Effects of betaxolol, propranolol, and atenolol on isoproterenol-induced beta-adrenoceptor responses.

Five healthy young men received, in a double-blind fashion, single oral doses of 10 mg betaxolol, 40 mg betaxolol, 50 mg atenolol, 40 mg propranolol, and placebo. After the dose each received serial 12-minute infusions of isoproterenol sulfate through the dose range 0.5 to 32 micrograms/min until the heart rate rose by 40 bpm or the subject could not tolerate the effects of the infusion. Heart rate, finger tremor, blood pressure, and forearm blood flow were measured after each infusion. Dose-response curves were constructed for the changes in these parameters with increasing doses of isoproterenol. The ascending order of potency of the drugs in preventing the changes in heart rate, finger tremor, diastolic blood pressure, forearm blood flow, and forearm vascular resistance induced by isoproterenol was placebo, 10 mg betaxolol, 50 mg atenolol, 40 mg betaxolol, and 40 mg propranolol. The ascending order of potency of the drugs in preventing the change in systolic blood pressure induced by isoproterenol was placebo, 10 mg betaxolol, 50 mg atenolol, 40 mg propranolol, and 40 mg betaxolol. Betaxolol, 10 mg, is equally cardioselective to 50 mg atenolol and at a dose of 40 mg betaxolol also exhibits cardioselectivity.

Effects of thyroid dysfunction on propranolol kinetics.

Propranolol kinetics was studied in six hyperthyroid and six hypothyroid patients who received single oral and intravenous doses of propranolol when they had thyroid dysfunction and again when they had become euthyroid. Change in thyroid status from hyperthyroid to euthyroid produced no change in the elimination half-life (t 1/2) of oral propranolol (3.2 +/- 0.5 to 4.1 +/- 0.7 hr), the oral clearance (38.4 +/- 7.3 to 27.4 +/- 2.4 ml/min/kg), the elimination t 1/2 of intravenous propranolol (2.5 +/- 0.3 to 3.5 +/- 0.7 hr), and the apparent volume of distribution (4.8 +/- 0.4 to 3.8 +/- 0.5 l/kg). The systemic clearance of propranolol, however, was greater when the patients were hyperthyroid (20.8 +/- 2.5 ml/min/kg) than when they had become euthyroid (11.7 +/- 1.7 ml/min/kg). The elimination t 1/2 after oral propranolol was longer in the hypothyroid (3.7 +/- 0.5 hr) than in the euthyroid state (2.0 +/- 0.1 hr). No other changes were observed in the kinetic parameters measured when these hypothyroid patients had become euthyroid. Adequate beta-adrenoceptor blockade in hyperthyroid patients may require higher propranolol dosage than expected.

Intra-articular ultrasonic stimulation and intracutaneous electrical stimulation: evoked potential and visual analogue scale data.

The reproducibility of focussed ultrasound-induced intra-articular pain was compared with that of electrically induced cutaneous pain over a period of time by measuring both the evoked potential (EP) amplitude and visual analogue scale (VAS) score. The responses to ultrasound were more variable than those to electrical stimulation. A greater degree of accommodation occurred during electrical stimulation compared with ultrasound stimulation. A statistically significant correlation between the EP amplitude and the VAS score was found for each form of stimulation. Changes in EP amplitude correlated with changes in the perception of pain as measured by the VAS score, rather than stimulus intensity, which remained constant for each subject throughout the duration of the experiment. A single oral dose of pethidine produced a statistically significant decrease in the EP amplitude and the VAS score in each case.

Clinical pharmacokinetics of beta-adrenoceptor antagonists. An update.

The beta-adrenoceptor antagonists have been widely used clinically for over 20 years and their pharmacokinetics have been more thoroughly investigated than any other group of drugs. Their various lipid solubilities are associated with differences in absorption, distribution and excretion. All are adequately absorbed, and some like atenolol, sotalol and nadolol which are poorly lipid-soluble are excreted unchanged in the urine, accumulating in renal failure but cleared normally in liver disease. The more lipid-soluble drugs are subject to variable metabolism in the liver, which may be influenced by age, phenotype, environment, disease and other drugs, leading to more variable plasma concentrations. Their clearance is reduced in liver disease but is generally unchanged in renal dysfunction. All the beta-adrenoceptor antagonists reduce cardiac output and this may reduce hepatic clearance of highly extracted drugs. In addition, the metabolised drugs compete with other drugs for enzymatic biotransformation and the potential for interaction is great, but because of the high therapeutic index of beta-adrenoceptor antagonists, any unexpected clinical effects are more likely to be due to changes in the kinetics of the other drug. Because satisfactory plasma concentration effect relationships have been difficult to establish for most clinical indications, and little dose-related toxicity is seen, plasma beta-adrenoceptor antagonist concentration measurement is usually unnecessary. The investigation of the clinical pharmacokinetics of the beta-adrenoceptor antagonists has added greatly to our theoretical and practical knowledge of pharmacokinetics and made some contribution to their better clinical use.

