Celiprolol, Atenolol, and Placebo Br J Sports Med: First Published As 10.1136/Bjsm.31.2.120 on 1 June 1997
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120 BrJ Sports Med 1997;31:120-125 Exercise metabolism in healthy volunteers taking celiprolol, atenolol, and placebo Br J Sports Med: first published as 10.1136/bjsm.31.2.120 on 1 June 1997. Downloaded from A Head, S Maxwell, M J Kendall Abstract Prolonged aerobic exercise`-5 and 1 blockade6 7 Objective-Previous studies have shown both have important roles in the prevention that P, selective agents have fewer adverse and management of cardiovascular disease. effects on exercise metabolism than non- However, fatigue is a commonly reported side selective P blockers, and this has been effect of P blockade, and may be due to attributed to their reduced blockade of P2 reduced cardiac output, reduced liver and receptors. This study aimed at determin- muscle glycogenolysis, and reduced lipolysis,89 ing whether a P blocker with partial all of which may reduce the capacity for agonist activity at P1 and P2 receptors exercise to some degree. (celiprolol) was better than a conventional As the therapeutic effects of 3 blockers are P, receptor-blocker (atenolol) in prolong- due to their f, receptor blocking properties, ing exercise capabilities. some reduction in adipose lipolysis (f3 and 12 Methods-After four days of treatment mediated)'0 11 must remain an unavoidable side with celiprolol 200 mg, atenolol 50 mg, or effect of 01 receptor blockade. Celiprolol is a selective 1 receptor placebo, 22 healthy volunteers exercised 13 on a treadmill for blocker'2 with some partial agonist activity at two hours at 50% of both ,13 and P2 receptors.'4 The purpose of this their maximal oxygen uptake. Resting study was to examine exercise metabolism, and heart rate and blood pressure were re- particularly fat oxidation, during submaximal corded before and after exercise. During exercise preceded by four days' oral adminis- exercise, fat oxidation, plasma free fatty tration of a ,1 selective drug (atenolol), a 13 acids, glycerol, glucose, and ammonia selective drug with 12 agonist properties were measured together with heart rate (celiprolol), or placebo. and perceived exertion. Results-Mean exercising heart rate was Method significantly lower in those taking either of SUBJECTS the P blockers than in those taking pla- Twenty four healthy subjects (12 male, 12 http://bjsm.bmj.com/ cebo, and significantly lower for those tak- female, body mass index _ 32) underwent a ing atenolol rather than celiprolol. Fat routine medical examination and a blood test. oxidation was significantly lower for those No abnormalities were found. Two subjects taking celiprolol (38.8 (SD 12.2)%, P<0.01) (one male, one female) were later excluded and atenolol (36.6 (15.9)%, P<0.01) com- from the trial when it was discovered that they pared with placebo (45.6 (14.1)%). For the were taking previously undisclosed drugs. The first 15 minutes of exercise, fat oxidation remaining 22 subjects then carried out a fitness was significantly lower for those taking test (constant speed and increasing gradient on September 28, 2021 by guest. Protected copyright. atenolol (24.6 (12.8)%, P<0.01) than protocol, two minute stages until exhaustion) celiprolol (29.6 (14.3)%). The rise in to measure maximal oxygen uptake (Vo2 max). plasma free fatty acids and glycerol dur- Subjects were non-specifically trained with a was Vo2 max of less than 60 ml/kg/min. On another ing exercise also significantly attenu- day, a habituation walk was on Department of Sport ated by both blockers in comparison completed a Sciences, Brunel P motorised treadmill at a speed and gradient University College, with the rise in those taking placebo producing an exercise intensity of 50% of their Osterley Campus, (P<0.01). Vo2 max. No blood samples were taken during Borough Road, Conclusions-Both celiprolol and atenolol this stage of the trial, but heart rate, perceived Isleworth, Middlesex reduced fat oxidation compared with pla- exertion (category ratio scale during steady TW7 5DU, cebo. For the first 15 minutes of exercise United Kingdom state exercise and Borg scale during incremen- A Head fat oxidation was preserved by celiprolol, tal exercise),'5 16 subjective feeling,'7 and ex- but not atenolol. This preservation of fat pired air were measured every 15 minutes. Clinical Investigation oxidation during the early part of exercise Subjects also completed a mood state Unit, Queen Elizabeth may confer some small benefit to patients questionnaire'8 before and after exercise. The Hospital, Birmingham who take blockers and intend to exercise B15 2TH, P study was approved by the South Birmingham United Kingdom regularly. However, we did not detect Health Authority research ethics committee. S Maxwell significant differences between atenolol All subjects gave written, informed consent to M J Kendall and celiprolol in overall mean fat oxida- participate in the