Reduction In Exercise Tachycardia Research Articles

COMPARISON OF SOME PROPERTIES OF PRONETHALOL AND PROPRANOLOL

Much evidence has accumulated to justify the classification of pronethalol (Alderlin; I.C.I.) as a sympathetic β-receptor antagonist described in terms of Ahlquist's (1948) dual-receptor hypothesis. There has now been confirmation in animal experiments of antagonism to adrenergically induced vasodilatation (Ahlquist, 1963; Abboud, Eckstein & Zimmerman, 1963), cardiac stimulation (Meester, Hardman & Barboriak, 1963; Kako, Krayenbuhl, Luthy & Hegglin, 1964; Donald, Kvale & Shepherd, 1964), bronchodilatation (Nagasaka, Schaepdryver & Heymans, 1964), uterine relaxation (Levy & Tozzi, 1963) and gut relaxation after block or loss of α-receptors (Lum & Kermani, 1963). In human pharmacological studies antagonism to catecholamine-induced vasodilatation and cardiac stimulation (Dornhorst & Robinson, 1962; Lowe & Robinson, 1964) has been reported. Reduction of exercise tachycardia in man has been described by Bishop & Segel (1963), Chamberlain & Howard (1964), Harrison, Braunwald, Glick, Mason, Chidsey & Ross (1964) and Schroder & Werko (1964). The effects of pronethalol in experimental cardiac arrhythmias in dogs and guinea-pigs have been investigated. Antagonism of arrhythmias induced by cardiac glycosides has been reported by Erlij & Mendes (1964), Vaughan-Williams & Sekiya (1963) and Somani, Hardman & Lum (1963). Prevention of arrhythmias induced by adrenaline during anaesthesia with a hydrocarbon has been found by Murray, McKnight & Davis (1963) and by Hess & Hampton (1964). Somani et al. (1963) have shown that pronethalol will block ectopic ventricular tachycardia produced by large doses of adrenaline, and Ehringer & Gogel (1963) claim that it reduces the apical myocardial necrosis produced in rats by large doses of isoprenaline. This interest in the cardiovascular actions of pronethalol is also shown in various clinical reports. Success in the treatment of some cardiac arrhythmias, including digitalis intoxication, has been reported by Stock & Dale (1963) and Grandjean & Rivier (1963). Encouraging results in the treatment of angina have been found in a multicentre double-blind trial (Alleyne, Dickinson, Dornhorst, Fulton, Green, Hill, Hurst, Laurence, Pilkington, Prichard, Robinson & Rosenheim, 1963) and in a small, placebo-controlled, trial of effort tolerance (Apthorp, Chamberlain & Hayward, 1964). Potential therapeutic value of pronethalol in the management of phaeochromocytoma (Dornhorst & Laurence, 1963) and hypertrophic obstructive cardiomyopathy (Harrison et al., 1964; Cohen, Effat, Goodwin, Oakley & Steiner, 1964) has been described. Effective treatment of ventricular arrhythmias occurring during halothane anaesthesia has been reported by Johnstone (1964) and by Payne & Senfield (1964). These reports confirm the suggestions by Black & Stephenson (1962) that sympathetic β-receptor antagonists might be valuable in the study and treatment of certain cardiac disorders. The overt toxic effects of pronethalol described by Black & Stephenson (1962) were tremors and convulsions. These signs were correlated with the evidence that the brain concentrations of pronethalol were of the order of 100-times the blood concentration. The acute toxic signs appeared at doses seven- to ten-times greater than those needed for effective β-receptor blockade. While tremors and convulsions have not been described in man, effective doses are often associated with unpleasant subjective side-effects. Mild disorientation, slight inco-ordination, nausea and vomiting have been described (Alleyne et al., 1963). Since the toxic signs in animals are seen with the inactive (+)-isomer as as well as with the active (–)-isomers (Howe, 1963), it has been assumed that the effects of pronethalol on the central nervous system are probably not due to β-receptor blockade. A more serious toxic manifestation was found in mice. Studies showed that pronethalol was a moderately potent carcinogen in this species. Malignant tumours, mainly thymic lymphosarcomata, began to appear after 10 weeks continuous dosing (Paget, 1963; Alcock & Bond, 1964). This combination of nonspecific central actions and carcinogenic potential in a compound of clinical interest put a premium on finding a less toxic compound. A preliminary communication (Black, Crowther, Shanks, Smith & Dornhorst, 1964) on such a compound has been published; this compound is propranolol (Inderal; LCI.). The relationship of propranolol to pronethalol is shown by the structural formulae: This paper presents details of the comparative activity of these compounds. Detailed studies of their toxicity by our colleagues have shown that daily treatment of mice with propranolol over a period of 18 months did not produce thymic tumours (Alcock, Baker & Tucker, 1965).