Celiprolol. A preliminary review of its pharmacodynamic and pharmacokinetic properties and its therapeutic use in hypertension and angina pectoris.

Celiprolol is a new 'cardioselective' beta-adrenoceptor blocking drug with intrinsic sympathomimetic (partial agonist) activity and a weak vasodilating effect. Celiprolol appears not to cause bronchoconstriction or inhibit the effect of bronchodilating drugs in asthmatic patients and there is some evidence that it may have mild bronchodilating activity in such patients. Some studies suggest that celiprolol, because of vasodilation, may be less likely to reduce blood flow to the peripheries than other beta-adrenoceptor blocking drugs and hence cause fewer peripheral vascular side effects. Significant inhibition of exercise tachycardia occurs 24 hours after a single oral dose of celiprolol. In preliminary therapeutic trials celiprolol 200 to 600mg once daily was similar in efficacy to propranolol 40mg to 80mg twice daily or atenolol 100mg once daily in patients with mild to moderate hypertension or angina pectoris. If the apparent pharmacodynamic advantages of celiprolol are confirmed in well designed therapeutic trials then celiprolol should represent a definite advance in beta-adrenoceptor blocking therapy.

The pharmacodynamics of dilevalol.

Dilevalol, the R-R1 isomer of labetalol, has been shown in animal studies to be a non-selective beta-adrenoceptor antagonist with beta 2-agonist activity and minimal alpha-antagonist activity. This paper describes the results of studies in man which have investigated the dose dependency and selectivity of dilevalol as an adrenoceptor antagonist and demonstrated its lack of alpha-antagonist activity. It also describes the results of studies which have investigated the magnitude of its partial agonist activity and demonstrated the selectivity of the partial agonist activity for the beta 2-adrenoceptor. Oral dilevalol 200 mg reduces an exercise tachycardia by about 25% and 400 mg does not increase the effect. Dilevalol 200 mg had no effect on the rise in blood pressure induced by infusions of phenylephrine, demonstrating its lack of alpha-antagonist activity. The increases in heart rate, systolic blood pressure, forearm blood flow and finger tremor induced by infusions of salbutamol are inhibited by dilevalol 200 and 400 mg and propranolol 80 mg to a similar degree indicating the lack of selectivity of the beta-antagonist activity of dilevalol. The effects of increasing oral doses of dilevalol on sleeping heart rate were used to assess the magnitude of its partial agonist activity. Heart rate four hours after dilevalol 200 and 400 mg was seven beats per minute higher than after placebo. Dilevalol 200 and 400 mg did not alter daytime supine heart rate, blood pressure or cardiac output but did increase forearm blood flow and finger tremor indicating that the partial agonist activity is mainly at the beta 2-adrenoceptor.

Pharmacokinetics of candesartan after single and repeated doses of candesartan cilexetil in young and elderly healthy volunteers.

