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%.     

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.     

The effects of selective beta-adrenoceptor antagonists and partial agonist activity on renal function during exercise in normal subjects and those with moderate renal impairment.

1. The effects of sustained moderate exercise in the sitting position on renal haemodynamics and glomerular filtration were measured in six normotensive patients with moderately impaired renal function and seven age-matched normal volunteers. 2. The changes in the effects of exercise on renal function induced by chronic cardioselective beta-adrenoceptor blockade by drugs with (epanolol) and without intrinsic sympathomimetic activity (atenolol) were examined. 3. Both beta-adrenoceptor blockers attenuated the heart rate increase with exercise, but only atenolol lowered blood pressure significantly. In resting volunteers on atenolol, associated with the fall in blood pressure there was a significant reduction in glomerular filtration rate. 4. Glomerular filtration fell significantly in all groups with exercise, and renal blood flow also fell in parallel. These changes were not influenced by drug treatment. 5. The exercise-induced rise in PRA was suppressed by atenolol but not by epanolol. 6. The renal function and haemodynamic responses to moderate exercise does not appear to be mediated by the systemic renin-angiotensin system or by beta 1-adrenoceptors.     

The effect of the beta-adrenoceptor antagonist pindolol on exercise performance.

1 Fifty-two patients who had been treated for essential hypertension for at least 5 years with once-a-day pindolol alone or in combination with a diuretic participated in a strenuous exercise programme. The 24 h antihypertensive efficacy of once-a-day pindolol was shown in blood pressure readings made before the intake of the day's dose. 2 During the first stage of the study before interruption of therapy, pindolol maintained effective blood pressure control and prevented an excessive rise in blood pressure and heart rate following strenuous exercise. 3 Following a 6 week period of interruption of pindolol therapy, higher blood pressure and heart rate levels were reached following exercise. 4 After reintroduction of a single dose of pindolol, improvement in blood pressure control and lower heart rate levels were again seen following exercise. 5 Compared with the period without drug systolic and diastolic blood pressures were lowered to about the same extent at rest and during exercise after maintenance pindolol and after a single dose of pindolol following a 6 week interruption period, but pre-exercise levels rose considerably during the period when therapy was discontinued.     

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 tryptophan depletion and enhancement on subjective and behavioural aggression in normal male subjects

In order to investigate the link between aggression and 5-HT, we looked at effects of changes in plasma tryptophan on healthy male subjects. Twenty-four with high trait aggression (H) and 24 with low (L) drank an amino acid mixture with (T+) or without (T–) trytophan. These caused plasma tryptophan enhancement and depletion, respectively, at 4.5 h. Group H subjects given T– became more angry, aggressive, annoyed, hostile and quarrelsome on subjective measures, whereas those given T+ responded in the opposite way. On a behavioural measure of aggression, group H subjects responded more aggressively after T– than T+. In contrast, there was no consistent effect on subjective or behavioural aggression in group L subjects. Feelings of well-being in group H were decreased by T– and increased by T+. In group L, T+ reduced feelings of well-being, possibly due to the sedative effect of tryptophan in this group, which correlated positively with plasma trytophan concentration. Changes in plasma tryptophan are probably followed by changes in central 5-HT turnover. We conclude that, in those with pre-existing aggressive traits, acute falls in central 5-HT can cause increased subjective and objective aggression, while rises can have the opposite effect. The absence of changes in a low aggressive group suggests that the primary effect may be on impulsivity, possibly mediated by 5-HT_1a receptors, expressing underlying aggressive traits. The findings on mood changes provide support for earlier reports of a lowering of mood with tryptophan depletion.     

Effects of selective antagonism of beta-adrenoceptor sub-types on responses to isoprenaline in rat distal colon in vitro.

