Assessment of cardiac autonomic tone in conscious rats.

Cardiac autonomic tone can be assessed either by estimating separately vagal and sympathetic tones or by evaluating the net effect of their interaction, the so-called sympathovagal balance (SVB). To compare the most commonly used methods in rats, telemetric recordings of the electrocardiogram were performed in normotensive WKY rats, and in groups of spontaneously hypertensive (SHR) rats that were either untreated or chronically treated with the cholinesterase inhibitor, pyridostigmine, to enhance vagal tone. Cardiac autonomic blockers were administered alone and in combination, so that heart rate (HR) could be measured (1) under resting conditions, (2) with either autonomic branch blocked, and (3) with both branches blocked (which provided intrinsic HR, iHR). SVB was assessed as the ratio of resting HR to iHR. This calculation pointed to a sympathetic predominance in untreated SHRs and even more so in WKY rats, and to a marked vagal predominance in pyridostigmine-treated SHRs. By contrast, the ratio between low and high frequency components (LF/HF) of RR interval spectra did not significantly differ between the groups. Each autonomic tone was quantified as the HR change induced by its selective blocker or as the difference between iHR and HR after blockade of its counterpart. Both pharmacological methods indicated vagal enhancement in treated SHRs, but provided opposite results in terms of vagal vs. sympathetic predominance. These data seriously question the use of the LF/HF ratio as an index of SVB, and the possibility to reliably estimate vagal and sympathetic tones separately through current pharmacological approaches in conscious rats.

Echocardiographic assessment of right ventricular systolic function in conscious healthy dogs following a single dose of pimobendan versus atenolol.

OBJECTIVE: To quantify drug-induced changes in right ventricular (RV) systolic function after administration of pimobendan and atenolol. ANIMALS: 80 healthy privately-owned dogs. METHODS: Using a prospective, blinded, fully-crossed study design with randomized drug administration, RV systolic function was determined twice at two time periods; before and 3 h after administration of pimobendan (0.25 mg/kg PO) or atenolol (1 mg/kg PO). Indices of RV systolic function included tricuspid annular plane systolic excursion (TAPSE), fractional area change (FAC), pulsed-wave tissue Doppler-derived systolic myocardial velocity of the lateral tricuspid annulus (S'), and speckle-tracking-derived global longitudinal RV free wall strain and strain rate. The effect of treatment on percent change from baseline RV function was analyzed with a linear mixed model including the covariates heart rate, body weight, age, gender, drug sequence, and time period. RESULTS: All indices showed a significant (p < 0.0001) increase and decrease from baseline following pimobendan and atenolol, respectively. Significant differences from baseline were attributed to drug treatment (p < 0.0001); whereas, effects of other covariates were not significant. The greatest percent changes, but also highest variability, were observed for S' and strain rate (p < 0.0001). Post-atenolol, a significantly greater proportion of dogs exceeded the repeatability coefficient of variation for FAC and S' compared to TAPSE (p ≤ 0.007). CONCLUSIONS: Echocardiographic indices in healthy dogs tracked expected changes in RV systolic function following pimobendan and atenolol and warrant study in dogs with cardiovascular disease.

Comparison of atenolol versus bisoprolol with noninvasive hemodynamic and pulse wave assessment.

We aimed to compare atenolol versus bisoprolol regarding general hemodynamics, central-peripheral blood pressure (BP), pulse wave parameters, and arterial stiffness. In this open-label, crossover study, we recruited 19 hypertensives, untreated or with stable monotherapy. Patients were randomized to receive atenolol (25-50 mg) or bisoprolol (2.5-5 mg), and then switched medications after 4 weeks. Studies were performed at baseline and after each drug period. In pulse wave analyses, both drugs significantly increased augmentation index (P < .01) and ejection duration (P < .02), and reduced heart rate (P < .001), brachial systolic BP (P ≤ .01), brachial diastolic BP (P ≤ .001), and central diastolic BP (P ≤ .001), but not central systolic BP (P ≥ .06). Impedance cardiographic assessment showed a significantly increased stroke volume (P ≤ .02). There were no significant differences in the effects between drugs. In conclusion, atenolol and bisoprolol show similar hemodynamic characteristics. Failure to decrease central systolic BP results from bradycardia with increased stroke volume and an earlier reflected aortic wave.