A prospective study of the effects of prolonged timolol therapy on α‐ and β‐adrenoceptor and angiotensin II receptor mediated responses in normal subjects

Aims Long‐term treatment with β1‐selective adrenergic antagonists gives rise to cross‐sensitisation of cardiac β2‐adrenoceptor responses, with no corresponding alteration in β1‐adrenoceptor responses. We performed a prospective randomised double‐blind placebo‐controlled cross‐over study of the effects of nonselective β‐blockade with timolol on α‐adrenergic and angiotensin II receptor mediated responses in normal subjects. We also wished to study the time course of β1‐ and β2‐adrenergic responses after withdrawal of timolol. Methods Six healthy males received timolol 10 mg twice daily or placebo for 14 days. On day 11 of treatment, vascular α1‐, α2‐ and angiotensin II receptor responses were assessed by measuring the blood pressure increases in response to intravenous phenylephrine, α‐methylnoradrenaline and angiotensin amide respectively, following one dose of timolol 10 mg (to block the β‐adrenergic effects of phenylephrine and α‐methylnoradrenaline). Both systolic and diastolic blood pressure increased in response to each of these drugs, but these increases were not different on timolol treatment or placebo. Following cessation of treatment with timolol or placebo, β1‐ and β2‐adrenoceptor mediated responses were assessed by measuring the heart rate responses to treadmill exercise and intravenous salbutamol infusion respectively. Half each of the subjects underwent this 2 days and 3 days respectively, after the end of treatment. Results Both exercise‐induced and salbutamol‐induced tachycardia were not different following placebo or 3 days following the end of timolol treatment. However, 2 days following timolol treatment, both were attenuated; the reduction in salbutamol‐induced tachycardia was significant, whilst the reduction in exercise tachycardia did not reach statistical significance. We also measured metabolic responses to exercise and to salbutamol infusion. Exercise induced a rise in plasma potassium and noradrenaline. Salbutamol produced a fall in plasma potassium, a rise in plasma glucose and insulin and also a rise in plasma noradrenaline. All of these changes were not different following placebo or 3 days after the end of timolol treatment; by contrast, 2 days following timolol treatment, all were significantly attenuated, with the exception of the rise in plasma glucose. In addition, the rise in both plasma glucose and insulin in response to an oral load of 75 g glucose were not different post‐placebo, 2 or 3 days post‐timolol. Conclusions These results show that, following 14 days of nonselective β‐adrenoceptor blockade with timolol, there is evidence of residual β‐adrenoceptor blockade 2 days after drug withdrawal; this finding is in contrast with the known plasma profile of timolol (half‐life 3–6 hours), but is consistent with our previous observations of the slow speeds of association and dissociation of timolol with β‐adrenoceptors in vitro. There is no evidence, in this study, of β‐adrenergic sensitisation following timolol withdrawal, nor of cross‐regulation of vascular α1‐, α2‐ or angiotensin II receptors in response to nonselective β‐adrenoceptor blockade.

Comparison of some properties of pronethalol and propranolol. 1965.

Comparison of some properties of pronethalol and propranolol. 1965.

The effects of lower than conventional doses of oral nadolol on relative beta 1/beta 2‐adrenoceptor blockade.