1. The effects of the beta 1- and beta 2-adrenoceptor selective antagonists, CGP 20712A and ICI 118551 respectively, on responses to isoprenaline-induced relaxation of rat distal colon were investigated in order to determine the contributions of these subtypes to relaxation. In addition, the properties of ICI D7114, a novel putative stimulant of atypical beta-adrenoceptors, were investigated. Our preliminary experiments with ICI D7114 showed that this compound lacked agonist activity in rat distal colon and in fact antagonized responses to isoprenaline. We therefore studied the antagonism of isoprenaline by ICI D7114 in more detail. 2. Longitudinal segments of rat distal colon were suspended in Krebs solution at 37 degrees C for isometric recording. The Krebs solution contained EDTA (23 microM) and prazosin (0.1 microM) and was gassed with 95/5% O2/CO2. After an initial equilibration period, reproducible contractions to a submaximal concentration of methacholine (1 microM) were obtained before carrying out a concentration-response curve (CRC) to isoprenaline in a non-cumulative manner. Four consecutive CRCs to isoprenaline were carried out in each tissue with a 1 h interval between each curve. Antagonists were present in increasing concentrations during the intervals between CRCs. Control tissues received no antagonists to allow estimation of the magnitude of time-dependent changes. 3. Isoprenaline produced a concentration-dependent inhibition of methacholine-induced contractions. CRCs to isoprenaline were reproducible with no significant time-dependent changes. Propranolol produced no shift of the isoprenaline CRC at 0.01 microM and a 5 fold shift at 0.1 microM. No further shift was observed with 1 microM.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of ICI 141,292 on exercise tachycardia and isoprenaline-induced beta-adrenoceptor responses in man.

The beta-adrenoceptor blocking properties and cardioselectivity of ICI 141, 292 were investigated in healthy male subjects. Seven subjects received in random order oral doses of ICI 141,292 20, 50, 100, 200 and 400 mg, atenolol 50 and 100 mg and placebo. ICI 14 292 had no effect on supine heart rate which was reduced by atenolol 100 mg. ICI 141,292 50, 100 and 200 mg had no effect on standing heart rate which was reduced by 400 mg at 2 h. Both doses of atenolol caused greater reductions. The maximum percent reduction of an exercise tachycardia after ICI 141,292 200 mg (23.9 +/- 3.7%) and 400 mg (24.3 +/- 5.2%) were similar to atenolol 50 mg (27.3 +/- 4.7%) but less than atenolol 100 mg (30.8 +/- 2.9%) (P less than 0.02). Six subjects received in random order single oral doses of ICI 141,292 100, 200 and 400 mg, atenolol 50 mg, propranolol 40 mg and placebo. Following each dose each subject received graded infusions of isoprenaline sulphate until heart rate increased by 40 beats min-1. Dose-response curves were constructed for the changes in heart rate, finger tremor, blood pressure and forearm blood flow produced by each infusion. At the 4 micrograms min-1 dose of isoprenaline, ICI 141,292 200 mg caused more attenuation than atenolol 50 mg but less than propranolol 40 mg in the changes of heart rate, diastolic blood pressure and finger tremor (P less than 0.02). ICI 141,292 400 mg caused more attenuation of the changes of all parameters than atenolol 50 mg but less attenuation of the changes in diastolic blood pressure and finger tremor than propranolol 40 mg (P less than 0.02). These results indicate that ICI 141,292 is a cardioselective beta-adrenoceptor antagonist with partial agonist activity.     

Naltrexone alters subjective and psychomotor responses to alcohol in heavy drinking subjects.

Preclinical studies support endogenous opioid system involvement in alcohol reinforcement and consumption; however, recent clinical trials and human laboratory studies have provided mixed findings of the effects of naltrexone (a non-selective opioid antagonist) on alcohol responses. This study used a within-subject design (n = 23) to investigate naltrexone effects (0, 50 and 100 mg qd) on subjective and psychomotor responses to alcohol (none, moderate, high) in heavy drinkers. Before alcohol administration, subjects reported decreased desire to drink alcohol when maintained on 50 mg compared with placebo naltrexone. Following alcohol administration, active naltrexone significantly increased subjective ratings of sedative, and unpleasant/sick effects and decreased ratings of liking, best effects and desire to drink. Naltrexone generally did not alter subjective or objective indicators of drunkenness. Finally, high doses of naltrexone and alcohol interacted to produce the greatest decreases in liking and best effects. Findings support the role of endogenous opioids as determinants of alcohol's effects and suggest that naltrexone may be particularly clinically useful in those treatment patients who continue to drink heavily.     