Assessment of the pharmacological effects of inotropic drugs on left ventricular pressure and contractility: an evaluation of the QA interval as an indirect indicator of cardiac inotropism.

INTRODUCTION: The ICH S7A and S7B guidelines require that effects of test substances on the cardiovascular system be assessed with respect to blood pressure, heart rate and electrocardiogram intervals. Where adverse effects are identified additional supplemental studies, including ventricular contractility, should be conducted as deemed appropriate. However, there is an absence of definitive guidance regarding when to pursue supplementary studies, in part due to ill-defined criteria of what constitutes an adverse effect and to surgical/technical monitoring limitations of study designs. However with advances in technology it is now feasible to develop models for assessing LVP and contractility in conjunction with standard assessments. The objectives of this study were to 1) develop a model for chronic evaluation of LVP and contractility, 2) illustrate changes in LV contractility without concurrent proportional changes in heart rate and/or systemic blood pressure and 3) determine if the QA interval, the time between the Q on the ECG and the beginning of the upstroke on the arterial blood pressure, can be used as a indicator of altered LV contractility. METHODS: Dogs (N=4) were implanted with a telemetry transmitter. LVP, contractility, ECG and BP were assessed prior to and up to 24 h following administration of Atenolol (10 mg/kg) and Pimobendan (0.45 mg/kg). RESULTS: Atenolol caused an approximately 30% decrease in HR, followed by a sustained decrease in maximum left ventricular contractility (+dP/dt mmHg/s). No effects were noted on blood pressure. Pimobendan caused a 100% increase in contractility (+dP/dt mmHg/s) which remained elevated for approximately 4 h. No effects were noted on blood pressure. Heart rate was highly variable initial decreasing, followed by a highly variable increase until 4 h postdose. Following administration of both compounds changes in maximum left ventricular contractility correlated with reverse changes in QA interval duration. DISCUSSION: This model demonstrates that evaluation of LV contractility complements measurements of heart rate and blood pressure as part of a more complete cardiovascular safety assessment strategy. Furthermore, we demonstrate an apparent correlation between dP/dt and QA interval and concluded that QA interval can be utilized as an indicator of a potential inotropic effect. However further confirmation should be assessed through additional in-vivo measurements of LVP and contractility.

Assessment of long-term antihypertensive treatment by clinic and ambulatory blood pressure: data from the European Lacidipine Study on Atherosclerosis.

OBJECTIVES: Information on the features of long-term modifications of clinic and 24-h ambulatory blood pressure (ABP) by treatment is limited. The present study aimed to address this issue. METHODS: Ambulatory BP monitoring and clinic BP (CBP) measurements were performed at baseline and at yearly intervals over a 4-year follow-up period in 1523 hypertensives (56.1 +/- 7.6 years) randomized to treatment with lacidipine or atenolol in the European Lacidipine Study on Atherosclerosis (ELSA). RESULTS: CBP was always greater than ABP, while reductions in all BP values (greater for CBP than for ABP) were on average maintained throughout 4 years, CBP changes showing limited relationship with ABP changes (r = 0.14-0.27). BP reductions by treatment during daytime and night-time were correlated (r = 0.63-0.73). BP normalization was achieved in a greater percentage of patients for CBP (41.7%) than for ABP (25.3%), with systolic BP control being always less common than diastolic BP control. BP normalization was more frequent at single yearly visits than throughout the 4 years. Twenty-four-hour BP variability was reduced by treatment over 4 years in absolute but not in normalized units. CONCLUSIONS: The present study provides the best evidence available on long-term effect of antihypertensive treatment on both ABP and CBP. On average, ABP was sustainedly reduced by treatment throughout the follow-up period, but 24-h BP was more difficult to control than CBP. In several patients, ABP control was unstable between visits, the percentage of patients under control over 4 years being much less than that of those controlled at each year. Treatment induced a reduction in absolute but not in normalized BP variability estimates. This has clinical implications because of the prognostic importance of ABP mean values and variability.

