Comparative β-adrenoceptor blocking effect and pharmacokinetics of bucindolol and propranolol in man

Summary The -adrenoceptor blocking properties and pharmacokinetics of bucindolol 150 mg were compared to those of propranolol 80 mg and a placebo in a double-blind trial in 6 healthy volunteers. Heart rate (HR), systolic (SBP) and diastolic (DBP) blood pressures and peak expiratory flow rate (PEFR) at rest and during vigorous exercise, and plasma renin activity (PRA) at rest, were measured before and at intervals up to 24 h after oral administration of the drugs. Bucindolol reduced exercise tachycardia and decreased exercise PEFR, thus behaving as a non-selective -adrenoceptor blocking drug. In contrast to propranolol, bucindolol did not reduce resting HR and PRA, probably because of its intrinsic sympathomimetic activity. It decreased resting DBP in relation to its peripheral vasodilator properties. The effects of bucindolol developed as early as 30 min after administration and lasted up to 24 h, whereas its T_max and T_1/2 were 1.6 and 3.6 h respectively. Comparison of the time courses of plasma bucindolol and the cardiac -adrenoceptor blockade strongly suggests that in man bucindolol undergoes an extensive first-pass effect, leading to the formation of one or more active metabolites.     

Hemodynamic profile of activation of histamine H3 receptors by R-α-methylhistamine in the guinea pig

• 1.1. The effect of R-α-methylhistamine, a histamine H₃ receptor agonist, was studied on cardiovascular hemodynamics in bilateral vagotomized, anesthetized guinea pigs.
• 2.2. R-α-methylhistamine (100 μg/kg, IV) a dose that selectively activates histamine H₃ receptors, produced hypotension and bradycardia. Total peripheral resistance (TPR) and rate pressure product (RPP) were also decreased at this dose.
• 3.3. Pretreatment with the ganglionic blocker hexamethonium (20 mg/kg, IV) blocked the blood pressure (BP), heart rate (HR), TPR, and RPP effects of R-α-methylhistamine (100 μg/kg, IV). Hexamethonium did not block the hypotensive and TPR lowering actions of the muscarinic agonist methacholine (1 and 3 μg/kg, IV).
• 4.4. Pretreatment with the α₁-adrenoceptor antagonist prazosin (0.5 mg/kg IV), blocked R-α-methylhistamine's (100 μg/kg, IV) effects on BP, TPR, and RPP. Prazosin did not antagonize the bradycardia effect of R-α-methylhistamine.
• 5.5. Pretreatment with the β-adrenoceptor antagonist atenolol (1 mg/kg, IV) did not alter the BP, TPR, or RPP actions of R-α-methylhistamine. The HR effects of R-α-methylhistamine were blocked by atenolol.
• 6.6. The hemodynamic effects of R-α-methylhistamine were compared to the hemodynamic profile of the calcium channel blocker, verapamil (0.5 mg/kg, IV). Verapamil had little effect on TRP and had a greater cardiac depressant effect as evidenced by a significant reduction in HR and cardiac output (CO).
• 7.7. In summary, these results show that activation of prejunctional H₃ receptors with R-α-methylhistamine decreases basal, BP, HR, TPR, and RPP in anesthetized guinea pigs. The fall in BP is mediated by a decrease in TPR. Furthermore, the inhibitory effects of R-α-methylhistamine on sympathetic control of the vasculature appears to impart a greater physiologic effect on the H₃-histamine mediated hypotension than its inhibitory effects on sympathetic agents to the heart.