Candesartan cilexetil is rapidly and completely hydrolysed to the active compound candesartan during absorption from the gastrointestinal tract. Candesartan is a potent, long-acting, selective angiotensin II AT1 receptor blocker. The pharmacokinetics of candesartan were investigated after single and repeated once-daily doses of candesartan cilexetil in the dose range 2-16 mg in both younger (19-40 years) and elderly (65-78 years) healthy volunteers in five studies. Blood pressure, heart rate, and hormones associated with the renin-angiotensin system, and safety of candesartan cilexetil administration were also assessed. Placebo comparisons were made in four studies. Frequent blood samples were collected after the first single dose of candesartan cilexetil, and during the last dosing interval after 1 week repeated once-daily administration. Serum and plasma were analysed for candesartan cilexetil, candesartan and its inactive metabolite, CV-15959, as well as angiotensin I and II, aldosterone, plasma renin activity (PRA) and angiotensin-converting enzyme (ACE) activity. The AUC and Cmax of candesartan showed dose-proportional increases in the dose range of 2-16 mg candesartan cilexetil after both single and repeated once-daily tablet intake, indicating linear pharmacokinetics in both younger and elderly healthy subjects. The pharmacokinetics did not change on repeated dosing and, as expected from the half-life of candesartan of approximately 9 h in younger subjects, there was almost no accumulation after repeated once-daily dosing. The time to peak candesartan concentrations after tablet intake was consistently approximately 4 h at all dose levels. Both Cmax and AUC of candesartan were increased after single and repeated once-daily dosing in the elderly compared to younger subjects by approximately 50%. However, no accumulation after repeated once-daily dosing were seen in the elderly. The half-life of candesartan in the elderly (9-12 h) was somewhat longer than in the younger healthy adult volunteers (approximately 9 h) and no gender-related differences in the disposition of candesartan were observed. Serum concentrations of CV-15959 were much lower than candesartan, and reached peak serum concentrations later, about 4-9 h after dose intake. The elimination of CV-15959 was somewhat slower than that of candesartan. Candesartan cilexetil, the prodrug to candesartan, was not measurable in serum. No differences in ACE activity or serum aldosterone concentrations were observed between subjects receiving candesartan cilexetil and placebo tablets. Plasma angiotensin I and II concentrations and PRA were augmented after single doses and further increased after 1 week repeated candesartan cilexetil dosing. Single and repeated doses of candesartan cilexetil were well tolerated in the younger and elderly volunteers. Only mild adverse events were recorded, with 'headache' as the most commonly reported event, and no increase in the number of reported adverse events was observed with higher doses of candesartan cilexetil. No clinically significant changes in respect to vital signs, physical examination, ECG, and clinical laboratory tests were observed.

Circadian variation of alpha 1-adrenoceptor-mediated pressor response to phenylephrine in man.

The variability in the pressor effects of the alpha 1-adrenoceptor agonist phenylephrine was observed under placebo conditions in ten healthy subjects in a double blind randomized study. Phenylephrine infusions were administered before administration of placebo (baseline) and 2, 4, 8, 12, 24 and 48 h later. The doses of phenylephrine required to increase systolic blood pressure by 20 mmHg after 8 and 12 h (5.30 and 9.30 pm, 81.4 +/- 15.3 and 71.1 +/- 16.0 micrograms min-1, respectively) were significantly (P < 0.01) less than the baseline values (8.30 am, 108.0 +/- 27.6 g min-1). These results might indicate a circadian variation in the phenylephrine-induced alpha-adrenoceptor-mediated vascular response in healthy subjects. These observations lend further insight into circadian variations of vascular tone that might contribute to circadian rhythms in cardiovascular disease.

Computer-assisted measurement of peripheral blood flow.

An automated system for the measurement of peripheral blood flow using venous occlusion plethysmography based on the low-cost Apple II microcomputer, together with purpose-built compressor unit and data acquisition interface, has been developed. The computer performs the dual role of controlling the timing of inflation and deflation of the occluding cuffs and recording the resulting increase in limb circumference. Ten 8 s epochs of data are acquired and analysed per session. Flow rate is computed using a least squares fit between 0.5 and 4.0 s after cuff inflation, giving on-line indication of blood flow. Venous capacitance and digital systolic pressure may be measured using additional algorithms. The system has been used for the investigation of circulatory disorders and in the assessment of drugs acting on the peripheral circulation.

Evaluation of the effect on heart rate variability of some agents acting at the beta-adrenoceptor using nonlinear scatterplot and sequence methods.