Chronic effects of AJ-9677 on energy expenditure and energy source utilization in rats.

The effects of AJ-9677 on metabolic parameters were examined in rats that had or had not been chronically treated with this beta3-adrenoceptor agonist. A challenge administration of AJ-9677 increased both the temperature of brown adipose tissue and energy expenditure in both groups of rats. However, whereas the former effect was subject to desensitization, the latter effect was augmented by prior chronic administration of AJ-9677. Whereas a challenge administration of AJ-9677 induced a decrease in the respiratory quotient that persisted for at least 15 h in rats pretreated with vehicle, the initial decrease in this parameter lasted for only 4 h in rats pretreated with AJ-9677. These results suggest that, in rats subjected to chronic treatment with AJ-9677, a challenge administration of this drug increased energy expenditure by stimulation not only of fat oxidation but also of glucose oxidation.

Assessment of autonomic cardiovascular indices in non-stationary data in rats.

The analysis of heart rate in the frequency domain has become increasingly important in physiological studies, and supports the use of heart rate variability as an index of autonomic cardiovascular control. A new index, the instant centre frequency (ICF) has been proposed as a global index of the instantaneous relationship between sympathetic and vagal modulation. The aim of this study was to assess ICF, RR intervals, and heart rate variability measures as indices of sympathovagal balance during a pharmacological blockade of the autonomic nervous system in normotensive rats. RR intervals and arterial blood pressure of 10 conscious Wistar rats equipped with telemetry probes, were evaluated before, during, and after injection of: (1) saline (100 microl kg(-1) i.v.); (2) phentolamine (5 mg kg(-1) i.v.); (3) atropine methyl nitrate (0.5 mg kg(-1) i.v.); and (4) atenolol (1 mg kg(-1) i.v.). RR interval series were analysed by the smoothed pseudo-Wigner-Ville distribution. A general linearised model was used to evaluate the parameters. ICF was calculated in the same way as the peak power frequency by use of the first moment of instant spectrum. We calculated the ICF of the whole spectrum (ICF(T)), ICF in high frequency (ICF(H)) and ICF in low frequency (ICF(L)). The RR intervals and ICF indexes varied similarly and presented the lowest coefficient of variation among animals exposed to the same autonomic conditions. ICF(T)-ICF(L) and ICF(H)-ICF(T) were strongly correlated with normalised HF and normalised LF. In normotensive rats, RR intervals and ICF indices may reliably capture the effects of the sympathetic and parasympathetic nervous system on the sinus node.

The effect of four different antihypertensive medications on cardiovascular regulation in hypertensive sleep apneic patients--assessment by spectral analysis of heart rate and blood pressure variability.

OBJECTIVE: To study the effect of antihypertensive medications on autonomic nervous system in patients with hypertension and sleep apnea syndrome using frequency domain measures of heart rate and blood pressure variabilities. METHODS: The beta-receptor blocking agent atenolol (50 mg), the calcium antagonist isradipine SRO (2.5 mg), the diuretic hydrochlorothiazide (25 mg) and the ACE inhibitor spirapril (6 mg) once daily were given in a double-blind crossover schedule for 8 weeks. Cardiovascular autonomic control was assessed using frequency domain measures of heart rate variability during the spontaneous and controlled breathing tests. During orthostatic maneuver and cold pressor test the blood pressure variability analysis also was performed. RESULTS: In general, the responses of heart rate and blood pressure variabilities were abnormal in the patients with arterial hypertension and sleep apnea syndrome compared to reference data. Of the four drugs, only atenolol effected heart rate and blood pressure variabilities as it shifted the autonomic regulation to the vagal direction. Other antihypertensive drugs did not change any parameter of heart rate or blood pressure variabilities. CONCLUSION: The short-term treatment with atenolol in patients with arterial hypertension and sleep apnea syndrome is associated with normalization of autonomic nervous control judged by heart rate and blood pressure variability. Thus, beta-receptor blockade may have adjunctive beneficial effects beyond blood pressure reduction in these patients. However, the long-term effects of blood pressure reduction on autonomic nervous control remain to be studied.