     

Comparison of the effects of xamoterol,atenolol and propranolol on breathlessness,fatigue and plasma electrolytes during exercise in healthy volunteers

Summary The influence of clinical doses of drugs that affect -adrenoceptors has been examined on heart rate, blood pressure, duration of exercise, and on electrolyte concentrations (Na, K, Ca and Mg) during recovery from exercise in healthy volunteers. The drugs used were a ₁-adrenoceptor antagonist atenolol, a nonselective -adrenoceptor antagonist propranolol, and a cardioselective, partial ₁-adrenoceptor agonist with 43% ISA activity, xamoterol.The duration of exercise was smaller on propranolol. Maximum exercise heart rate and blood pressure were reduced significantly by propranolol and atenolol. Xamoterol reduced maximum exercise heart rate and had no effect on blood pressure. The degree of breathlessness and fatigue revealed no differences between treatments.Recent evidence has suggested an association between hyperkalaemia and hypomagnesaemia with an increase in the occurrence of arrythmias following acute myocardial infarction. Exercise-induced hyperkalaemia has been suggested as a factor in sudden death. The results confirmed a rise in serum potassium during exercise and attenuation of the fall during recovery under -adrenoceptor blockade. Xamoterol was no different from placebo in these respects. Exercise also produced a rise in magnesium levels and during recovery the level fell below baseline. Both these effects were attenuated by propranolol. Calcium levels were not affected by any of the treatments.     

The effects of rilmenidine and atenolol on mental stress, dynamic exercise and autonomic function in mild to moderate hypertension.

1. The effects of 4 week treatment with rilmenidine or atenolol on tests of mental stress, dynamic exercise, autonomic function and psychometric tests were evaluated in a randomized, double-blind, placebo-controlled, cross-over study. 2. After a 4 week placebo run-in, 12 patients with essential hypertension (blood pressure [BP] 160/95 +/- 15/7 mmHg) received rilmenidine 1-2 mg day-1, and atenolol 50-100 mg day-1, each for 4 weeks, with a 4 week placebo wash-out between drug treatments. 3. Both agents produced a comparable reduction in supine and erect BP. During the mental arithmetic test, BP and heart rate (HR) responses were similar for rilmenidine and atenolol. 4. During bicycle exercise, the increase in HR was significantly greater after rilmenidine (+50 vs 41 beats min-1, P = 0.04). During recovery, the areas under the curve for diastolic BP (46,450 vs 51,400 mmHg s, P = 0.02) and HR (49,445 vs 63,597 beats min-1 s, P = 0.001) were significantly less with atenolol than rilmenidine. 5. Neither rilmenidine nor atenolol affected mental performance as judged by arithmetic and psychomotor tests. Physiological responses to autonomic function tests (deep breathing, facial immersion, isometric handgrip and cold pressor) were preserved with both drugs. The standing to lying ratio was higher on atenolol (P = 0.01) and Valsalva ratio was higher on rilmenidine (P = 0.03). 6. In conclusion, rilmenidine and atenolol exerted comparable antihypertensive effects both at rest and during mental and dynamic stress. Atenolol attenuated HR responses to dynamic exercise and the Valsalva manoeuvre; rilmenidine did not interfere with the physiological responses of BP and HR during autonomic function tests.     

The effects of combined angiotensin converting enzyme inhibition and beta-adrenoceptor blockade on plasma renin activity in anaesthetized dogs.

1. The effects of beta-adrenoceptor blockade on the changes in plasma renin activity (PRA) following angiotensin enzyme (ACE) inhibition were investigated in pentobarbitone-chloralose anaesthetized dogs. 2. ACE-inhibition, with enalapril (2 mg kg-1), caused a significant reduction in systemic arterial blood pressure (BP) with little or no effect on cardiac function, and a significant elevation of plasma renin activity (PRA). By contrast beta-adrenoceptor blockade with atenolol (1 mg kg-1), caused a similar reduction in BP but in addition, significantly reduced cardiac function and PRA. 3. A combination of enalapril with atenolol, caused a significant reduction in BP, cardiac function and PRA, hence there was no elevation of PRA, as was seen following ACE-inhibition with enalapril alone. 4. The observations with beta-adrenoceptor blockade alone, show that there is an important homeostatic role for the renal sympathetic innervation, mediated by beta-adrenoceptors, in controlling basal renin levels. Furthermore, the renal sympathetic innervation appears to be an important contributor to the renin release caused by an ACE-inhibitor as the additional presence of a beta-adrenoceptor blocking agent will prevent this release. 5. BW B385C (2 mg kg-1), which combines both ACE-inhibition and beta-adrenoceptor blocking properties, also produced reductions in BP and cardiac function similar to those seen with the enalapril/atenolol combination. In addition, for an equivalent degree of ACE-inhibition by BW 385C, to that seen with enalapril alone, the elevation of PRA was attenuated.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lisinopril reduces postexercise albuminuria more effectively than atenolol in primary hypertension