1. The aim of the present study was to evaluate the relative beta 1/beta 2 antagonist selectivity of the beta-adrenoceptor blocker nadolol, in lower than conventional clinical doses. 2. Eight normal volunteers received single oral doses of either placebo (PL), nadolol 5 mg (N5), 20 mg (N20) or 80 mg (N80) in a single-blind, randomised crossover design. beta 1-adrenoceptor antagonism was assessed by attenuation of exercise tachycardia, and beta 2-adrenoceptor blockade by effects on salbutamol-induced chronotropic, hypokalaemic and finger tremor responses. The relative percentage attenuation of beta 2 and beta 1-mediated responses was calculated and expressed as beta 2:beta 1 selectivity ratios. 3. Nadolol produced dose-related reductions in exercise tachycardia in keeping with increasing beta 1-adrenoceptor blockade; mean % reduction (95% CI) compared with placebo: N5 10.7 (6.6 to 14.8), N20 21.4 (17.3 to 25.4), N80 38.9 (34.8 to 42.9). However, even the lowest dose of nadolol (5 mg) produced almost complete blunting of beta 2-mediated effects and significantly increase exercise hyperkalaemia; peak exercise hyperkalaemia (mmol l-1) (means and 95% CI): PL 4.88 (4.68 to 5.07), N5 5.36 (5.17 to 5.55), N20 5.48 (5.28 to 5.67), N80 5.42 (5.22 to 5.61). beta 2:beta 1 selectivity ratios significantly increased as the dose of nadolol was reduced. 4. These data suggest that whereas in the clinical dose range nadolol behaves as a non-selective beta-adrenoceptor antagonist, as the dose is reduced this drug demonstrates an increasing degree of selectivity for the beta 2-adrenoceptor.(ABSTRACT TRUNCATED AT 250 WORDS)

A comparative pharmacokinetic and pharmacodynamic study of conventional and sustained‐release preparations of acebutolol in healthy volunteers

Pharmacokinetics and the degree of beta-blockade of sustained release (SR) acebutolol (500 mg/day) and conventional acebutolol (200 mg tid) were examined after the first oral dose and after 10 days of treatment in ten healthy volunteers. After the first dose, acebutolol Cmax did not significantly differ between the two formulations; however, on day 10 acebutolol Cmax was significantly higher after SR formulation. Cmax of diacetolol, the major metabolite, did not differ between SR and conventional acebutolol neither on day 1 nor on day 10. The dose-corrected relative bio-availability of acebutolol was not different from 100% on day 1 and day 10; however the dose-corrected diacetolol AUC, SR/conventional ratio, was significantly lower than 100% on days 1 and 10. Both acebutolol preparations exerted a significant reduction in exercise tachycardia over 24 h on day 1 and day 10; however, conventional acebutolol exhibited a greater reduction 24 h after the first dose. Exercise-induced increase in systolic blood pressure was similarly inhibited by both treatments except for 24 h after the first dose when systolic blood pressure was significantly higher with SR than with conventional acebutolol. The percent reduction in heart rate during exercise was linearly correlated with log acebutolol plasma concentrations for each treatment regimen. These results suggest that beta-blockade exerted by SR acebutolol in healthy volunteers is equivalent to that of conventional acebutolol.

Bronchoconstriction of the asthmatic airway by inhaled and ingested propranolol

Responsiveness to inhaled histamine and DL propranolol hydrochloride was measured in 31 adult asthmatics and compared with bronchoconstriction provoked by acute oral propranolol dosing (max 160 mg). Twelve asthmatics developed greater than or equal to 15% reduction in the forced expired volume in 1 s (FEV1), 2 h after less than or equal to 100 mg oral propranolol; cardiac beta-adrenoceptor blockade was confirmed by cycle exercise tests in the 19 without airway response. The provocative inhaled dose of each aerosol causing a 20% fall in FEV1 (PC20) was lower, histamine 0.43 mg.ml-1, propranolol 3.12 mg.ml-1, in the 12 with a positive oral test compared with the 19 with a negative test, PC20 histamine 1.65 mg.ml-1, PC20 propranolol 16.2 mg.ml-1 (P less than 0.001 for both aerosols). A correlation was demonstrated between the PC20 values for asthmatics with a negative oral test (r = 0.72, P less than 0.001, n = 19) but not for the remainder (r = 0.14, P greater than 0.05, n = 12). Plasma propranolol concentrations (CL, ng.ml-1) after the final oral dose did not correlate with the % delta FEV1 (26.3) (r = -0.28) when an airway response was provoked or with the reduction in exercise tachycardia (25.9%) (r = 0.31) when no bronchoconstriction occurred. CL exceeded the limit of detection after the final inhaled propranolol dose (7.5 ng.ml-1) and was weakly related to the PC20 propranolol value (r = 0.53, P = 0.01, n = 27). The prevalence of a positive oral challenge was low in this group (39%).(ABSTRACT TRUNCATED AT 250 WORDS)

