolol 600 mg, acebutolol 400 mg, metoprolol 200 mg, propranolol 80 mg and placebo.3. Bronchial beta-adrenoceptor blockade was assessed as the displacement of the bronchodilator dose response curve to inhaled isoprenaline after each beta blocking drug compared to placebo and expressed as the dose ratio. Bronchodilatation was measured as change in specific airway conductance (sGaw) in the body plethysmograph. Cardiac beta-adrenoceptor blockade was assessed as the percentage reduction in exercise heart rate during the 5th minute of exercise at 70% of the subject's maximum work rate.4. There was a significant reduction in exercise heart rate with all 4 beta-blocking drugs when compared with placebo, 22% for diacetolol, 24% for acebutolol, 25% for propranolol and 28% for metoprolol. The reduction with metoprolol was significantly greater than the reduction with the other three beta-adrenoceptor antagonists.5. Mean dose ratios for the airway isoprenaline dose response curves after each of the 4 beta-blocking drugs were 2.4 for diacetolol, 2.7 for metoprolol, 8 for acebutolol and 72 for propranolol. The difference between diacetolol and metoprolol was not significant.6. Thus diacetolol appears to be more cardioselective than acebutolol and both are more cardioselective than propranolol in man. Metoprolol is probably more cardioselective than diacetolol though interpretation of the differences in exercise heart rate is complicated by the fact that diacetolol has some intrinsic sympathomimetic activity.     

The effect of propranolol on the rise in plasma ammonia during modest exercise

Summary Changes in plasma ammonia in response to exercise with and without pretreatment with propranolol have been studied. A standardised submaximal treadmill exercise test was used to assess the effects of placebo or propranolol 40 mg, 80 mg, or 160 mg twice daily given in random order for 3 days, the last dose being taken 90 min before exercise. After placebo the mean incremental rise in plasma ammonia in response to exercise was 16 µmol·l^–1. The corresponding rise after propranolol 40mg was 56 µmol·l^–1 (p<0.01). All three doses of propranolol produced similar effects on plasma ammonia and exercise heart rates.     

Effects of labetalol and propranolol on blood pressure at rest and during isometric and dynamic exercise

Summary The influence of intravenous labetalol and propranolol on the blood pressure response to isometric and dynamic exercise was examined in a double blind study in eight, young, normotensive volunteers. Effects were recorded after propranolol 7.5, 15 and 30 mg i. v., and after labetalol 30, 60 and 120 mg i. v. In control experiments saline was administered. Mean blood pressure rose with successive handgrip tests following saline and propranolol, but not after labetalol, and the difference was significant. The total dose of each drug produced the same reduction in heart rate during sub-maximal bicycle exercise. The exercise-induced systolic blood pressure response did not differ between the drugs.     

Evaluation of a radioreceptor assay for beta-adrenoceptor antagonists in plasma

Summary A radioreceptor assay (RRA) recently developed in this laboratory for beta-adrenoceptor antagonists in plasma was evaluated in normal volunteers and compared with a radioimmunoassay (RIA) for propranolol. The RRA depends upon the ability of beta-adrenoceptor antagonists to compete with a radiolabelled ligand for beta-adrenoceptor binding sites on lung membranes. Unlike other assays, it measures biologically active drugs including active metabolites of the parent compound. In volunteers given a single oral dose of (±)-propranolol, considerable differences between the two assay methods were demonstrated. In other experiments this difference was shown to relate to the RIA's sensitivity to the inactive (+)-isomer of propranolol and possibly to inactive metabolites. The facility of the RRA in measuring plasma levels of several other non-selective beta-adrenoceptor antagonists was also demonstrated. By employing (–)-propranolol as the standard in the RRA, all of these drugs can be directly compared with a single and relatively simple assay technique.     