Physical exercise causes transient albuminuria. The mechanisms of postexercise albuminuria are not fully clarified but stimulation of the reninangiotensin system (RAS) probably plays a major role through intrarenal haemodynamic changes causing an elevated filtration pressure. In a randomised, double-blind, crossover study we compared the effects on urinary albumin excretion (UAE) of lisinopril (L) and atenolol (A) therapy, i.e. we aimed to investigate whether inhibition of the RAS or inhibition of ₁-adrenoceptor-mediated effects of the sympathetic nervous system differed with regard to changes in UAE. Sixteen patients with uncomplicated primary hypertension were studied. Four standardised bicycle ergometer exercise tests were performed, before and after each active treatment period. UAE 30 min postexercise, determined by radioimmunoassay, was significantly lowered by both treatments: -278 g·min^-1 (L) and-199 g·min^-1 (A). The reduction of postexercise UAE achieved by treatment with the angiotensin-converting enzyme (ACE) inhibitor (L) was significantly greater than that achieved by the ₁-selective adrenoceptor blocker treatment. Blood pressure (BP) at rest and during exercise were equally reduced by both drugs. In conclusion, this study showed that antihypertensive treatment with an ACE inhibitor was more effective in reducing exercise-induced albuminuria than a ₁-selective adrenoceptor-blocking agent with a similar degree of BP reduction in patients with uncomplicated primary hypertension. This suggests that the RAS plays a major role in postexercise albuminuria in hypertensive subjects. The clinical significance of this finding, however, remains to be clarified.     

Effects of single oral doses of bisoprolol and atenolol on airway function in nonasthmatic chronic obstructive lung disease and angina pectoris

Summary A randomized, placebo-controlled, double-blind crossover investigation in 12 patients with non-asthmatic chronic obstructive lung disease and co-existing stable angina pectoris was done to compare two ₁-selective adrenoceptor blocking agents, atenolol 100 mg and bisoprolol 20 mg. Systolic and diastolic blood pressures (SBP, DBP), heart rate (HR) as well as airway resistance (AWR, and less frequently forced expiratory volume in 1 s (FEV₁) and intrathoracic gas volume (ITGV) were measured in the sitting position before and at various times up to 24 h after drug intake.During the first 4 h both beta-blockers produced a significant reduction in HR in comparison to placebo (p<0.01). Atenolol 100 mg significantly increased AWR relative to placebo and bisoprolol (p<0.05). After 24 h, a significant reduction in HR (p<0.01) could only be demonstrated after bisoprolol, whereas atenolol alone led to a significant elevation in AWR relative to placebo and bisoprolol (p<0.05) at that time.It is concluded that bisoprolol appears to have a high degree of beta₁-selectivity, thus providing a wide split between beta₁- and beta₂-adrenoceptor blockade. Bisoprolol in its therapeutic dose range is expected to be relatively safe as regards bronchoconstriction in patients suffering both from hypertension and/or angina pectoris and chronic obstructive lung disease.     