There is evidence that the processes regulating heart rate variability (HRV) reflect nonlinear complexity and show "chaotic" determinism. Data analyses using nonlinear methods may therefore reveal patterns not apparent with the standard methods for HRV analysis. We have consequently used two nonlinear methods, the Poincaré plot (scatterplot) and cardiac sequence (quadrant) analysis, in addition to the standard time-domain summary statistics, during a normal volunteer investigation of the effects on HRV of some agents acting at the cardiac beta-adrenoceptor. Under double-blind and randomized conditions (Latin square design), 25 normal volunteers received placebo, salbutamol 8 mg (beta 2-adrenoceptor partial agonist), pindolol 10 mg (beta 2-adrenoceptor partial agonist), or atenolol 50 mg (beta 1-adrenoceptor antagonist). Single oral doses of medication (at weekly intervals) were administered at 22:30 hours, with sleeping heart rates recorded overnight. The long-term (SDNN, SDANN) and short-term (rMSSD) time-domain summary statistics were reduced by salbutamol 8 mg and increased by atenolol 50 mg compared with placebo. The reductions in both SDNN and SDANN were greater after salbutamol 8 mg compared with pindolol 10 mg. The reduced HRV after pindolol 10 mg differed from the increased HRV following atenolol 50 mg. The Poincaré plot, constructed by plotting each RR interval against the preceding RR interval, was measured using a reproducible computerized method. Scatterplot length and area were reduced by salbutamol 8 mg and increased by atenolol 50 mg compared with placebo; scatterplot length and area were lower after pindolol 10 mg compared with atenolol 50 mg. Geometric analysis of the scatterplots allowed width assessment (i.e., dispersion) at fixed RR intervals. At the higher percentiles (i.e., 90% of scatterplot length: low HR), salbutamol 8 mg reduced and atenolol 50 mg increased dispersion; at lower percentiles (i.e., 10%, 25%, and 50% length), atenolol 50 mg and pindolol 10 mg increased dispersion compared with placebo and salbutamol 8 mg. Cardiac sequence analysis (differences between three adjacent beats; delta RR vs. delta RRn + 1) was used to assess the short-term patterns of cardiac acceleration and deceleration. Four patterns were identified: +/+ (a lengthening sequencing), +/- or -/+ (balanced sequences), and finally -/- (a shortening sequence). Cardiac acceleration episodes (i.e., number of times delta RR and delta RRn + 1 were both changed) were increased in quadrants -/- and +/+ following pindolol 10 mg and salbutamol 8 mg; the beat-to-beat difference (delta RRn + 1) was reduced after salbutamol 8 mg compared with the three other groups. These results demonstrated a shift towards sympathetic dominance (beta-adrenoceptor partial agonist salbutamol 8 mg) or parasympathetic dominance (beta 1-adrenoceptor antagonist atenolol 50 mg); pindolol 10 mg exhibited HR-dependent effects, reducing HRV at low but increasing variability at high prevailing heart rates. These nonlinear methods appear to be valuable tools to investigate HRV in health and to study the implications of perturbation of HRV with drug therapy in disease states.

Heart rate variability effects of an agonist or antagonists of the beta-adrenoceptor assessed with scatterplot and sequence analysis.

There is evidence that the processes regulating heart rate variations reflect non-linear complexity and show 'chaotic' determinism. Data analyses using non-linear methods may therefore reveal patterns not apparent with conventional statistical approaches. We have consequently investigated two non-linear methods, the Poincaré plot (scatterplot) and cardiac sequence (quadrant) analysis, and compared these with standard time-domain summary statistics, during a normal volunteer investigation of an agonist and antagonists of the cardiac beta-adrenoceptor. Under double-blind and randomized conditions (Latin square design), 12 normal volunteers received placebo, celiprolol (beta 1- and beta 2-adrenoceptor partial agonist), propranolol (beta 1- and beta 2-adrenoceptor antagonist), atenolol (beta 1-adrenoceptor antagonist) and combinations of these agents. Single oral doses of medication (at weekly intervals) were administered at 22:30 hours with sleeping heart rates recorded overnight. The long (SDNN, SDANN) and short-term (rmsSD) time-domain summary statistics were reduced by celiprolol--effects different from the unchanged or small increases after atenolol and propranolol alone. The Poincaré plot was constructed by plotting each RR interval against the preceding RR interval, but unlike previous descriptions of the method, an automated computer method, with a high level of reproducibility, was employed. Scatterplot length and area were reduced following celiprolol and different from the small increases after propranolol and atenolol. The geometric analysis of the scatterplots allowed width assessment (i.e. dispersion) at fixed RR intervals. Differences between the drugs were confined to the higher percentiles (i.e. 75% and 90% of scatterplot length: low heart rate). The long-term time-domain statistics (SDNN, SDANN) correlated best with scatterplot length and area whereas the short-term heart rate variability (HRV) indices (rmsSD), pNN50) correlated strongly with scatterplot width. Cardiac sequence analysis (differences between three adjacent beats; delta RR vs delta RRn+1) assessed the short-term patterns of cardiac acceleration and deceleration, four patterns are identified: +/+ (a lengthening sequencing), +/- or -/+ (balanced sequences), and finally -/- (a shortening sequence). A running count of events by quadrant, together with the average magnitude of the differences was computed. The beta-adrenoceptor partial agonist celiprolol increased acceleration sequences. The duration of beat-to-beat difference shortened after celiprolol; this contrasted with increased duration of beat-to-beat difference after propranolol and atenolol. These results demonstrated a shift towards sympathetic dominance after the beta-adrenoceptor partial agonist celiprolol contrasting in parasympathetic dominance after the beta-adrenoceptor antagonists propranolol and atenolol. These non-linear methods appear to be valuable tools to investigate HRV in health and in cardiovascular disease and to study the implications of alterations in autonomic control during therapeutic intervention.