Understanding the morning rise in blood pressure

1. The morning period has been recognized as the highest risk period of the day for cardiovascular events, particularly stroke and is also associated with a rapid surge in blood pressure. 2. Evidence now exists to show that the morning surge in blood pressure is an independent risk factor in some elderly hypertensive subjects. 3. However, methods to assess the contribution of the morning blood pressure surge from ambulatory recordings or home recordings, using clock times or times of waking, do not take into consideration the individual patterns of blood pressure change which can range from a rapid rise prior to or following waking to a slow increase over several hours. 4. In the present review we describe a novel method for determining the individual changes using a double logistic equation fitted to the individual pattern of blood pressure change. 5. Methods are presented to determine the rate of rise function over the morning period as well as predicting the change over a fixed time window which may be useful in refining the contribution of the blood pressure surge to cardiovascular risk. 6. Hypertensive people have an exaggerated rise in morning blood pressure as well as a greater rate of rise. 7. Antihypertensive drugs and dosing regimes are being developed which may be useful adjuncts to standard therapy for preventing morning hypertension and hopefully also reducing cardiovascular damage or events.     

Changes in haemodynamics and left ventricular function during intravenous nifedipine infusion with and without additional propranolol in patients with coronary artery disease. A randomized,placebo controlled trial

Summary The haemodynamic effects of a combined intravenous treatment of nifedipine and propranolol in ten patients with coronary artery disease compared to a single treatment with nifedipine or placebo were investigated.Nifedipine infusion resulted in a reduction of left ventricular (LV) afterload and LV volumes with an increase in heart rate and EF and no change of the double product, coronary sinus flow, LV diastolic parameters and dp/dt_max. Addition of propranolol lowers myocardial oxygen demand by reducing heart rate and dp/dt_max together with a sustained afterload reduction with no change in LV volumes and EF.The vasodilatatory action of nifedipine pretreatment balanced the negative effects of acute beta-receptor blockade on LV function and allows the reduction of myocardial oxygen demand without a deterioration of LV function.     

Pharmacokinetic-pharmacodynamic modelling of oxprenolol in man using continuous non-invasive blood pressure monitoring

Summary The relationship between the plasma concentration of oxprenolol and its haemodynamic effects during physical exercise was studied in 6 healthy volunteers, in whom BP and heart rate (HR) were continuously monitored by non-invasive techniques (Fin-A-Press-Tonometer) during repeated three-minute exercise periods for 8 h after treatment. Using the fitted pharmacokinetic curve, the drug effect was related to its plasma concentration using the E_max model.The mean EC50 for the relationship between drug concentration and heart rate during exercise (HR_ex) was 73.1 ng/ml, and for systolic blood pressure during exercise (SBP_ex) it was 112.7 ng/ml. E_max was 29.0% for HR_ex, and 33.2% for SBP_ex. There were no consistent differences between the parameters for the effects on HR_ex and SPB_ex.Thus, using a new, non-invasive technique for continuous measurement of blood pressure, the effect of a beta-adrenoceptor blocking drug on SBP_ex was described with similar accuracy as its effect on HR_ex.     

Effects of low-dose atenolol on postural and postprandial changes in heart rate,blood pressure,venous plasma catecholamines,and plasma renin activity

Summary The administration of a single dose of atenolol 50 mg 1 h before a standard 3100 kJ cold meal in fasting healthy subjects reduced the supine preprandial heart rate and systolic blood pressure, and blunted the postural and postprandial rises in mean heart rate and systolic blood pressure relative to placebo. It did not affect the preprandial supine diastolic blood pressure, nor the postural rise and postprandial drop in diastolic blood pressure.Preprandial administration of atenolol blunted the postural and postprandial rises in mean plasma renin activity, and it enhanced the rise in plasma noradrenaline during eating in the sitting position, and the postprandial concentrations of noradrenaline.The findings do not permit the conclusion that beta₁-adrenergic stimulation was the predminant cause of these atenolol-responsive changes.     

Effect of metoprolol and propranolol on platelet aggregation and cAMP level in hypertensive patients

Summary Ten patients with uncomplicated moderate essential hypertension were recruited to evaluate the effect of the non-selective beta-blocker propranolol and the beta₁-selective beta-blocker metoprolol on platelet aggregation and cAMP formation. Five patients began treatment with propranolol 80 mg b. i. d. and 5 with metoprolol 100 mg b. i. d., and after 2 weeks the treatments were exchanged. ADP- and adrenaline-induced platelet aggregation and the basal level of platelet cAMP were measured at the end of each treatment period. Platelet aggregation was tested turbidometrically, using the threshold value for irreversible aggregation, and cAMP measurements were performed using a protein-binding assay.Both ADP and adrenaline thrshold values were significantly lower after propranolol than after metoprolol.The basal cAMP level was lower during propranolol than metoprolol treatment.The results indicate that platelet aggregation and basal cAMP level are influenced by beta-blockers in proportion to their affinity to different beta-adrenoceptors. This may be of value in the beta-blocker treatment of patients at high thrombotic risk.     