Exercise and the pharmacokinetics of propranolol,verapamil and atenolol

Summary The volumes of distribution of the-adrenoceptor blocking agents propranolol and atenolol, and the calcium antagonist verapamil, during exercise have been investigated. Changes in the plasma concentrations of atenolol and propranolol during exhaustive exercise at 70% of maximal aerobic power were compared after 1 week of oral treatment (propranolol 80 mg b. d. and atenolol 100 mg once daily) in 12 healthy volunteers. In a second study the effect of 10 min exercise at 50 % of maximal aerobic power on steady state plasma concentrations of propranolol, atenolol and verapamil was compared in 7 healthy subjects. The drugs were administered by a continuous intravenous infusion.The plasma concentration of atenolol was not changed by exercise in either study, but the plasma concentrations of propranolol and verapamil were significantly increased in both studies. However, after correction for changes in plasma volume during exercise, the plasma propranolol concentration was not significantly elevated in the second study.From the results it is concluded that exercise led to a reduction in the volume of distribution of propranolol during prolonged exercise (25 min) at 70 % Wmax, which was not clearly demonstrable during 10 min exercise at 50 % W_max. The volume of distribution of verapamil was reduced during 10 min exercise at 50 % Wm, No change in the volume of distribution of atenolol during exercise could be shown. The changes in the volumes of distribution of propranolol and verapamil during exercise may contribute to preventing an increase in the half-life of these drugs in patients performing prolonged physical exercise.     

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.     

Withdrawal phenomena after atenolol and bopindolol: haemodynamic responses in healthy volunteers.

1. The effect of withdrawal of atenolol and bopindolol administration was studied in 12 normal volunteers; six on each drug. 2. Following sub-maximal cycle-ergometer exercise training six sets of base-line observations were made of heart-rate (HR) and blood pressure (BP) responses; supine, 60 degrees head-up tilt, during graduated isoprenaline infusion and sub-maximal cycle exercise. 3. The results show that withdrawal phenomena occur following both drug treatments. Atenolol produced a hypersensitivity to isoprenaline and a small overshoot of HR in response to physiological manoeuvres. In contrast bopindolol produced a prolonged state of reduced sensitivity to isoprenaline and some evidence of overshoot of HR with physiological manoeuvres. The differences between the responses may be explained by the different properties of the two beta-adrenoceptor blocking drugs. 4. Some subjects showed clear evidence of overshoot of HR and BP on exercise demonstrating that certain individuals may be more prone to have withdrawal effects than others. 5. The length of time during which withdrawal phenomena can occur is probably longer than has previously been realised. 6. Hormonal changes were found in the withdrawal period (Walden et al., 1990).     

Effects of dilevalol,an R,R-isomer of labetalol,on blood pressure and renal function in patients with mild-to-moderate essential hypertension

Summary The effects of oral dilevalol (an R, R-isomer of labetalol), a new -adrenoceptor blocker with ₂-receptor stimulating and -recepter blocking properties on blood pressure, renal function, plasma renin activity (PRA) and plasma aldosterone have been studied in 15 patients with mild-to-moderate essential hypertension treated with it for 6 weeks.Two patients with apparent treatment failure and one patient who developed muscle pain and cramps, and had an elevated creatine phosphokinase level, were excluded from the study.Dilevalol monotherapy 100 mg once daily for 6 weeks significantly lowered both the systolic and diastolic blood pressure compared to placebo. Total renal vascular resistance was significantly reduced, and RBF and GFR remained unchanged. Dilevalol significantly decreased PRA.The results suggest that prolonged daily treatment with dilevalol preserves renal function and produces a concomitant hypotensive action in patients with mild-to-moderate essential hypertension. The ancillary pharmacological properties of dilevalol rather than PRA suppression may be relevant to its renal effects.     