Selectivity of xamoterol, prenalterol and salbutamol as assessed by their effects in the presence and absence of ICI 118 551.

Selectivity for beta 1- and beta 2-receptors to xamoterol, prenalterol and salbutamol were tested using ICI 118 551, a specific beta 2-receptor antagonist. Measurements were made of heart rate at rest and exercise, blood pressure, forearm blood flow and finger tremor. The actions of xamoterol were similar to those previously demonstrated, and were unaffected by beta 2-blockade, indicating selectivity for the beta 1-receptor. Salbutamol was selective for the beta 2-receptor and prenalterol was active at both.

Effects of azepexole and clonidine on baroreceptor mediated reflex bradycardia and physiological tremor in man.

The effects of oral administration of azepexole 10 mg, clonidine 300 micrograms and placebo on baroreceptor mediated reflex bradycardia and physiological tremor were investigated in six healthy volunteers. Both azepexole and clonidine reduced (P less than 0.05) systolic (120.5 +/-2.5 to 105.0 +/- 3.3 mm Hg; 115.8 +/- 2.6 to 104.7 +/- 2.8 mm Hg respectively) and diastolic (52.5 +/- 2.6 to 47.2 +/- 1.4 mmHg; 53.7 +/- 1.6 to 49.0 +/- 1.5 mmHg respectively) pressure when compared to placebo and to pre-treatment values. This reduction in pressure was not accompanied by a change in heart rate. Both azepexole and clonidine enhanced (P less than 0.05) baroreflex sensitivity to increases in systolic arterial pressure with phenylephrine. Clonidine facilitated (P less than 0.05) baroreflex sensitivity during the strain phase of the Valsalva manoeuvre, whereas azepexole reduced it (P less than 0.05). Neither clonidine nor azepexole altered finger tremor when compared to placebo or pre-treatment values. Azepexole produced (P less than 0.05) sedation compared to placebo but not when compared to pre-treatment values. Clonidine caused significant increases in sedation when compared to both placebo and to pre-treatment values. The differences between azepexole and clonidine may be due to the greater specificity of azepexole for the alpha 2-adrenoceptor than clonidine.

Comparative effects of adimolol, labetalol and propranolol on heart rate and blood pressure in man.

The cardiovascular effects of adimolol, a new, potent, long acting beta-adrenoceptor blocking drug were investigated in three studies. In the first study blood pressure and heart rate were measured in five male volunteers before and at 2, 4, 6, 8, 24, 32, 48, 72 and 96 h after single oral doses of adimolol. All doses of adimolol reduced supine, standing and exercise heart rates in a dose dependent manner. The maximum effect ranged from 18% following 25 mg to 29% following 600 mg and all doses showed an effect at 96 h (range 3.5-17.2%). In the second study the effects of adimolol, 25 and 400 mg, labetalol, 200 and 800 mg, propranolol 40 mg and placebo were compared on supine and standing heart rate and blood pressure and on exercise heart rate before and at 2, 4, 6 and 8 h after single oral doses. The exercise heart rate was significantly reduced at all times following adimolol 25 and 400 mg, labetalol 800 mg and propranolol 40 mg. At 2 h all the drugs significantly reduced standing systolic blood pressure. In the third study, 4 h after single oral doses of adimolol 400 mg, labetalol 400 mg and propranolol 40 mg six subjects received serial 4 min infusions of phenylephrine. The blood pressure was measured after each infusion. Labetalol 400 mg significantly shifted the blood pressure dose-response curve to the right. There was no difference between propranolol 40 mg and adimolol 400 mg. These studies show that adimolol is a potent, long acting beta-adrenoceptor blocking drug without evidence of alpha-adrenoceptor blockade in man.

The selectivity of xamoterol, prenalterol, and salbutamol as assessed by their effects in the presence and absence of ICI 118,551.