Interindividual differences in β-receptor density contribute to variability in response to β-adrenoceptor antagonists

To determine the role of changes in receptor density and the considerable interindividual variability in the response to beta-adrenergic antagonists, we determined the relationship between the beta-blockade produced by propranolol and the beta-adrenergic receptor density (Bmax) in 16 healthy subjects who received 10, 20, 40, and 80 mg propranolol every 8 hours for 1 day at each dosage level. The extent of beta-blockade produced was assessed as the reduction in exercise tachycardia. The extent of beta-blockade correlated with pretreatment lymphocyte Bmax (30 mg/day: r = 0.6290, p less than 0.05; 60 mg/day: r = 0.5279, p less than 0.05; 120 mg/day: r = 0.5888, p less than 0.01; 240 mg/day: r = 0.6783, p less than 0.005). When the extent of beta-blockade was corrected for plasma propranolol concentrations, the correlation was further improved (30 mg/day: r = 0.7636, p less than 0.001; 60 mg/day: r = 0.7218, p less than 0.002; 120 mg/day: r = 0.7814, p less than 0.001; 240 mg/day: r = 0.6899, p less than 0.005). We conclude that the density of beta-adrenergic receptors is one of the principal factors that control beta-receptor response to antagonists in human beings.

Absence of excess peripheral muscle fatigue during beta-adrenoceptor blockade.

1. In eight normal volunteers, the adductor pollicis (AP) was fatigued using intermittent trains of programmed, supramaximal stimulation at 1, 10, 20, 50, 100 and 1 Hz. Activity protocols were performed both with and without circulatory occlusion, both without and during propranolol 80 mg thrice daily in order to investigate the effects of beta-adrenoceptor blockade on 'peripheral' fatigue mechanisms. 2. The degree of beta-adrenoceptor blockade was assessed by the reduction of exercise tachycardia during cycle ergometry, e.g. pulse rates at 210 watts were reduced from 190 +/- 15 to 127 +/- 5 beats min-1 (mean +/- 1 s.d.) indicating that beta-adrenoceptor blockade was substantial and highly significant (P less than 0.001). 3. Before, during and following fatiguing activity with circulatory occlusion force declines were identical during and without beta-adrenoceptor blockade. During and following activity without occlusion, there were slight declines in force which were questionably significantly different at 20 Hz (P less than 0.05). 4. The compound muscle action potential (CMAP) amplitude, measured from the skin surface over the muscle, was unaltered by beta-adrenoceptor blockade before, during or after activity whether with or without circulatory occlusion. 5. The maximal relaxation rate (MRR) was not significantly reduced in previously unfatigued muscle during beta-adrenoceptor blockade. During activity, both with and without circulatory occlusion, there was no evidence that MRR was reduced significantly more during beta-adrenoceptor blockade. 6. The absence of a convincing effect of beta-adrenoceptor blockade on peripheral fatigue mechanisms may indicate that central mechanisms are involved or that impairments of peripheral force production, of a specific nature or as a result of exacerbation of limitations of circulatory oxygen transport, though small are detected during voluntary exercise and give rise to increases in motor unit recruitment and/or firing rates, and hence increased perception of fatigue.