The effect of sulindac on dermal responses to bradykinin in normal subjects given an angiotensin converting enzyme inhibitor.

The ability of sulindac to modify the weal response to four doses of intradermal bradykinin in subjects given enalapril was tested in a double-blind cross-over study in normal volunteers. The dose-dependent increase in skin thickness after bradykinin was significantly reduced by prior administration of sulindac. Certain of the actions and adverse effects of angiotensin converting enzyme inhibitors may be due to the interaction of prostaglandins and bradykinin.     

Cardiovascular and biochemical responses to nebulised salbutamol in normal subjects.

When conventional therapeutic doses of nebulised salbutamol were given to normal volunteers, there was a significant rise in pulse rate, systolic blood pressure and plasma glucose and a significant fall in diastolic blood pressure and serum potassium in comparison with placebo. Such changes may be potentially hazardous in certain situations. Patients with airways obstruction due to chronic bronchitis who have coexistent ischaemic heart disease or diuretic induced hypokalaemia may be at particular risk from the unwanted cardiovascular and biochemical responses to nebulised salbutamol.     

Exercise haemodynamics and maximal exercise capacity during beta-adrenoceptor blockade in normotensive and hypertensive subjects.

1. The effects of atenolol administration on maximal exercise capacity and exercise haemodynamics have been compared in eight normotensive and eight mildly hypertensive subjects, matched for sex, age, body weight, and maximal oxygen uptake, and familiar with maximal exercise testing. 2. Supine and exercise blood pressure, and exercise total peripheral resistance were significantly higher, and exercise cardiac output was significantly lower in the hypertensive than in the normotensive subjects. 3. Administration of atenolol (1 X 100 mg day-1) for 3 days reduced supine and exercise systolic blood pressure, heart rate, and cardiac output, and increased exercise stroke volume. Supine and exercise diastolic blood pressure and exercise total peripheral resistance were unaffected by atenolol. The effects of atenolol did not differ in the normotensive and the hypertensive subjects. 4. Maximal work load, maximal oxygen uptake, and maximal heart rate were reduced to a similar extent in normotensive and hypertensive subjects during atenolol treatment. 5. It is concluded that there is no difference in the effects of short-term atenolol administration on exercise haemodynamics and maximal exercise capacity in normotensive and mildly hypertensive subjects.     

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.     

The effect of age on theophylline clearance in normal subjects.

Dose-interval AUC and clearance of theophylline at steady-state were determined in healthy male subjects in each of three age groups (18-35, 36-54 and 55-70 years old). Mean AUC in the oldest group was significantly higher than in the youngest and clearance in both the middle and oldest groups was significantly lower than in the youngest. Though clearance was significantly correlated with age, age alone accounted for only 31% of the variability in clearance.     

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.     

The effect of acetazolamide on hypercapnic and eucapnic/poikilocapnic hypoxic ventilatory responses in normal subjects

We have studied the effect of acetazolamide 500 mg bd for three days on ventilatory response to C0₂ (HCVR) and hypoxia under both isocapnic and poikilocapnic conditions (isocapnic and poikilocapnic HVR) in five normal subjects. Although acetazolamide reduced calculated arterial pH (7.41 [SEMI 0.01 to 7.37 [SEMI 0.01: p < 0.01) there was no significant change in either isocapnic HVR (with PetC0₂ held at the post-drug resting level) or poikilocapnic HVR in terms of slope and ventilation at Sa0₂=80%. HCVR slope rose slightly (+1.82 [SEM] 0.43 to + 2.2 [SEMI 0.291/min/mmHg: NS) and there was a significant increase in ventilation at PetC0₂ = 50 mmHg (9.42 [SEMI 3.3 to 31.4 [SEM] 6.31/min: p < 0.01). These findings are consistent with the claim that acetazolamide stimulates central chemoreceptors and inhibits peripheral chemoreceptors. Increased sensitivity to C0₂ would reverse the suppressive effect of respiratory alkalosis on hypoxic ventilatory drive following rapid ascent to high altitude, and this probably accounts for the efficacy of acetazolamide in the prophylaxis of acute mountain sickness. However, inhibition of peripheral chemoreceptors may also result in symptomatic benefit by reducing sleep disturbance due to periodic breathing.     