study. tion or perceived exertion in this study. Correspondence to: (BrJ Sports Med 1997;31:120-125) STUDY DESIGN Dr Head. The study was a double blind, randomised Accepted for publication Keywords: atenolol; celiprolol; exercise; 1B blockade; fat crossover design, with all subjects completing 18 December 1996 oxidation all conditions: celiprolol 200 mg daily, atenolol Impact ofceliprolol and atenolol on exercise metabolism 121 50 mg daily, or placebo once daily. Drug treat- sons between treatments adjusted using the a are presented as ment was for four days, with subjects taking Scheff& method. All data Br J Sports Med: first published as 10.1136/bjsm.31.2.120 on 1 June 1997. Downloaded from final dose on the morning ofthe fifth (trial) day. means (SD). Power calculations from a previ- Trial days were at least seven days apart with a ous pilot study indicated that 18 complete sets minimum of two days washout. A double of data were required to achieve a significant placebo technique was used, and compliance difference (a = 0.05, f = 0.1) for fat oxidation. was monitored by pill counting. Where data were missing-for example, be- cause of difficulty with blood sample collec- EXERCISE TRIALS tion, missing cells of data were replaced with Subjects arrived at the clinical investigation column means. The maximum number of unit at 0830 on the fifth day of medication and missing cells (seven out of a possible 330) was having fasted overnight. Diet and activity for plasma ammonia data. patterns were recorded and replicated for each trial period. Upon arrival a final dose of the Results drug was taken and after 30 minutes a "Treatment" refers to data collected during standardised 1 MJ carbohydrate breakfast con- exercise trials performed while taking one of sumed. Subjects then rested for 90 minutes three treatments: celiprolol 200 mg, atenolol before walking for two hours on a motorised 50 mg, or placebo. "Time" (minutes) refers to treadmill at 50% of their Vo, max. the time of collection of sample during each Every 15 minutes during the two hours' trial. exercise, expired air was analysed to determine energy expenditure and fat and carbohydrate utilisation. Heart rate, perceived exertion, and AGE, WEIGHT AND Vo2 MAX OF SUBJECTS of the was 22 (3.96) subjective feeling were measured and recorded The mean age subjects max was 44.4 (4.70) and 100 ml of water given as refreshment. years, and the mean Vo, the as being Blood samples (7 ml) were taken from an in- ml/kg/min, confirming subjects fit but not endurance dwelling venous cannula 15 minutes before moderately specifically exercise, at time 0 and every 30 minutes during trained. exercise and split into vacutainers containing lithium heparin or sodium fluoride potassium ENERGY EXPENDITURE DURING EXERCISE TRIALS oxalate. These samples were then centrifuged The mean energy expenditure during the two at 3000 rpm for eight minutes at 4°C, and hours' exercise trial was 3645 (993) kJ for those plasma was separated and stored at -80GC. taking placebo, 3579 (1077) kJ for atenolol, Further whole blood samples were used for and 3523 (913) kJ for celiprolol. There were no packed cell volume and haemoglobin'9 deter- significant differences between treatments. mination for calculation of plasma volume changes. HEART RATE AND BLOOD PRESSURE On completion of the two hours' walk, Table 1 shows the mean resting heart rates and http://bjsm.bmj.com/ subjects continued for four two-minute stages, systolic and diastolic blood pressures (mmHg). each at a speed and gradient producing 60%, Resting heart rate before exercise was higher 70%, 80%, and 90% Vo, max. During this for those taking celiprolol (68.7 (9.6) beats/ phase, expired air was collected during the last min, P<0.05) and lower for atenolol (54.0 minute, and heart rate, perceived exertion, and (7.9) beats/min, P<0.01) than for placebo blood samples were taken during the last 15 (65.2 (7.7) beats/min). Resting systolic pres- seconds of each stage. sure was also higher for celiprolol (126.1 (7.1) Fat oxidation was measured by indirect mmHg, P<0.01) and lower for atenolol (116.0 on September 28, 2021 by guest. Protected copyright. calorimetry'0 21 (coefficient of variation (C of (9.0) mmHg, P<0.01) than for placebo (121.8 V)) for respiratory exchange ratio (RER) after (9.4) mmHg). 30 minutes' exercise over the five days was Figure 1 shows the heart rate at 15 minute 2.2%, the C of V for mean percentage fat oxi- intervals during exercise with each treatment. dation (derived from RER) over five days was The mean heart rate was significantly lower for 16.9 %). Glucose assay (within run C of V celiprolol 200 mg (114 (7) beats/min, P<0.01) 2.6%, between runs 4%) was carried out by and for atenolol 50 mg (99 (7) beats/min, Sigma procedure No 16 UV," determination of P<0.01) than for placebo (132 (7) beat/min), free fatty acids (within run C of V 2.1%, and significantly lower for atenolol than between runs 5.1%) by the WAKO chemicals celiprolol (P<0.01).