Effect of acute administration of propranolol and atenolol on baroreflex function in normal man

Summary The acute administration of the -adrenoceptor antagonists propranolol (80 mg) and atenolol (50 mg) on baroreflex function were investigated in healthy volunteers.Two h after administration both propranolol and atenolol significantly prolonged the supine R-R interval (1126, 1128 ms respectively) compared to placebo (1012 ms); systolic arterial pressure also fell (102.9, 102.0 mm Hg respectively) compared to placebo (112.6 mm Hg). Baroreflex function, assessed using glyceryl trinitrate to deactivate the baroreceptors was unchanged by these drugs compared to placebo. Baroreflex sensitivity (slope of the linear regression line relating R-R interval to systolic blood pressure) using phenylephrine to activate the baroreceptors, was also unchanged (17.2, 17.9 ms/mm Hg respectively) compared to placebo (19.9 ms/mm Hg). However both regression lines were shifted (p<0.05) to the left compared to placebo.     

Effect of diltiazem on the pharmacokinetics of propranolol,metoprolol and atenolol

Summary The pharmacokinetic interaction between diltiazem and three -adrenoceptor blockers propranolol, metoprolol and atenolol was investigated in healthy volunteers given diltiazem 30 mg or placebo t.d.s. for 3 days, followed by a single dose of propranolol 20 mg, metoprolol 40 mg or atenolol 50 mg.The AUCs of propranolol and metoprolol were significantly increased after diltiazem and it significantly prolonged the elimination half-life of metoprolol. In contrast, it did not significantly affect the pharmacokinetics of atenolol. Propranolol significantly decreased the resting pulse rate after diltiazem pretreatment as compared to placebo.The results indicate that diltiazem impaired the clearance of propranolol and metoprolol, which are principally metabolized by an oxidative pathway, and that the kinetic interaction between diltiazem and propranolol may partly be related to the significant reduction in the pulse rate produced by the latter.     

Early rise in blood pressure following administration of adrenocorticotropic hormone-[1-24] in humans

1. An elevation in blood pressure has been consistently observed 24 h after adrenocorticotropic hormone (ACTH) administration and is caused by increased ACTH-stimulated cortisol secretion, in association with increased cardiac output. The aim of the present study was to investigate the previously undefined time of onset of this increase in blood pressure in normal humans. 2. Ten normal healthy volunteers received 250 mg ACTH-[1-24], in 500 mL normal saline, infused at a constant rate over 8 h. Six subjects also received a placebo infusion (normal saline only). Blood pressure, heart rate and cortisol levels were determined hourly. Adrenocorticotropic hormone (ACTH-[1-24] plus native ACTH) was measured at 0, 1, 7 and 8 h. 3. Infusion of ACTH-[1-24] produced maximal secretion rates of cortisol, resulting in a mean peak plasma level of 985 +/- 46 nmol/L at 8 h. In response, blood pressure and heart rate rose significantly by 2 h and remained generally elevated for the duration of the infusion. 4. The early onset of haemodynamic responses is consistent with classical steroid receptor-mediated genomic mechanisms, but could be due non-genomic mechanisms. 5. The cardiovascular consequences of therapeutic use of ACTH are well recognized. This results of the present study suggest that even diagnostic administration of ACTH, delivered over a few hours, may raise blood pressure.     