Lack of effect of physical exercise on pharmacokinetics of acetaminophen tablets in healthy subjects

The study was designed to evaluate the effect of physical exercise on the pharmacokinetics of acetaminophen. Ten healthy volunteers were drawn to the investigation. Each person was subjected to the pharmacokinetic study twice, i.e. at rest and on an exercise day. On the exercise day the subjects were performing 3 hours long physical exercise which consisted of a walk on a treadmill at 3 mph for 20 minutes of each half an hour. Acetaminophen was given orally at a single dose of 1.0 g prior to the exercise. Blood for pharmacokinetic assay was sampled within 24 hours following the drug administration. Acetaminophen concentrations were determined by the FPIA method. The total concentrations versus time curve were described by the one-compartment open model for extravascular administration. It was revealed, that the standard submaximal physical exercise does not affect the pharmacokinetics of acetaminophen statistically significantly.     

Desensitization of the beta-adrenoceptor of lymphocytes from normal subjects and asthmatic patients in vitro.

1 A lymphocyte culture method has been developed for studying in vitro the effect of prolonged exposure (24 h) to isoprenaline (10(-8) to 10(-6) mol/l) and prostaglandin E1 (PGE1; 2.8 x 10(-6) mol/l). 2 The cyclic AMP response to isoprenaline is reduced by prolonged exposure to isoprenaline. The degree of desensitization is in proportion to the concentration of isoprenaline in the culture medium. 3 Culture with isoprenaline does not reduce the cyclic AMP response to PGE1. 4 Culture for 24 h with PGE1 (2.8 x 10(-6) mol/l) reduces the cyclic AMP response to PGE1. It also significantly reduces the response to isoprenaline. 5 Lymphocytes from asthmatic patients show a similar degree of desensitization to isoprenaline (after 24 h culture with isoprenaline) to that seen in lymphocytes from normal subjects. 6 A modified assay for phosphodiesterase (PDE) activity was developed. PDE activity increased 24.5% (P less than 0.02) after culture with PGE1 but was not significantly affected by culture with isoprenaline. 7 It is concluded that desensitization caused by prolonged exposure to various stimulators of adenylate cyclase is an event dependent on several components, not all of which are yet defined.     

The influence of sodium and potassium supplements on the diuretic responses to frusemide administration in normal subjects.

1 Twelve normal subjects received (1) normal diet, (2) normal diet with 100 mmol supplementary sodium chloride and (3) normal diet with 96 mmol supplementary potassium chloride, each for 10 days, in a balanced cross-over study according to a Latin Square design. At the end of each study period, the subjects received 80 mg frusemide orally. Each study period was separated from the other by 10 days. 2 Changes in urinary electrolyte excretion occurred within the first four days of each dietary period then remained constant, with significant differences in urinary Na/K ratio between the dietary regimes. 3 Between-subject correlations, using the mean values over the three study periods, demonstrated significant associations between plasma uric acid and urinary Na/K ratio and between plasma prolactin and urinary potassium excretion. 4 Urinary potassium excretion and Na/K ratio following frusemide were influenced significantly by alteration of diet but there was no change in sodium excretion. 5 Between-subject correlations of pretreatment variables with diuretic response, using the mean values over the three study periods, demonstrated significant associations between both pretreatment urinary Na/K ratio and plasma uric acid and respectively the urinary potassium excretion and urinary Na/K ratio in response to frusemide. 6 While the response to frusemide was altered by short-term changes in dietary sodium and potassium, the difference was less than expected from observations in two populations with customary diets differing in similar manner.