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.     

Effect of ICI 118551 on bronchial beta-adrenoceptor function and exercise heart rate in normal man.

To determine whether the beta 2-selectivity of ICI 118551 extended to human airways, we measured bronchial beta-adrenoceptor blockade and the reduction in exercise heart rate in six normal subjects on different occasions after ingestion of ICI 118551 20 or 50 mg, propranolol 40 mg or placebo in random order. Bronchial beta-adrenoceptor blockade after each active drug was measured as the displacement of the airway dose-response curve to salbutamol and expressed as a dose ratio. Exercise heart rate was measured during the fifth minute of steady state exercise at 70% of the subject's maximum work load. The mean dose ratios for the salbutamol airway dose-response curves following ICI 118551 20 and 50 mg and propranolol 40 mg were 11, 55 and 48 respectively. The mean reductions in exercise heart rate for the three drugs were 0.6, 6.6 and 16.6% respectively. These results confirm that the beta 2-selectivity of ICI 118551 includes airway beta 2-adrenoceptors in man.     

An investigation into the cardiac and pulmonary beta-adrenoceptor blocking activity of ICI 66,082 in man.

1 Oral ICI 66,082 (200 mg) or water (control treatment) were each administered to six healthy volunteers. 2 The heart rate (HR) and peak flow rate (PFR) were measured at rest and during vigorous exercise before and at intervals up to 24 h after each treatment. 3 ICI 66,082 produced significant reductions in exercise HR at all times compared with the changes after the control treatment (P less than 0.001), whereas with resting HR, corresponding significant reductions only occurred at 2,3 and 4 h (P less than 0.05). 4 Although there was no change in resting PFR, significant reductions in exercise PFR, compared with the changes after the control treatment, occurred at all times excepting at 2 h after ICI 66,082 (P less than 0.025). 5 The findings are consistent with ICI 66,082 possessing partial cardioselectivity. 6 Plasma levels and renal excretion of the drug were determined. Urinary recovery was variable which, together with the plasma concentration/effect relationships obtained, raise the possibility that ICI 66,082 is metabolized in man.     

Effects of lidocaine on myocardial function and on isoprenaline-induced circulatory changes in man.

14 non-cardiac patients aged 42 to 71 years (mean 49 years) were studied. Part I 1 mg/kg or 2 mg/kg of lidocaine were administered i.v. on two consecutive days and systolic time intervals (STI) were obtained at one minute intervals for 30 minutes. No change in STI was observed after lidocaine injection. In Part II, a bolus of 5 mug of isoprenaline was given i.v. before and after an injection of 2 mg/kg of lidocaine. Isoprenaline caused a highly significant increase in the heart rate, shortening of the total electromechanical systole, pre-ejection period, electromechanical delay, isovolumic contraction time as well as PEP/LVET and ICT/QS1, indices (in all cases p less than 0.001). 2 mg/kg lidocaine had no blocking or potentiating action on the catecholamine-induced circulatory changes. In Part III, after the isoprenaline challenge, a dose of 2 mg/kg of lidocaine was administered and the bolus injection was followed by an infusion of 30 mug/kg/min. Lidocaine per se caused no change in STI in the course of the infusion over 90 minutes, and there was no difference between isoprenaline-induced changes in STI before and during lidocaine infusion. These results suggest that lidocaine has no negative inotropic effect in the therapeutic dose range in man. Lidocaine caused no change in the systolic time intervals, it had no blocking or potentiating action on the isoprenaline-induced circulatory changes, and it had no negative inotropic effect in therapeutic doses in man.     

The effects of beta-adrenoceptor blockade on breathing during progressive exercise in normal man.