Beta-adrenergic stimulation of energy expenditure and forearm skeletal muscle metabolism in lean and obese men.

The effect of beta-adrenergic stimulation on whole body energy expenditure and forearm skeletal muscle metabolism was investigated in lean and obese men. Whole body energy expenditure was determined during rest and during intravenous infusion of increasing doses of the nonselective beta-agonist isoprenaline (Iso). Forearm skeletal muscle metabolism was investigated with Iso infusion with and without simultaneous infusion of the beta 1-blocker atenolol (AT) by measuring skeletal muscle blood flow (SMBF) and arteriovenous concentration differences of various metabolites. The changes in SMBF were estimated from forearm total (venous occlusion plethysmography), skin (laser doppler), and fat tissue blood flow (133Xe washout). The increase in whole body energy expenditure with Iso was similar in lean and obese subjects. With Iso, the rise in arterial or arterialized glycerol and nonesterified fatty acids (NEFA) was lower in obese than lean subjects, which may reflect a lower beta-adrenergically mediated lipolysis in obesity. During infusion of increasing doses of Iso, the respiratory exchange ratio decreased significantly in lean subjects but not in the obese subjects, which indicates a more pronounced increase in fat oxidation in lean subjects. This is confirmed by the data on skeletal muscle metabolism, where NEFA uptake was increased in lean subjects, whereas the obese subjects showed a tendency toward an increased glucose uptake and a significantly increased lactate release. With Iso plus AT (mainly beta 2-adrenergic stimulation), both groups showed an increased skeletal muscle lactate release. In conclusion, although the thermogenic response to Iso was similar in lean and obese subjects, the utilization of fat seems to be impaired in obesity.

An assessment of lacidipine and atenolol in mild to moderate hypertension.

1. The aim of this randomised, double-blind four way crossover study was to assess the interaction between the new calcium antagonist, lacidipine and atenolol, in patients with mild to moderate hypertension. 2. Sitting blood pressure at 4 h post-dosing with lacidipine (4 mg) and atenolol (100 mg) alone was significantly lower compared with placebo (137/89 +/- 3/3 mmHg; 142/89 +/- 5/3 mmHg; and 154/98 +/- 5/3 mmHg respectively; P < 0.001). Co-administration of both drugs produced a significant additive effect compared with atenolol and lacidipine alone (124/80 +/- 4/2 mmHg; P < 0.002). 3. Heart rate on treatment with lacidipine alone was significantly greater at 4 h compared with placebo (86 +/- 1 beats min-1 and 74 +/- 2 beats min-1 respectively; P < 0.001). When both drugs were used in combination, there was a significant decrease in pulse rate compared with lacidipine alone (58 +/- 1 beats min-1 and 86 +/- 1 beats min-1 respectively; P < 0.001). 4. Home blood pressure recordings confirmed the statistically significant reduction in blood pressure on co-dosing (120/82 +/- 10/2 mmHg) compared with lacidipine (140/92 +/- 5/3 mmHg) and atenolol (146/90 +/- 6/3 mmHg) given alone (P < 0.05). 5. Lacidipine alone produced a significant exercise tachycardia compared with atenolol alone and the atenolol/lacidipine combination (97 +/- 8 beats min-1; 65 +/- 4 beats min-1 and 75 +/- 7 beats min-1 respectively; P < 0.001). Exercise tolerance was not adversely affected by the co-administration of both lacidipine and atenolol.