A Comparison of the Cardioselectivity of Five β-Adrenoceptor Blocking Drugs

The cardioselectivities of five beta-adrenoceptor antagonists were compared. Six normal subjects received, in a double-blind random order, 200 mg acebutolol, 50 mg atenolol, 10 mg betaxolol, 100 mg metoprolol, 80 mg propranolol, and placebo. All beta-adrenoceptor antagonists produced a similar reduction in exercise tachycardia. Isoprenaline infusions in incremental doses were given. Dose-response curves were constructed and the doses of isoprenaline required to increase heart rate by 25 beats/min (I25), forearm blood flow by 3 ml/100 ml/min (IF3), and finger tremor by 200% (IT200), and decrease diastolic blood pressure by 25 mm Hg (ID25), after each treatment were compared. After propranolol, I25, ID25, IF3, and IT200 were greater (p less than 0.02) than after atenolol, betaxolol, and metoprolol; I25, ID25, and IT200 were greater than after acebutolol. After acebutolol I25, ID25, and IF3 were greater than after atenolol and betaxolol; IT200 was greater than after betaxolol. Atenolol and betaxolol caused less reduction in the isoprenaline-induced changes in blood glucose, plasma potassium, lactate, renin activity, and serum insulin than propranolol. Acebutolol caused less attenuation of blood glucose and plasma lactate, and metoprolol less attenuation of plasma renin activity, than propranolol. It is concluded that acebutolol, atenolol, betaxolol, and metoprolol cause less blockade of beta 2-adrenoceptors than propranolol, and atenolol and betaxolol are more cardioselective than acebutolol.

Effect of Beta-Adrenoceptor Blockade and Calcium Antagonism, Alone and in Combination, on Thermoregulation During Prolonged Exercise*

The effect of clinically used doses of propranolol, atenolol, nifedipine, propranolol plus nifedipine, and atenolol plus nifedipine on thermoregulatory responses of 11 healthy men was studied during 2-h block-stepping in heat. Drug intervention did not alter ventilation during exercise. In contrast, propranolol and atenolol produced equivalent reductions in exercise tachycardia, implying a similar level of beta 1-adrenoceptor blockade. The heart rate response to exercise was unaffected by nifedipine and during dual beta-adrenoceptor blockade and calcium antagonism was equivalent to that with beta-adrenoceptor blockade alone. While rectal temperature rises were not modified by drug ingestion, propranolol and, to a lesser degree, atenolol and combination therapy, but not nifedipine alone, attenuated skin temperature rises. Moreover, although atenolol, nifedipine, and their combination did not alter sweating, propranolol and its combination with nifedipine enhanced sweating during the 1st and 2nd h of exercise. This study concludes that nifedipine does not modify thermoregulation during exercise and allows for greater confidence of its use during cardiac rehabilitation. Furthermore, the present data confirm that propranolol does enhance sweating during exercise and demonstrate that this effect is not mediated simply by an earlier onset of rapid sweating nor abolished by concomitant calcium antagonism.

Transdermal delivery of bupranolol: pharmacodynamics and beta-adrenoceptor occupancy.

Bupranolol is a non-selective beta-adrenoceptor antagonist with a Ki-value of 6-15 nmol/l (equivalent to 1.5-4 ng/ml in plasma) at beta 1- (rat salivary gland) and beta 2-adrenoceptors (rat reticulocytes) in receptor binding studies with 3H-CGP 12177 in the presence of human plasma. After oral administration of 200 mg bupranolol to healthy volunteers, the maximal plasma concentration was observed within 1.2 h but it only reached a level close to the Ki-value. Elimination from plasma was rapid (t 1/2 = 2.0 h). Administration of 30 mg bupranolol in a transdermal delivery system (TTS) every 24 h to 6 healthy volunteers for 72 h yielded steady state plasma concentrations 4- to 5-times above the Ki-value as shown by in vitro inhibition of beta-adrenoceptor binding by plasma samples. The pharmacodynamic effect, measured as the reduction in exercise tachycardia, showed a stable inhibitory effect; antagonism of a bolus injection of isoprenaline indicated a 10- to 15-fold right shift of the dose-response curve during the observation period of 72 h. It is concluded that steady-state plasma concentrations and effect of the elsewise rapidly eliminated beta-blocker bupranolol can be achieved by a transdermal delivery system applied each day.

Effects of the beta 2-adrenoceptor antagonist ICI 118,551 on exercise tachycardia and isoprenaline-induced beta-adrenoceptor responses in man.