血灵侧脑室注射对大鼠动脉血压和心率的影响

目的：血灵是降血压中药制剂。本实验探讨血灵对心血管中枢的作用及其机理。方法：将药物微量地注射入麻醉大鼠侧脑室,观察注药后６０ｍｉｎ内血压和心率的变化。结果：（１）侧脑室注射血灵（１０ｍｇ／２０ｕｌ）引起动脉血压明显升高,２５ｍｉｎ时达到峰值,增幅为２６．５９％;心率增加,增幅为１５．７６％,侧脑室注射相同窖的ＮＳ。血压和心率无明显影响。（２）血压升高与侧脑室注射血灵的剂量呈明显的剂量－效应关系。（     

上肢有创血压与无创血压的差异分析

目的研究桡动脉有创动脉压与肱动脉无创动脉压之间的差异及其影响因素。方法对入住ICU的60例患者进行IABP与NBP的同步测量。结果收缩压均值,右侧IABP最高,左侧NBP最低。NBP与IABP收缩压测量值之间分组比较,PPI<0.45时NBP9.38%>IABP;0.45≤PPI≤0.55时NBP42.59%>IABP;PPI>0.55时NBP58.82%>IABP。结论在临床实践中,NBP与IABP的实际差异与理论相比有所不同。监测血压时应首选右臂,应用IABP时使用方波试验来判断IABP值的准确性;使用NBP时应对患者的血管硬化程度进行评估。     

Peripheral vascular effects of bufuralol in hypertensive and normal subjects: A comparison with propranolol and pindolol

Summary In a double-blind, single oral dose, crossover study, the effects of bufuralol (60 mg) on heart rate, blood pressure, and peripheral vascular responses were compared with those of propranolol (160 mg), pindolol (10 mg), and placebo in a group of 12 healthy volunteers.All three beta-adrenoceptor antagonists reduced exercise tachycardia, but at the doses chosen the effects of bufuralol were less than those of propranolol.Forearm blood flow was reduced by propranolol and pindolol, but not by bufuralol.The antihypertensive and peripheral vascular effects of bufuralol (30–60 mg bd) were also compared with those of propranolol (40–80 mg bd) in a double-blind crossover study in 10 patients with mild hypertension.Propranolol and bufuralol produced comparable reductions in systemic blood pressure over a two-week period, but the decreases in forearm and finger blood flow were greater with propranolol.These studies suggest that bufuralol is a beta-adrenoceptor antagonist with antihypertensive properties, and that it produces less peripheral vasoconstriction than propranolol or pindolol.     

Importance of sleep blood pressure

1. Blood pressure varies throughout the day and night and is maintained at different times by different control systems. 2. During the awake interval, the sympathetic nervous system is preeminent but during sleep the renin angiotensin system is the controller. 3. Sleep blood pressure is a more powerful predictor of non-haemorrhagic cerebro- and cardiovascular events in animals and humans, despite the sleep value being lower than the day value. 4. Drugs that act independently of the hormonal or neural systems, such as diuretics and calcium channel blockers, have similar effects during sleep and awake intervals. Beta-blockers have little effect during sleep when the activity of the sympathetic is low while drugs that interfere with the action of the renin angiotensin system have a greater blood pressure lowering effect during sleep. 5. One aim of therapy should be to ensure that blood pressure is low during sleep and drugs should be used in doses that lower blood pressure throughout the 24 h period.     

Atenolol blunts blood pressure increase during dynamic resistance exercise in hypertensives

AIMS

This study was conducted to determine whether atenolol was able to decrease BP level and mitigate BP increase during dynamic resistance exercise performed at three different intensities in hypertensives.

METHODS

Ten essential hypertensives (systolic/diastolic BP between 140/90 and 160/105 mmHg) were blindly studied after 6 weeks of placebo and atenolol. In each phase, volunteers executed, in a random order, three protocols of knee-extension exercises to fatigue: (i) one set at 100% of 1 RM; (ii) three sets at 80% of 1 RM; and (iii) three sets at 40% of 1 RM. Intra-arterial radial blood pressure was measured throughout the protocols.

RESULTS

Atenolol decreased systolic BP maximum values achieved during the three exercise protocols (100% = 186 ± 4 vs. 215 ± 7, 80% = 224 ± 7 vs. 247 ± 9 and 40% = 223 ± 7 vs. 252 ± 16 mmHg, P < 0.05). Atenolol also mitigated an increase in systolic BP in the first set of exercises (100% =+38 ± 5 vs.+54 ± 9; 80% =+68 ± 11 vs. +84 ± 13 and 40% =+69 ± 7 vs.+84 ± 14, mmHg, P < 0.05). Atenolol decreased diastolic BP values and mitigated its increase during exercise performed at 100% of 1 RM (126 ± 6 vs. 145 ± 6 and +41 ± 6 vs.+52 ± 6, mmHg, P < 0.05), but not at the other exercise intensities.