1 We have studied the effects of single oral doses of 80 mg propranolol and 100 mg atenolol on breathing during progressive exercise in nine healthy men in a double-blind, placebo-controlled experiment. As judged by their effects on exercise heart rate significant levels of beta-adrenoceptor blockade were achieved. 2 At the two lower levels of work rate (50 watts and 100 watts) minute ventilation on atenolol was lower than on placebo while at the highest level of work (200 watts) minute ventilation was higher on atenolol than on placebo. The regression of VE atenolol on VE placebo was 1.28 which is significantly different from unity (P less than 0.001). The results with propranolol were more scattered and failed to reach the 5% level of significance. 3 Effects on the pattern of breathing are small but when minute ventilation is matched with placebo, atenolol results in larger tidal volumes and prolonged inspiratory and expiratory time. 4 These observations are discussed in relation to other work in the literature.     

The effect of beta-adrenoceptor blockade on factors affecting exercise tolerance in normal man.

1 We have studied the effects of single oral doses of 80 mg propranolol and 100 mg metoprolol on the cardiovascular and respiratory responses to progressive exercise in nine healthy men in double-blind, placebo-controlled experiment. As judged by their effects on exercise heart rate and cardiac output the doses of the two drugs used were equivalent. 2 Beta-adrenoceptor blockade reduced oxygen consumption by 3.5% over the whole work range with an increase in the respiratory exchange ratio of 0.056 units. Carbon dioxide production and exercise ventilation were unchanged. The two drugs had similar effects. Possible mechanisms for these observations are discussed. 3 Perceived exertion during exercise was increased by both the beta-adrenoceptor blocking drugs and this may be of relevance to the symptom of fatigue reported by patients on these drugs. Endurance, assessed as either total work done or maximal work achieved, was reduced by 15%.     

Effects of verapamil and elgodipine on isoprenaline-induced metabolic responses in rabbits

Verapamil (0.17 microg kg(-1) min(-1) intravenous, i.v.) but not elgodipine (35 ng kg(-1) min(-1)) modestly enhanced the weak blood glucose increase induced by the i.v. infusion of isoprenaline (0.3 microg kg(-1) min(-1)) in conscious rabbits. However, elgodipine but not verapamil suppressed the increase in circulating insulin evoked by the agonist. Both drugs enhanced the rise in plasma lactate mediated by isoprenaline but only elgodipine potentiated the lipolytic effect of the agonist. In isolated islets elgodipine (10(-6) M) blocked forskolin (10(-6) M)-induced insulin release. However, in rabbit adipocytes elgodipine potentiated both glycerol release and cAMP accumulation induced by isoprenaline (10(-8)-10(-6) M). Excess K(+) (40-60 mM) did not alter basal lipolysis or the response to isoprenaline in either rabbit or mouse adipocytes. Therefore, Ca2+ influx through L-type Ca2+ channels does not seem to play a significant role in the lipolytic effect of isoprenaline. Metabolic alterations found with Ca2+ channel antagonists were of minor intensity and probably devoid of pathological implications.     

Metabolic responses to a new beta-adrenoceptor agonist, ICI 118,587, in conscious rats

The effect of a new beta-adrenoceptor agonist, ICI 118,587, on the blood levels of cyclic AMP, glucose, lactate, and FFA was studied in conscious rats. ICI 118,587 (200 micrograms/100 g s.c.) increased the cyclic AMP level in the normal and reserpine-pretreated rat, and increased the FFA level in the reserpine-pretreated rat. Adrenaline (10 micrograms/100 g s.c.) increased the levels of cyclic AMP, glucose, and lactate in the normal rat, and increased the FFA level in the reserpine-pretreated rat. The increases in these metabolites induced by this particular dose of adrenaline were inhibited by ICI 118,587. In the normal or reserpine-pretreated rat, ICI 118,587 acts as a beta-agonist on metabolism, and is capable of antagonizing the metabolic effects of adrenaline.     

The effects of ICI 118,587 and atenolol on the responses to exercise and on breathlessness in healthy subjects.

