Journal of Human Hypertension (2001) 15, 715–721 2001 Nature Publishing Group All rights reserved 0950-9240/01 $15.00 www.nature.com/jhh ORIGINAL ARTICLE Integrated effects of the vasodilating beta- blocker nebivolol on exercise performance, energy metabolism, cardiovascular and neurohormonal parameters in physically active patients with arterial hypertension HG Predel1, W Mainka1, W Schillings1, H Knigge1, J Montiel1, Jv. Fallois2, R Agrawal2, T Schramm1, C Graf1, BM Giannetti3, B Bjarnason-Wehrens1, U Prinz1 and RE Rost1 1Institute of Cardiology and Sports Medicine, German Sports University, Cologne, Germany; 2Berlin- Chemie AG, Glienicker Weg 125, D-12489 Berlin, Germany; 3CRM GmbH, Weiherstraβe 19, D-53359 Rheinbach, Germany Objective: The present study was designed to investi- rate at rest and during maximal and submaximal exer- gate the integrated effects of the beta-1-selective cise. Maximal physical work performance, blood lactate blocker with vasodilator properties, nebivolol, on sys- and rel. oxygen uptake (rel. VO2) before and after nebiv- temic haemodynamics, neurohormones and energy olol treatment at rest and during maximal and submaxi- metabolism as well as oxygen uptake and exercise per- mal exercise remained unaltered. Free fatty acid, free formance in physically active patients with moderate glycerol, plasma catecholamines, beta-endorphines and essential hypertension (EH). atrial natriuretic peptide (ANP) increased before and Design and methods: Eighteen physically active after treatment during maximal and submaximal exer- patients with moderate EH were included: age: 46.9 ؎ cise but remained unaltered by nebivolol treatment. In years, weight: 83.9 ؎ 2.81 kg, blood pressure (BP): contrast, plasma ANP levels at rest were significantly 2.38 mm Hg, heart rate: 73.6 ؎ higher in the presence of nebivolol, endothelin-1 levels 1.86 ؎ 3.90/102.5 ؎ 155.8 2.98 min−1. After a 14-day wash-out period a bicycle were unchanged. spiroergometry until exhaustion (WHO) was performed Conclusions: Nebivolol was effective in the control of followed by a 45-min submaximal exercise test on the BP at rest and during exercise in patients with EH. Fur- 2.5 mmol/l lactate-level 48 h later. Before, during and thermore, nebivolol did not negatively affect lipid and directly after exercise testing blood samples were taken. carbohydrate metabolism and substrate flow. The expla- An identical protocol was repeated after a 6-week treat- nation for the effects on ANP at rest remain elusive. This ment period with 5 mg nebivolol/day. pharmacodynamic profile of nebivolol is potentially suit- Results: Nebivolol treatment resulted in a significant (P able in physically active patients with EH. Ͻ 0.01) decrease in systolic and diastolic BP and heart Journal of Human Hypertension (2001) 15, 715–721 Keywords: physical performance; nebivolol; energy metabolism Introduction metabolic and humoral effects mediated by suitable forms of physical activity carried out at appropriate Various prospective studies have shown that intensity, duration and frequency.1–4 On this basis, improvements in cardiovascular morbidity and mor- exercise therapy should play an important role in tality can be achieved by the cardiopulmonary, the management of cardiovascular disease.5,6 Parti- cularly in the treatment of essential hypertension, physical exercise has become established as an Correspondence: Prof HG Predel, MD, German Sports University, effective therapeutic approach.7–10 Positive effects of Cologne, Institute of Cardiology and Sports Medicine, Carl- Diem- controlled exercise programmes in hypertensive Weg 6, 50933 Ko¨ln, Germany. E-mail: PredelȰhrz.dshsFkoeln.de Received 6 December 2000; revised 10 May 2001; accepted 30 subjects have been reported to include a reduction May 2001 in systolic and diastolic blood pressure,11–13 Nebivolol in physically active patients HG Predel et al 716 improvements of blood lipid profile and insulin sen- swimming). The type, duration and intensity of sitivity of the working skeletal muscle,14–17 resto- exercise was monitored by questionnaires combined ration of endothelial function,18 a shift of the auto- with computed evaluation (own programmes, nomic balance towards parasympathetic tone19 and unpublished). Patients were eligible if they exhib- an improvement in quality of life.20 ited diastolic blood pressure values between 95 and However, if non-pharmacological measures alone 110 mm Hg on two different occasions during the 2- fail to lower blood pressure to a normal level accord- week run-in phase and if they were able to tolerate ing to WHO/ISH guidelines,21 additional antihyper- a workload of at least 75 Watts over a period of tensive drug treatment is necessary. Antihyperten- 3 min during the bicycle exercise test performed at sive drug treatment should not only reduce major the end of the run-in period. All subjects gave their cardiovascular end points (myocardial infarction, informed consent in accordance