ICI 118,551, 5 to 80 mg orally, did not significantly alter resting heart rate or blood pressure. In doses less than 40 mg the reduction in exercise tachycardia was under 10 beats/min. ICI 118,551, 10 to 40 mg, did not appear to reduce the maximum rise in systolic pressure with isoprenaline but did attenuate the changes in diastolic pressure, forearm blood flow and finger tremor. It also attenuated the isoprenaline-induced changes in serum glucose, insulin and potassium. On these observed changes, the effect of ICI 118,551 20 mg was similar to that of 40 mg and of propranolol 10 mg, but greater than that of atenolol 25 mg. An isoprenaline tachycardia was attenuated by all doses of ICI 118,551 studied. After atropine (0.04 mg/kg) ICI 118,551 20 mg still significantly reduced the effects of isoprenaline suggesting that functional beta 2-adrenoceptors may be present in the human heart. In doses less than 40 mg, ICI 118,551 appears to be a selective and competitive antagonist of beta 2-adrenoceptors in man.

Assessment of "optimal" beta blockade in treating patients with angina pectoris.

Assessment of optimal beta blockade in treating patients with angina pectoris remains a challenge. Reduction in resting heart rate is a poor guide to therapy; the dose response curves are flat and drugs with intrinsic sympathomimetic activity may not lower resting heart rates despite their efficacy. Log plasma concentrations of beta blockers correlate with reduction in exercise tachycardia but not with improvement in exercise tolerance of reduction in myocardial ischaemia. Although useful, reduction in frequency of anginal attacks and nitroglycerin consumption during therapy is a poor guide in assessing optimal beta blockade. The best way to assess optimal therapy is to demonstrate maximum increase in exercise performance in association with reduction in myocardial ischaemia and adequate suppression of exercise-induced increase in heart rate and blood pressure. This requires repeated exercise testing at multiple work loads after various doses of the drug until there is no further increase in exercise duration or reduction in heart rate. When given in optimal and equipotent doses all beta blockers are equally effective antianginal agents and can be prescribed twice daily.

Penbutolol: beta-adrenoceptor interaction and the time course of plasma concentrations explain its prolonged duration of action in man.

Beta-adrenoceptor binding of (-) penbutolol and its active metabolite 4-hydroxy-penbutolol to rat reticulocyte membranes was shown in the presence of native human plasma. Due to the high plasma protein binding (approximately 99%) the apparent Ki-values of penbutolol were shifted 100-fold to the right after inclusion of plasma in the assay; the Ki was approximately 40-70 ng/ml. That value is comparable to the IC50-values calculated from clinical studies. The interaction of 4-hydroxy-penbutolol with beta-adrenoceptors was not affected to the same extent by inclusion of plasma protein binding approximately 80%, apparent Ki-value approximately 7 ng/ml. Thus, the active metabolite of penbutolol displays higher potency at beta-adrenoceptors in vitro due to its lesser degree of plasma protein binding. A prediction procedure for antagonist activity after penbutolol administration using beta-adrenoceptor interaction and plasma concentration kinetics suggests that, in addition to a rapid elimination process from human plasma, a slow elimination phase of penbutolol (or an active metabolite) is necessary to explain the long duration of action observed in clinical studies after a single oral dose. Inhibition in vitro of beta-adrenoceptor binding by plasma samples obtained after oral administration of 40 mg penbutolol to 3 healthy volunteers indicated a biphasic concentration-time profile of the antagonist in plasma and was in accordance with the time course of the reported reduction in exercise tachycardia. Finally, plasma concentrations of penbutolol equivalents derived from the receptor assay were in the range of penbutolol concentrations detected by physico-chemical methods.(ABSTRACT TRUNCATED AT 250 WORDS)

Beta-blocking and electrophysiological effects of propafenone in volunteers.

The chemical structure of propafenone (P) and certain experimental findings suggest that this antiarrhythmic compound could possess beta-blocking properties. To evaluate the clinical relevance of the latter cardiovascular effects of P during exercise were studied. After oral administration of P 150 and 300 mg in solution, six healthy volunteers were subjected to graded exercise. These doses of P, which are usually effective against arrhythmias, decreased exercise-induced tachycardia, whereas the systolic blood pressure was lowered but only at rest, and the diastolic pressure was slightly raised. However, taking into account dose ratio, and the intensity and duration of the reduction in exercise tachycardia, this effect of P was only about 5% at its maximum compared to propranolol and similar active beta-blocking compounds. The reduction in heart rate produced by P was not correlated with the plasma level nor did it show dose dependency, in contrast to beta-blocking agents, and also in contrast to its electrophysiological effects on the PQ interval.