Comparison of the effects of dilevalol and propranolol on systemic and regional haemodynamics in healthy volunteers at rest and during exercise

The effects of single oral doses of dilevalol 400 mg and propranolol 80 mg on systemic and regional haemodynamics at rest and after sub-maximal exercise, were compared, in a placebo-controlled, randomised, double-blind, crossover study in 6 healthy male volunteers.At rest, as compared to placebo, neither dilevalol nor propranolol significantly affected arterial pressure and heart rate but, whereas propranolol decreased cardiac output (–27% at 2 h) and tended to increase total peripheral resistance, dilevalol tended to increase cardiac output and decreased total peripheral resistance (–7% at 2 h). Neither dilevalol nor propranolol affected brachial artery diameter. Propranolol tended to decrease brachial artery flow (–20% at 2 h) and to increase brachial vascular resistance (+25% at 2 h), but dilevalol did not and the brachial irrigation ratios did not change. Neither of the drugs affected carotid haemodynamics or plasma atrial natriuretic factor. Both drugs tended to decrease plasma renin activity, and dilevalol (+82% at 2 h) increased norepinephrine more than propranolol (+19% at 2 h).After exercise, dilevalol and propranolol produced similar falls in the induced increases in arterial pressure, heart rate and cardiac output, and had the same effects on regional haemodynamics, plasma renin activity and atrial natriuretic factor. Finally, dilevalol greatly increased plasma norepinephrine.We conclude that the ₂-adrenoceptor agonist activity of dilevalol was clearly expressed at rest, thus inducing vasodilation and counteracting the -adrenoceptor blockade-induced negative chronotropic and inotropic effects. However, during sub-maximal exercise, only the -adrenoceptor antagonist activity of dilevalol was apparent.     

Double-blind comparison of once-daily bopindolol,pindolol and atenolol in essential hypertension

Summary The efficacy of once-daily bopindolol, a nonselective-adrenoceptor blocking agent with partial agonist activity, and of pindolol and atenolol in the treatment of essential hypertension has been compared. 369 patients were investigated in a double-blind parallel-group study. The treatment period was 10 weeks. Blood pressure normalisation (diastolic BP equal to or less than 90 mmHg) was to be achieved by a stepwise increase in the dose of the test drugs, and, if required, by addition of a diuretic. Normalisation of blood pressure was achieved in 71 to 76% of the subjects, with no significant differences between bopindolol, pindolol, and atenolol. Special attention was given to evaluation of side effects by using two methods for registration of all adverse events during the study. A low incidence of drug-induced side effects was observed, with no significant difference between bopindolol, pindolol, and atenolol. There was no evidence of unsuspected adverse reactions due to bopindolol.     

The effects of pafenolol and metoprolol on ventilatory function and haemodynamics during exercise by asthmatic patients

Summary Pafenolol, a new ₁-adrenoceptor antagonist, has been shown in animal studies to be more selective for the ₁-adrenoceptor than metoprolol. In a double-blind crossover study in 8 asthmatic patients its effect on heart rate and ventilatory capacity was studied during exercise. Exercise tests on a bicycle ergometer were performed before and 60, 120 and 180 min after i.v. administration of saline, metoprolol 15 mg, and pafenolol 5 and 7.5 mg. Plasma concentration determinations of metoprolol and pafenolol were estimated. Pafenolol 5 mg had the same blocking effect on exercise tachycardia as metoprolol 15 mg, while pafenolol 7.5 mg tended to have a more pronounced effect. On a molar basis the potency ratio for ₁-adrenoceptor — mediated effects of the drugs was about 1:3. Systolic blood pressure during exercise showed similar changes. There was a linear relation between the plasma concentration and the effect on exercise tachycardia. During exercise FEV, did not show any significant difference between the treatments, although there was a tendency towards lower values after metoprolol than after saline and pafenolol. After the last exercise test, when the patients inhaled terbutaline (1.25 mg), there was a significant increase in FEV₁ after all treatments, but there was a significant difference (14±5%,p<0,05) between the values after metoprolol and saline. The difference was also significant between pafenolol 5 mg and metoprolol (14±4%,p<0.05). This indicates less blockade of ₂-adrenoceptors by pafenolol than by metoprolol. Thus, increased selectivity for ₁-adrenoceptors was found for pafenolol as compared to metoprolol, which has been previously found to be a ₁-adrenoceptor antagonist with the same selectivity as, for example, atenolol.     