with the Declar- sudden death, stroke) but also effectively control ation of Helsinki. Ethics committee approval was blood pressure at rest and during exercise without obtained. negative impact on physical performance and qual- In order to exclude the presence of manifest car- ity of life. diac, hepatic or renal disease, all patients had a Nebivolol is a lipophilic beta-receptor blocker of physical examination performed, laboratory tests the so called third-generation with distinct ␤-1 carried out and an ECG recorded. selective and vasodilating properties.22,23 A number At each visit, seated blood pressure was taken. of experimental and human pharmacological studies After a 14-day wash-out period, a maximal bicycle suggest that the vasodilatation is triggered via the exercise test (Siemens Erlangen, Germany, Type 380 endothelial nitrogen oxide system. The pharmaco- bicycle ergometer) with concomitant spiroergometry logical profile is characterised by the significant (Oxycon Alpha Spiroergometry System by Ja¨ger antihypertensive effects as well as a lowering of car- Wu¨ rzburg, Germany) was performed in the sitting diac pre- and after-load.24 position. The spiroergometry was performed accord- Up to now, however, there is still a lack of infor- ing to the WHO protocol (start: 25 Watts, 25 Watt mation about possible interactions of nebivolol with increments at 2-min intervals), with tests carried out concomitant physical activity in patients with in the morning in an air-conditioned laboratory with essential hypertension (EH). In this context, the uniform ambient air temperature and humidity effects of nebivolol on parameters of physical per- (Figure 1). The following parameters were determ- formance in connection with systemic haemody- ined: maximum work capacity, exercise-induced namics, energy metabolism, lactate levels, oxygen increase in blood pressure, perceived exertion (Borg uptake and subjective feeling of physical stress are scale), lactate, maximum oxygen uptake, carbohydrate of fundamental interest. and lipid metabolism as well as humoral factors. In this open, pilot study, therefore, effects of nebi- In order to guarantee uniform caloric and fluid volol on the above-mentioned parameters have intake across all patients, patients were put on a been evaluated. standardised diet 24 h before study start. Moreover, patients were requested to abstain from alcohol, tea Patients, investigational design and or coffee. Forty-eight hours later, patients underwent a 45- methods min submaximal test at 5-min intervals. Workload Eighteen physically active patients with mild pri- was adjusted individually at an intensity corre- mary hypertension (age: 46.9 Ϯ 2.38 years, weight: sponding to a lactate level of 2.5 mmol/l as determ- 83.9 Ϯ 2.81 kg, blood pressure: 155.8 Ϯ 3.90/102.5 ined before during maximal exercise test. Ϯ 1.86 mm Hg, heart rate: 73.6 Ϯ 2.98 min−1 mean Lactate and glucose concentrations were determ- duration of hypertension: 85.2 months) were ined in arterialised blood from the hyperaemic ear included in the study. The antihypertensive medi- lobe. Prior to and after the exercise tests, venous cation was as follows: untreated (n = 13); angioten- blood was obtained from the cubital vein for the sin-converting enzyme (ACE)-inhibitor (n = 3), beta- determination of the metabolic and neurohormonal blocker (n = 1), AT-1 antagonist (n = 1). Regular parameters. physical activity was defined as an exercise-related Subsequently, patients were treated with 5 mg additional caloric requirement between 2000 and nebivolol for a period of 42 days (one tablet a day 2500 kilocalories (kcal) per week due to mostly at 8.00 am) and the exercise tests were repeated dynamic exercise (eg, jogging, cycling or according to the same protocol at the end of the Figure 1 Study flow chart. Journal of Human Hypertension Nebivolol in physically active patients HG Predel et al 717 Table 1 Workload, heart rate, BP, lactate, oxygen uptake, RPE at peak exercise level (n = 18) Before After P treatment treatment Workload (Watt) Mean 218.06 212.50 0.4486 NS s.e.m. 13.97 12.82 Heart rate (min−1) Mean 168.11 146.72 0.0001 s.e.m. 4.16 4.60 Blood pressure (mm Hg) Mean 231.94 203.61 0.0001 s.e.m. 4.26 4.12 Lactate (mmol/l) Mean 7.70 6.59 0.1095 NS s.e.m. 0.51 0.65 Workload at 4 mmol/l n = 14 n = 14 lactate (Watt) Mean 159.79 168.57 0.1156 NS s.e.m. 12.04 13.05 Figure 2 Systolic blood pressure profile during maximal exer- Rel. oxygen uptake cise test. (ml/min/kg) Mean 34.75 34.14 0.6440 NS s.e.m. 2.03 1.91 study. On ergometry days, dosing of nebivolol was RPE postponed to after the exercise test in order to cap- Mean 18.22 17.94 0.5306 NS ture the trough effect. s.e.m. 1.48 1.76 Triglyceride, free fatty acid, glycerine, high- and low-density lipoprotein (HDL/LDL) cholesterol plasma levels were analysed by standard tech- niques; insulin, cortisol and human growth hor- mone (hGH) plasma levels were determined by use of enzyme immunoassay (System E.