Assessment of gain of tachycardia and bradycardia responses of cardiac baroreflex.

The cardiac baroreflex was studied in humans by means of vasoactive drugs and in conscious rabbits by the drug and perivascular cuff methods, which provide somewhat different afferent drive. Mean arterial pressure (MAP)-heart rate (HR) curves were derived using 1) a single symmetric logistic function and 2) a compound function, where the two halves of separate logistic functions were centered on the resting value, one for the tachycardia response and the other for the bradycardia response. There were some differences in overall reflex parameters (plateaus, HR range, gain) between the two methods because of minor degrees of asymmetry. But the differences were small, and the single symmetric logistic adequately describes the overall properties. With the compound function, we assessed average gain, Gt and Gb, for the tachycardia and bradycardia responses and the corresponding normalized (range-independent) gains, Ct and Cb. The resting HR has a large effect on Gt/Gb, since it determines the HR range of each logistic. Moreover, Gt/Gb depends on both resting autonomic tone and reflex changes. However, Ct and Cb provide information about "intrinsic" differences in sensitivity; they are independent of resting HR but entirely dependent on reflex autonomic changes. In rabbits Ct and Cb tended to be larger with the cuff than with the drug method; in addition, with the former Ct less than Cb, whereas with the drug method Ct greater than or equal to Cb, which was consistent with differences in afferent drive. There were also differences between humans and rabbits in Ct/Cb of the vagal component of the reflex. The assessment of the normalized gains of the compound logistic function has substantial advantages over previous methods for assessing gain of the tachycardia and bradycardia responses.

Assessment of beta-1 selectivity of bisoprolol and atenolol by means of their influence on the lipolytic response to an infusion of terbutaline.

We have investigated the beta-1 selectivity of a new beta-blocker, Bisoprolol, by comparing its effect on lipolysis induced by intravenous terbutaline infusion with that of Atenolol. At a dose of 5 mg, Bisoprolol had virtually no beta-2 blocking activity as measured by free fatty acid (FFA) release during terbutaline infusion. At a dose of 10 mg, Bisoprolol had a small but statistically insignificant effect on FFA release similar to 50 mg Atenolol. At a dose of 20 mg, Bisoprolol had significant beta-2 blocking activity. At lower doses, therefore, Bisoprolol is a very selective beta-blocker.

Assessment of a fixed-dosage combination of atenolol and chlorthalidone (Tenoretic) in hypertensive Nigerians.

The antihypertensive effect of a fixed dosage combination of the cardioselective beta-adrenoceptor blocker, atenolol, and the oral thiazide-like diuretic, chlorthalidone (Tenoretic) was studied in 24 hypertensive Nigerians in a double-blind, cross-over comparison with three other treatments. These were atenolol alone, 100 mg daily, chlorthalidone alone, 25 mg daily, and atenolol (100 mg) plus chlorthalidone (25 mg) daily taken as separate formulations. Tenoretic was taken as a once-daily tablet containing 100 mg atenolol plus 25 mg chlorthalidone. The order of administration of the drugs was randomized. Each drug was taken for 4 weeks. The results showed that atenolol and chlorthalidone lowered blood pressure to the same extent. Combination of the two drugs whether taken separately or in fixed-dosage combination was better than either product singly. The drugs were well tolerated.

The assessment of the beta-adrenoceptor blocking activity and cardioselectivity of Koe 3290 in normal subjects.