The effects of ICI 118,587 and atenolol on the responses to submaximal exercise and on breathlessness were studied in six healthy subjects. Atenolol reduced heart rate at rest and during exercise whereas ICI 118,587 increased resting heart rate but caused a small reduction in the highest heart rate achieved during exercise. Neither ICI 118,587 nor atenolol significantly changed minute ventilation or oxygen uptake either at rest or during exercise. There were no effects on bronchomotor tone. The assessment of breathlessness was validated for the subjects participating in the study. Atenolol increased the intensity of breathlessness in relation either to ventilation or to oxygen uptake. This effect was not secondary to a change in bronchomotor tone but was possibly related to changes in pulmonary haemodynamics. On the other hand, the relationships of breathlessness to ventilation or to oxygen uptake were unchanged by ICI 118,587. The effects of ICI 118,587 on exercise tolerance and dyspnoea in patients with impaired cardiac function should now be determined.     

Influence of environmental temperature and humidity on bronchial responses during assessment of selectivity of beta-adrenoceptor antagonists in man.

1 The effects of beta-adrenoceptor antagonists given intravenously in single doses were examined in a double-blind, placebo controlled study performed in six healthy volunteers. Heart rate and peak expiratory flow rate (PEFR) were measured at rest and during standardised exercise. 2 Atenolol 0.2 mg/kg, betaxolol 0.15 mg/kg, practolol 1 mg/kg and propranolol 0.2 mg/kg all reduced heart rate to a similar extent during exercise at 2 and 4 h after administration; betaxolol 0.6 mg/kg had a significantly greater effect than the other treatments at all times. Only betaxolol 0.15 and 0.6 mg/kg significantly inhibited exercise tachycardia at 24 h. 3 None of the treatments studied had any effect on PEFR at rest or during exercise. 4 A second study was performed to determine whether this lack of effect of propranolol on exercise PEFR could have been due to the warm and humid conditions prevailing during the experiment. Eight healthy men underwent a standardised exercise test under alternately 'warm and humid' and 'cool and dry' conditions before and after propranolol 0.2 mg/kg or saline placebo intravenously. 5 Propranolol treatment did not influence resting or exercise PEFR in either environment, but did reduce FEV1 immediately after exercise under the cool and dry conditions but not under the warm and humid conditions. 6 Comparison of the effects of beta-adrenoceptor antagonists on exercise heart rate and PEFR is not a reliable or sensitive method of measuring the cardioselectivity of these drugs. 7 Environmental temperature and humidity should ideally be controlled when the action of any drug on airflow resistance is being studied.     

The absorption and elimination of ICI 74,917 in man.

1 The pharmacokinetics of ICI 74,917 were studied in both asthmatic patients and normal volunteers. 2 The tritiated compound was administered to the lungs by inhalation from an aerosol and a bronchoscope, and by intravenous, oral and buccal routes. Radioactivity was measured in plasma, urine, faeces, sputum and exhaled air. 3 After bronchoscopic administration 63% of the available dose was absorbed; after aerosol administration 8% was absorbed from the lung and more than 50% swallowed. 5 Intravenous studies indicated that the drug is excreted in the bile and urine in the ratio 2:1. 5 Minimal oral and no buccal absorption occurred. 6 There was no evidence of tritium exchange or drug metabolism. 7 The mean terminal half-life following administration by all route was 16.1 hours. However, the majority of the dose was rapidly excreted. 8 Aerosol administration is the method of choice for the clinical use of ICI 74,917.     

Observations on the mechanism underlying the differences in exercise and isoprenaline tachycardia after cardioselective and non-selective beta-adrenoceptor antagonists