Propranolol and atenolol inhibit norepinephrine spillover rate into plasma in conscious spontaneously hypertensive rats

Summary Radiotracer techniques capable of measuring norepinephrine clearance and spillover rate into plasma were used to test the hypothesis that the antihypertensive effects of propranolol and atenolol in conscious spontaneously hypertensive rats are associated with an inhibition of norepinephrine release from postganglionic sympathetic neurons. The 10%–15% fall in mean arterial pressure produced over 4 h by propranolol (1, 3.3 and 10 mg/kg, s. c.) and atenolol (1, 3.3 and 10 mg/kg, s. c.) was not dose-related, and only the largest dose of propranolol caused a significant bradycardia. Each dose of atenolol significantly lowered heart rate. The decrease in blood pressure caused by propranolol and atenolol was not related to the decrease in heart rate. Both propranolol and atenolol inhibited norepinephrine clearance by 12% to 16%. The 1 mg/kg doses of propranolol and atenolol significantly suppressed norepinephrine spillover rate by 21 % and 32%, respectively, at 4 h postinjection. As the dose of propranolol was increased, the inhibition of norepinephrine spillover was reversed as plasma epinephrine concentration rose by 125%. The suppression of norepinephrine spillover rate caused by atenolol was more persistent but did diminish after the 10 mg/kg dose, when plasma epinephrine concentration was elevated by 55%. Both drugs suppressed plasma renin concentration, but the inhibition of norepinephrine spillover rate by propranolol and atenolol was not related to the fall in plasma renin concentration. By comparison, treatment with the adrenergic neuron blocking agent bretylium (5, 10, 20 and 40 mg/kg, s. c.) elicited a dose-related vasodepression with no change in heart rate or plasma renin concentration. The 10 mg/kg dose of bretylium inhibited norepinephrine spillover rate by 40%, but increasing the dose did not produce a further suppression of norepinephrine spillover rate. Bretylium caused a dose-related elevation of plasma epinephrine concentration (354% increase at 40 mg/kg). In a separate study, propranolol (10 mg/kg) and bretylium (40 mg/kg) significantly increased epinephrine spillover rate by 85% and 118%, respectively. Based on these data, we conclude that the -adrenoceptor antagonists lower blood pressure by inhibiting norepinephrine release from postganglionic sympathetic neurons. Send offprint requests to T. K. Keeton at the above address     

Effects of tedisamil, atenolol and their combination on heart andrate-dependent QT interval in healthy volunteers

Aims Tedisamil is a new blocker of K⁺ currents in cardiac tissues, exerts bradycardic effects and has shown clinical efficacy in angina pectoris. Theoretically, when coadministered with a &bgr;-adrenoceptor blocker the tedisamil combination could induce dangerous bradycardia and QT interval prolongation. Therefore, the aim of this study was to evaluate the effects of tedisamil and atenolol alone and in combination, on heart rate and QT interval duration at rest and during exercise tests.
Methods The effects of tedisamil (100  mg twice daily) and atenolol (50  mg twice daily) on heart rate and QT interval duration were analysed in a three-period crossover study in healthy male volunteers.
Results This study showed that tedisamil exerted a significant ( P <0.05) bradycardic action at rest (−10 beats min⁻¹; 95% CI: -6 to -15 beats min⁻¹ ) similar to atenolol (−14 beats min⁻¹; -11 to -17) and drug combination (−9 beats min⁻¹; -6 to -12). During exercise, at the highest comparable workload, heart rate did not decrease significantly with tedisamil but decreased significantly with atenolol (−42  beats min⁻¹; -37 to -47) and combination (−47 beats min⁻¹ ; -41 to 52). Atenolol did not modify QT interval duration. Tedisamil alone and in combination with atenolol increased QT interval duration by 12% (95% CI: 7 to 17%) and 12% (8 to 16) respectively at RR=1000ms, but not at RR<700ms (combination). Tedisamil alone and in combination induced a reverse rate-dependent QT interval prolongation.
Conclusions These results indicate that the combination of tedisamil and atenolol is not associated with excessive bradycardia or excessive QT interval prolongation in healthy subjects.     