CONCLUSIONS

Atenolol was effective in both reducing systolic BP maximum values and mitigating BP increase during resistance exercise performed at different intensities in hypertensive subjects.     

Effects of prolonged administration of the angiotensin converting enzyme inhibitor CGS 16617 in normotensive volunteers

Summary A new, orally active angiotensin converting enzyme (ACE) inhibitor, CGS 16617, has been evaluated in normotensive subjects during acute and prolonged administration.Single ascending doses of CGS 16617 20 to 100 mg were given to 9 normotensive volunteers at one week intervals and the changes in blood pressure, plasma ACE and renin activity were examined up to 72 h after drug intake. Also, CGS 16617 50 mg/day or placebo were given for 30 days to 8 and 6 normotensive subjects, respectively, maintained on an unrestricted salt diet. Blood pressure was measured daily in the office and ambulatory blood pressure profiles were also obtained before, during and after therapy, using the Remler M 2000 blood pressure recording system.CGS 16617 was an effective and long lasting ACE inhibitor. It did not induce a consistant change in blood pressure, but, the individual responses were very variable and several subjects experienced a clear decrease in the average of the blood pressures recorded during the daytime.     

老年高血压病病人的动态血压特点

目的 探讨老年高血压的动态血压特点。方法 采用无创动态血压仪监测并比较12例正常老年对照组、51例非老年高血压组、52例老年高血压组的ABPM各参数。结果 老年高血压组24h、白天、夜间SBP、DBP均值除白天DBP外,均显著高于老年对照组(P<0.05,P<0.01,P<0.001)。血压负荷值老年高血压组24h、白天、夜间SBP显著增高(P<0.01,P<0.001),DBP无差异。老年高血压组呈现夜间SBP下降率减小(P<0.05)。老年高血压与非老年高血压组比较,前者DBP均值及负荷值明显降低(P<0.01,P<0.001),而SBP两组无差异。各期老年高血压比较除白天SBP负荷值有差异外(P<0.05),余参数均无差异。结论 老年高血压主要表现为收缩期高血压,并伴有夜间血压下降率的减小。     

The haemodynamic effects and pharmacokinetics of intravenous nicorandil in healthy volunteers

Summary We have studied the effects of intravenous nicorandil, a mixed arterial and venous vasodilator, in 48 healthy volunteers. Nicorandil (20, 28, 39, 54, 74, 103, 144, or 200 g·kg^–1) or placebo were given over 5 min to subjects supine (16 subjects, 2 doses) or sitting (32 subjects, 1 dose) in a single-blind crossover design. Electro-cardiographic intervals, blood pressure, and heart rate were measured before and for 8 h after dosing. Blood and urine safety laboratory studies were also performed before and after dosing.All intravenous infusions of nicorandil and placebo were well tolerated and there were no clinically important safety concerns. The most frequent adverse event after nicorandil was headache (24 events by 19 subjects), although its occurrence was not strictly dose related. One subject experienced transient symptomatic hypotension (144 g·kg^–1).Mean plasma nicorandil concentrations were dose-related and fell with a half-life of 0.7 to 1.2 h. Systemic clearance and volume of distribution tended to decrease as dose increased. Sitting subjects showed marginally lower (<20%) systemic clearances and larger values of C_max and AUC.Nicorandil produced dose-related reductions in blood pressure, with consistent statistically significant differences from placebo after the 144 and 200 g·kg^–1 doses. The falls in blood pressure were greater for diastolic pressure and in this supine position. At 200 g·kg^–1, the mean falls in systolic/diastolic pressures (mm Hg) during the first hour were 10.9/14.7 supine and 6.1/9.1 sitting; systolic pressure returned to baseline after 8 h and diastolic pressure after 4 h. Heart rate increased transiently (mean peak increase of 17–24 bpm at the end of the 144 and 200 g·kg^–1 infusions). Blood pressure and heart rate changes over time were statistically significantly correlated with plasma nicorandil concentrations. Individual areas under the blood pressure and heart rate change curves likewise correlated with plasma concentration curve areas.