1 Differences in ability to attenuate isoprenaline tachycardia between the cardioselective beta-adrenoceptor antagonist atenolol and the non-selective drug propranolol, when administered in equivalent anti-exercise tachycardia oral doses, were measured in four normal volunteers. 2 Propranolol at all dose comparisons showed a greater potency in antagonism of isoprenaline tachycardia than atenolol; this ranged from 6 at the lowest doses (40 and 50 mg respectively) to 13 at the highest doses (320 and 400 mg respectively). 3 After doses of each drug which produced equal inhibition of exercise tachycardia, isoprenaline induced a greater increase in heart rate and greater decrease in diastolic blood pressure after pre-treatment with atenolol than after propranolol. 4 The contribution of this isoprenaline induced vasodilatation to the reduced tachycardia response, 1 h after 25 mg oral atenolol, was measured in the same four subjects by correction of the hypotension with an intravenous angiotensin infusion. Reversal by angiotensin of the 17 mm Hg average fall in diastolic blood pressure during the sustained isoprenaline infusion did not reduce the tachycardia. 5 The hypotension that results from isoprenaline stimulation of unblocked vasodilator beta 2-adrenoceptors in normal subjects pre-treated with atenolol appears to make a negligible contribution to the tachycardia response and does not explain the different abilities of cardioselective and non-selective beta-adrenoceptor blocking drugs to antagonise isoprenaline tachycardia. Our results are compatible with the presence of beta 2-adrenoceptors in human atria.     

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

Summary ICI 141,292 is a -blocker with ₁-selective partial agonist activity. To study its cardioselectivity in humans, comparable -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.     

Effects of beta-adrenoceptor blockade on exercise performance and respiratory response in healthy, physically untrained humans.

The effects of propranolol 80 mg orally were compared with those of placebo on the response to a stepwise increasing exercise test in 17 healthy and physically untrained volunteers, of whom eight were female. Propranolol showed no significant effects on maximum work rate or perceived exertion rate. However, submaximal O2 uptake, CO2 output and minute ventilation tended to be lower after propranolol than after placebo. It is concluded that in subjects with a low work capacity, beta-adrenoceptor blockade does not impair maximal exercise capacity. The mechanisms underlying changes in respiratory response to exercise after propranolol are not fully explained. However, changes in substrate utilisation, the reduction in cardiac output and an alteration in respiratory drive may all be involved.     

Quantitative assessment of bronchial beta-adrenoceptor blockade in man.

1. We describe a method for assessing bronchial beta-adrenoceptor blockade quantitatively in man. Specific airway conductance is measured after increasing doses of inhaled salbutamol and the extent to which the dose-response curve is displaced to the right after beta-adrenoceptor blocking drugs is used to assess bronchial beta-adrenoceptor blockade. 2. Salbutamol dose-response curves were plotted for six normal subjects by measuring sGaw 15 min after increasing doses of inhaled salbutamol. Salbutamol produced a 30-70% increase in sGaw. 3. Salbutamol dose response curves were obtained 2 h after oral practolol (100 mg and 200 mg) and oral propranolol (40 mg and 80 mg) on separate days and were displaced to the right. 4. The mean dose ratios for practolol 100 mg and 200 mg were 1.2 and 2.1 and for propranolol 40 mg and 80 mg they were 21 and 61 respectively.     

Effects of in vivo beta-adrenoceptor down-regulation on cardiac responses to prenalterol and pirbuterol

The effects of beta-adrenoceptor down-regulation on rat left atrial responses to the full agonist isoproterenol and the partial agonists prenalterol and pirbuterol were studied. Atria from rats implanted with a mini-osmotic-pump subcutaneously delivering isoproterenol at 400 micrograms X kg-1 X h-1 for 4 days were 12-16 times less sensitive to isoproterenol than normal atria. Scatchard analyses indicated that the implantation of these mini-osmotic-pumps produced a 50% decrease in the number of beta-adrenoceptors in the ventricles with no alteration in the binding constant of [3H]dihydroalprenolol. Receptor down-regulation produced a parallel shift to the right of concentration-response curves to isoproterenol, and a complete suppression of responses to both partial agonists. The affinities of the partial agonists for the receptors were not altered; in desensitized atria the partial agonists were functional beta-antagonists blocking the responses to isoproterenol. The data are modeled by equations from classical receptor theory which predict the depression of responses to partial agonists with receptor down-regulation. These results are discussed with respect to the utility of prenalterol and pirbuterol in congestive heart failure since possible tachyphylaxis to these drugs with chronic usage could limit their value.