Beta-blockade and lipolysis during endurance exercise

Summary Inhibition of adipose tissue lipolysis may be involved in the impairment of endurance capacity after administration of a -adrenoceptor blocker. During endurance exercise, no significant decrease in plasma glycerol and free fatty acid (NEFA) concentrations after -adrenoceptor blockade is found. However, the levels during recovery from exhaustion are lower after -adrenoceptor blockade. This study was designed to investigate whether the lower levels after exercise are due to -adrenoceptor blockade or to the shorter time to exhaustion after administration of a -adrenoceptor blocker.In a single-blind study, 11 well-trained male subjects (age 23 (0.9) y) performed a cycle ergometer test at 70% W_max until exhaustion 2 h after intake of 80 mg propranolol. One week later, the test was repeated after intake of placebo and was stopped at the time of exhaustion in the previous test. Average exercise time was 24 min. During exercise plasma glucose was lower, whereas plasma lactate and the respiratory exchange ratio were significantly higher when the subjects were on propranolol. Glycerol and NEFA concentrations during exercise were not significantly different between the two conditions. Despite an identical exercise time, glycerol and NEFA concentrations during recovery were significantly lower after propranol treatment.In conclusion, lipolysis is inhibited during exercise after propranolol, probably causing a shift from fat to carbohydrate combustion.     

A dose-ranging study to evaluate the β1-adrenoceptor selectivity of bisoprolol

Summary A dose-ranging study was performed to compare the ₁-adrenoceptor selectivity of bisoprolol with that of atenolol and nadolol. Seven normal subjects (mean age 26 y) were given single oral doses of bisoprolol 5 mg (B5), 10 mg (B10), 20 mg (B20); atenolol 50 mg (A50), 100 mg (A100); nadolol 40 mg (N40); and placebo (PL), in a single blind randomised cross-over design. ₂-adrenoceptor responses were assessed by attenuation of finger tremor and cardiovascular responses to graded isoprenaline infusions. Dose-response curves were constructed, and doses of isoprenaline required to increase finger tremor by 100% (IT₁₀₀), heart rate by 25 beats/min (IH₂₅), SBP by 25 mm Hg (IS₂₅), cardiac output by 35% (IC₃₅), and decrease DBP by 10 mm Hg (ID₁₀), after each treatment were calculated. These indices were compared with placebo response and expressed as dose-ratios. Exercise heart rate (EHR) was used to assess ₁-adrenoceptor blockade.There were dose-related increases in plasma concentrations of bisoprolol and atenolol. Reduction of EHR was significantly less with B5 (16.8%) in comparison with all other treatments: B10 21.9%, B20 23.1%; A50 22.5%, A100 22.6%; N40 22.9%. There were small but significant reductions in isoprenaline-induced tachycardia with bisoprolol and atenolol, although mean dose-ratios were considerably less in comparison with N40 (IH₂₅ dose-ratios): B5 2.55, B10 3.18, B20 3.93, A50 2.91, A100 4.89, N40 17.23. There were similar patterns for the other isoprenaline responses.These results show that conventional doses of bisoprolol (10 mg) and atenolol (50 mg) produced equal antagonism of ₁ and ₂-adrenoceptors, and therefore possess equal degrees of ₁-adrenoceptor selectivity. Increasing doses of bisoprolol and atenolol were associated with partial loss of selective ₁-adrenoceptor blockade, although antagonism of ₂-adrenoceptors was significantly less compared with the effects of nadolol.     