1. The beta-adrenoceptor antagonist activity, cardioselectivity and antilipolytic properties of Koe 3290 were investigated in healthy subjects. 2. Koe 3290 12.5, 25, 50 and 100 mg, atenolol 25, 50 and 100 mg and placebo were given in double-blind randomised order to eight subjects. All doses of both Koe 3290 and atenolol reduced supine, standing and exercise heart rate (P less than 0.02). From 2 to 8 h after administration the exercise heart rate after Koe 3290 100 mg was similar to that for atenolol 50 mg. 3. The cardioselectivity of Koe 3290 and atenolol was compared. Koe 3290 50, 100 and 150 mg, atenolol 50 and 100 mg and placebo were given to six subjects in a double-blind random order. Isoprenaline dose-response curves were constructed for cardiovascular parameters and finger tremor. 4. For doses which were equipotent at the beta 1-adrenoceptor (Koe 3290 100 mg and atenolol 50 mg) atenolol caused less attenuation of heart rate, diastolic blood pressure, forearm blood flow and finger tremor (P less than 0.02). 5. There was no difference in the isoprenaline-induced changes in serum free fatty acids, blood glucose, plasma lactate or potassium after Koe 3290 and atenolol. Koe 3290 attenuated the rise in serum insulin more than atenolol (P less than 0.02). 6. Koe 3290 is an effective beta-adrenoceptor blocking drug in man. It is not as cardioselective as atenolol and does not possess specific antilipolytic properties.

[Effectiveness of atenolol in moderate arterial hypertension. Evaluation by stress test]. / Eficacia del atenolol en la hipertensión arterial moderada. Valoración mediante prueba de esfuerzo.

A study on the effect of atenolol on exercise blood pressure is presented. Twenty-eight patients with blood pressure over 95 mmHg have been studied by maximal or symptom-limited stress testing. The stress testing was repeated with the same protocol after four weeks of treatment with 100 mg of atenolol daily. Systolic blood pressure after treatment fell by 14% at rest, by 9.5% at submaximal effort and by 11% at maximal effort, while diastolic blood pressure by 15%, 11% and 12% respectively (p less than 0.001). This reduction was parallel to that on heart rate. After treatment, diastolic blood pressure fell to normal ranges in 64% of patients at rest and in 56% of them at maximal effort. Exercise tolerance was slightly better after treatment than before it, mean duration of effort raising from 12.6 to 13.03 minutes. Exercise-induced arrhythmias were frequent (46%) and severe in hypertensive patients, two of them having ventricular tachycardia. This rate was dramatically reduced (up to 7%) with atenolol, as well as its severity.

Assessment of the relative safety of the beta-blockers ICI 141,292 and atenolol in patients with bronchial asthma.

ICI 141,292 is a beta-blocker with beta 1-selective partial agonist activity. To study its cardioselectivity in humans, comparable beta-blocking doses of 200 mg ICI 141,292 and 100 mg atenolol were given to 12 patients with stable bronchial asthma. Both drugs significantly reduced the midexpiratory flow rate at 50% of vital capacity, whereas no significant reduction in FEV1 or peak expiratory flow rate were observed. It is concluded that the cardioselectivity of ICI 141,292 did not differ significantly from that of atenolol. Since they both had a measurable effect on respiratory mechanics, they should probably not be prescribed in bronchial asthma, or only with the greatest possible caution.

Enhancement of physiological finger tremor by intravenous isoprenaline infusions in man: evaluation of its role in the assessment of beta-adrenoceptor antagonists.

Graded intravenous isoprenaline infusions produce dose-related increases in finger tremor. The dose-response curves constructed with intra-arterial or intravenous isoprenaline behave similarly in the presence of both atenolol 50 mg and propranolol 40 mg. In Five subjects, practolol 120 mg, atenolol 50 mg, propranolol 40 mg and sotalol 200 mg reduced exercise heart rate by 20.2 +/- 2.3, 21.4 +/- 1.8, 17.4 +/- 2.5, 23.9 +/- 3.6% respectively: the differences were not significant. The corresponding dose-ratios for reduction of an isoprenaline tachycardia were 2.8, 2.3, 19.1 and 16.9 respectively. At doses which had comparable effects on an exercise tachycardia, the non-selective beta-adrenoceptor antagonists, propranolol 40 mg and sotalol 200 mg, attenuated the finger response to isoprenaline (dose ratios 33.3 and greater than 25.0 respectively) more than the beta 1-selective adrenoceptor antagonists, practolol 120 mg and atenolol 50 mg (dose ratios 1.0 and 2.3 respectively). In two out of five subjects, dose-response curves could not be constructed with sotalol, either at a dose of 200 or 100 mg. The enhancement of physiological finger tremor by intravenous infusions of isoprenaline may be useful in the investigation of beta 2-adrenoceptors and their antagonists in man.