Propranolol dosage, plasma concentration, and beta blockade.

One hundred sixty-nine normal men received varying propranolol dosage regimens and placebo. Dose level and frequency were compared with plasma propranolol levels and beta blockade, as assessed by reduction of exercise tachycardia. Propranolol levels above 20 ng/ml induced significant beta blockade. An average daily propranolol dose slightly in excess of 160 mg led to a minimum plasma level above 20 ng/ml. Approximately 50% of subjects achieved 20 bpm or greater decrease in exercise tachycardia with 160 mg per day. The degree of beta blockade at the daily minimum propranolol level was related to dose and not dose frequency. The relation of propranolol dose and plasma levels to beta blockade in normal subjects appears to reflect observations in large clinical trials.

The effects of oral acebutolol and propranolol on forearm blood flow in hypertensive patients.

1 Nine hypertensive patients received by mouth daily doses of 400 mg of acebutolol and then, after a 2 week washout period, 80 mg of propranolol for 2 week periods in an open study. 2 Both treatments caused equivalent cardiac blockade as assessed by reduction in exercise tachycardia. 3 Both treatments lowered blood pressure, although this effect on pressure was better maintained in the case of acebutolol. 4 Forearm blood flow, at rest, was significantly reduced at 2 h after dosing with propranolol, but not after acebutolol. 5 This difference between the two drugs is probably due to the cardioselectivity of orally administered acebutolol in man.

ALINIDINE REDUCES HEART-RATE WITHOUT BLOCKADE OF BETA-ADRENOCEPTORS

Alinidine is a new drug which reduces heart-rate in animals by an unknown mechanism. Oral administration of 40 and 80 mg significantly reduced an exercise tachycardia in healthy people, with small reductions in heart-rate in the standing and supine positions. Alinidine 80 mg reduced arterial pressure in the standing and supine positions. The reduction in exercise tachycardia produced by 80 mg alinidine was similar to that after 40 mg propranolol, but alinidine had no effect on an isoprenaline tachycardia. These observations indicate that alinidine reduces heart-rate without blocking beta-adrenoceptors and may be useful in patients with angina and in patients with tachyarrhythmias.

Acebutolol in hypertension‐double‐blind trial against placebo.

1. Eleven hypertensive patients were studied in a double-blind comparison of acebutolol, a beta-adrenoceptor blocker, and placebo. 2. Optimum dosage defined in an open assessment varied from 200--600 mg twice daily. 3. Blood pressure and pulse rate fell significantly while patients were lying, standing and after exercise. 4. Blood pressure remained as well controlled on each patient's optimum daily dose when taken once daily, and assessed 24 h post dose. 5. There was no correlation between blood pressure reduction and changes in heart rate. On once daily therapy while blood pressure remained unchanged at 24 h post dose there was a signficant reduction in beta-adrenoceptor blockade as measured by percentage reduction in exercise tachycardia. 6. There was no significant change in urinary catecholamine excretion or echocardiographically estimated cardiac output. 7. A correlation was found between the change in plasma renin activity (log transformed) and blood pressure reduction.

Acebutolol in hypertension: Relationships between drug concentration and effects

Relationships between plasma concentrations of acebutolol (Ac) and its N-acetyl metabolite (Am) and pharmacological effects were studied in patients with essential hypertension. In an acute study (N=7) 400 mg oral acebutolol produced similar peak plasma levels of Ac and Am but Am had a longer half life. Group mean pulse and blood pressure fell significantly, although the size of individual blood pressure fall varied five-fold. There was no significant change in plasma renin activity. Correlations were found between drug concentration and β-blockade, assessed as % reduction in exercise tachycardia, and between both of these and the fall in post exercise systolic blood pressure. Similar comparisons were made in a chronic optimum dose study (N=11) both pre-dose and three hours post-dose. Am concentration was consistently higher than Ac at both times. Blood pressure was lowered equally pre-and post-dose when compared to placebo and plasma renin activity (PRA) was reduced on active treatment. Correlations were again shown between drug concentrations and β-blockade but none were found with changes in blood pressure or PRA. Between subject differences in blood pressure response could not be fully explained in terms of the other measurements but it is unlikely that pharmacokinetic differences are the major source of this variability.