The selectivity of single oral doses of xamoterol, 200 mg, prenalterol, 50 mg, and salbutamol, 8 mg, was compared in eight healthy male volunteers by measuring their effects on sleeping heart rate, supine heart rate, blood pressure, forearm blood flow, finger tremor, and exercise heart rate in the presence and absence of the specific beta 2-adrenoceptor antagonist ICI 118,551, 25 mg. Xamoterol, 200 mg, increased sleeping heart rate and systolic blood pressure, decreased exercise heart rate, and had no effect on diastolic blood pressure, forearm blood flow, or finger tremor. The concurrent administration of ICI 118,551, 25 mg, did not alter these results. Supine heart rate was increased by xamoterol and did not differ from that for xamoterol with ICI 118,551. Prenalterol, 50 mg, increased sleeping heart rate, supine heart rate, systolic blood pressure, forearm blood flow, and finger tremor, decreased diastolic blood pressure, and had no effect on exercise tachycardia. The concurrent administration of ICI 118,551 with prenalterol reduced the increase in sleeping heart rate, supine heart rate, and forearm blood flow, and reduced the fall in diastolic blood pressure caused by prenalterol alone. The increase in finger tremor following prenalterol with ICI 118,551 tended to be less than that following prenalterol. Salbutamol, 8 mg, increased sleeping heart rate, supine heart rate, systolic blood pressure, forearm blood flow, finger tremor, and exercise heart rate, and caused a fall in diastolic blood pressure. When salbutamol, 8 mg, was administered with ICI 118,551, 25 mg, the only changes detected were a small initial increase in finger tremor and a small rise in diastolic blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Characterization of the beta-adrenoreceptors which mediate the isoprenaline-induced changes in finger tremor and cardiovascular function in man.

We have studied the contribution of beta 1- and beta 2-adrenoceptors to the isoprenaline-induced changes in heart rate, blood pressure, forearm blood flow, peripheral vascular resistance, and finger tremor. This was achieved by a comparison of the effects of atenolol 50 mg, ICI 118551 25 mg, propranolol 80 mg, atenolol 50 mg combined with ICI 118551 25 mg, propranolol 80 mg combined with ICI 118551 25 mg, and placebo. Atenolol 50 mg and ICI 118551 25 mg caused similar attenuations in the isoprenaline-induced changes in heart rate and diastolic blood pressure, but the responses after the combination of atenolol and ICI 118551 were similar to those after propranolol 80 mg. There was no difference in the forearm blood flow responses to isoprenaline after atenolol 50 mg and ICI 118551, but atenolol 50 mg did not reduce peripheral vascular resistance compared with placebo. Both responses after treatment with atenolol combined with ICI 118551 were similar to those after propranolol 80 mg. Finger tremor responses to isoprenaline were antagonized by ICI 118551 alone and in combination with propranolol and atenolol but not by atenolol alone, suggesting that the response is beta 2-adrenoceptor-mediated. We conclude that the cardiovascular responses to isoprenaline are mediated by both beta 1- and beta 2-adrenoceptors, whereas the finger tremor response is mediated by beta 2-adrenoceptors.

A placebo controlled comparison of the effects of metoprolol and celiprolol on echo-Doppler measurements of cardiovascular function in normal volunteers.

1. This study used a continuous-wave echo-Doppler method (Exerdrop) to investigate the effects of beta-adrenoceptor antagonism and partial agonism on cardiovascular responses at rest and during dynamic exercise. 2. A double-blind, randomised, placebo controlled comparison of metoprolol (50 mg) and celiprolol (200 mg) was undertaken in nine normal volunteers; single oral doses of medication were administered at weekly intervals. Rest and exercise (supine bicycle) haemodynamics were assessed at 0, 2, 4, 6 and 8 h following dosing. 3. Before dosing and after placebo, the aortic flow velocity, acceleration and velocity integral increased progressively during exercise, as did heart rate, blood pressure and cardiac output. 4. Following metoprolol 50 mg, heart rate was significantly reduced without change in systolic or diastolic blood pressure. Echo-Doppler peak acceleration and velocity decreased at rest. On exercise, heart rate and systolic blood pressure fell significantly; the increase in acceleration was significantly blunted compared with placebo (a decrease of 15.2% at rest and 22.9% at 75 watts; P < 0.01 vs placebo). Peak velocity fell significantly by 75 watts exercise. 5. Celiprolol 200 mg at rest significantly increased systolic blood pressure, peak acceleration and velocity. On exercise celiprolol, in contrast to metoprolol, did not reduce peak acceleration or peak velocity; however exercise heart rate and systolic blood pressure were significantly reduced. The difference between celiprolol and metoprolol in respect of peak acceleration persisted over the 8 h of the study. 6. These differences between metoprolol and celiprolol are compatible with the partial agonism of celiprolol.(ABSTRACT TRUNCATED AT 250 WORDS)