Dissociation of blood pressure and sympathetic activation of renin release in sinoaortic-denervated rats

1. Blood pressure (BP) and heart rate (HR) increase 6 and 24 h after sinoaortic baroreceptor denervation (SAD), whereas plasma renin activity (PRA) and renal renin mRNA levels remain unchanged. We postulated that a simultaneous rise in BP could offset the expected activation of renin associated with an increased renal sympathetic discharge secondary to SAD. 2. To test this hypothesis, the increase in BP associated with the onset of SAD was prevented by a continuous infusion of sodium nitroprusside (SNP; 30 microg/kg per h). Changes were measured in five groups of conscious adult male Wistar rats: (i) sham; (ii) SAD; (iii) SAD rats in which the BP was prevented from increasing by infusion of SNP; (iv) sham rats in which the BP was increased by 30% by infusion of phenylephrine (PE; 1.5-2.0 mL/h); and (v) SNP + PE for 3 h by infusion as above. 3. As expected, BP and heart rate (HR) increased significantly following SAD compared with sham rats (152 +/- 4 vs 116 +/- 3 mmHg, respectively, for BP and 503 +/- 6 vs 345 +/- 13 b.p.m., respectively for HR; n = 5; P < 0.05) but remained unchanged when SNP was infused for 3 h (106 +/- 1 mmHg and 455 +/- 9 b.p.m., respectively; n = 5; P < 0.05). 4. Similarly, BP and HR increased with PE infusion compared with PE + SNP (138 +/- 9.9 vs 113 +/- 2.3 mmHg for BP, respectively, and 325 +/- 9 vs 423 +/- 18 b.p.m. for HR, respectively; n = 5; P < 0.05). 5. Plasma renin activity remained unchanged in SAD compared with sham rats (1.67 +/- 0.35 vs 1.05 +/- 0.17 ng angiotensin (Ang) I/mL per h), but increased significantly when hypertension was prevented (5.86 +/- 0.77 ng AngI/mL per h; n = 5; P < 0.05). Renin mRNA levels in the kidneys were unchanged in all groups. 6. These results show that an elevation in BP appears to offset increased renal sympathetic discharge with no change in PRA.     

Duration and selectivity in β-adrenoceptor blocking action of a β-adrenoceptor blocking drug,D-32 in conscious dogs

Summary In conscious dogs, the selectivity and duration of -blocking activity, and serum concentration of a -blocking agent, D-32 [dl-1-tert-butylamino-3-(2,3-dimethylphenoxy)-2-propanol hydrochloride] was compared to that of propranolol, pindolol, atenolol and IPS-339 [dl-1-tert-butylamino-3-(9-fluorenylideneaminoxy)-2-propanol hydrochloride]. Ratios of doses causing a 50% inhibition of tachycardia to that on hypotension induced by isoprenaline were as follows: D-32 (0.69), propranolol (0.67), atenolol (0.03) and IPS-339 (6.3). Thus, present experiments indicate that, unlike atenolol and IPS-339, D-32, propranolol and pindolol are non-selective -adrenoceptor blocking agents. Atenolol and IPS-339, however, selectively blocked cardiac ₁, receptors and vascular ₂-receptor respectively, as would be expected. In an optimal dose range these two drugs can be used satisfactorily as a pharmacological tool for inhibiting responses mediated via the respective -receptors. After oral administration, the pharmacological half-life (time required for 50% recovery of -blocking action) was 15.8±4.5 h for propranolol (3 mg/kg), 21.8±6.4 h for D-32 (0.5 mg/kg), 30.5±3.1 h for atenolol (6 mg/kg) and 30–35 h for pindolol (0.2 mg/kg). The pharmacological half-life after i.v. administration was 4.4±0.7 h for propranolol (300 g/kg) and 5.9±0.4 h for D-32 (150 g/kg), whereas the serum half-life (time required for 50% decrease in serum concentration) of propranolol was 1.4h and that of D-32 was 1.3 h. The values for pharmacological half-life and serum half-life were significantly different. Thus, for determination of administration frequency and dosage of -adrenoceptor blocking drugs, not only pharmacokinetic but also pharmacological data (duration of action) are essential.