Theoretical and practical problems with the assessment of intrinsic efficacy of agonists: efficacy of reputed beta-1 selective adrenoceptor agonists for beta-2 adrenoceptors.

Agonist effects of the reputedly beta-1 selective adrenoceptor agonists prenalterol, dobutamine and tazolol were compared, in rat uterus, with those of the reportedly beta-2 selective agonist, terbutaline. Butoxamine was a simple competitive antagonist of responses to all agonists with a 10 to 16 times greater potency in rat uterus than in guinea-pig left atria. Similarly, atenolol was 50 to 80 times less potent as an antagonist of all agonists in rat uterus than guinea-pig left atria. The Schild regressions for both antagonists, when subjected to analyses of covariance of regression lines, yielded no evidence to suggest that the reputedly beta-1 selective agonists activated receptors different from those activated by terbutaline in rat uterus. These data indicated that the responses produced by these agonists in rat uterus were due to stimulation of beta-2 adrenoceptors under current classifications. An analysis of the relative intrinsic efficacy of prenalterol on beta-2 as opposed to beta-1 adrenoceptors indicated a nonselective efficacy at the receptor level. The implications of these data in terms of tissue-related efficacy (i.e., intrinsic activity) and receptor-related intrinsic efficacy (as defined by Furchgott) are discussed as a caveat to ascribing tissue selectivity to receptor selectivity without the appropriate data. Specifically, estimates of selective agonist efficacy at receptors should be made on the basis of selective intrinsic efficacy and not on measurements of agonists potency or maximal responses.

Assessment of beta-adrenoceptor antagonists in asthmatic patients.

1 Bronchial smooth muscle, skeletal muscle and cardiac beta-adrenoceptor antagonism have been compared in twelve asthmatic patients after three beta-adrenoceptor antagonists at two dose levels. The non-selective antagonist propranolol (40 and 160 mg), the non-selective antagonist with partial agonist activity pindolol (5 and 20 mg) and the beta 1-selective antagonist atenolol (50 and 200 mg) were studied on separate occasions. 2 Six placebo days were used in this double-blind crossover study to allow interpretation of individual as well as group results. 3 Bronchial smooth muscle effects were assessed by resting spirometry, histamine inhalation test and spirometric response to inhaled fenoterol. Skeletal muscle effects were assessed by resting tremor and fenoterol induced tremor. 4 Cardiac beta-adrenoceptor antagonism was assessed by measuring the effect on resting heart rate and on maximum heart rate in a standard exercise test. 5 Pindolol tended to cause least change from placebo in resting spirometry, caused significant tremor response, inhibited the fenoterol airway response, and tended to protect against inhaled histamine. 6 Atenolol 60 mg was the only drug to allow a fenoterol airway response similar to placebo. Atenolol increased the inhaled histamine responsiveness. 7 Propranolol 160 mg caused the most reduction in spirometry but also tended to cause the maximum reduction in exercise heart rate. Propranolol caused increased inhaled histamine responsiveness. 8 Initial sensitivity to inhaled histamine did not necessarily predict significant reduction in an asthmatics' spirometry by a beta-adrenoceptor antagonist. The effect of a beta-adrenoceptor antagonist on histamine responsiveness does not correspond to its effect on inhaled beta 2-adrenoceptor agonist responsiveness.