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. S. 300 Enzyme Test by Boehringer Mannheim, Germany). Beta endorphins were determined via radioimmunoassay (Nichols Institute, Wijchen, Holland). Plasma cat- echolamines were measured by HPLC (LKB, Bromma, Sweden). The statistical analysis was performed with a repeated measurement ANOVA model with REML estimates (including exercise and treatment effects and their interactions). In case the assumption of normal distribution was rejected, log transformation was performed. All data were given as mean Ϯ s.e.m. (standard error of mean).

Results Figure 3 Lactate, heart rate and relative VO2-uptake during maxi- mal exercise. A significant (P Ͻ 0.01) reduction in resting blood pressure was seen after a median of 42 days of nebi- volol treatment: diastolic blood pressure from a cise before and after nebivolol treatment at rest and mean of 102.5 Ϯ 1.86 to 91.9 Ϯ 1.40 mm Hg and during maximal and submaximal exercise were not systolic blood pressure from a mean of 155.8 Ϯ 3.90 significantly altered by nebivolol treatment. Further- to 132.8 Ϯ 3.82 mm Hg. This therapeutic effect was more, no alteration of received perception of exer- also seen with regard to the exercise-induced tion (RPE) was observed under nebivolol treatment increase in blood pressure during each exercise (Table 1 and Figure 3). level (Figure 2). Heart rate was significantly reduced Treatment with nebivolol did not induce any at rest as well as at each level of exercise (Table 1 changes in maximal or submaximal work capacity and Figure 3). relative to baseline. Maximal work capacity was Ϯ Absolute and relative oxygen uptake (rel. VO2), 218.06 13.97 Watts prior to treatment with a lac- lactate concentrations at the various levels of exer- tate level of 7.70 Ϯ 0.51 mmol/l. During nebivolol

Journal of Human Hypertension Nebivolol in physically active patients HG Predel et al 718 Table 2 Parameters of lipid and carbohydrate metabolism before (BE) and after (AE) maximal exercise (n = 18)

Baseline values Values after treatment

BE AE P BE AE P

FFA (mmol/dl) Mean 0.44 0.56 NS 0.43 0.44 NS s.e.m. 0.04 0.06 0.04 0.04 Free glycerin (mg/dl) Mean 0.87 1.72 Ͻ0.001 0.76 1.37 Ͻ0.001 s.e.m. 0.11 0.12 0.13 0.14 Glucose (mg/ml) Mean 105.11 134.39 Ͻ0.001 108.39 134.11 Ͻ0.001 s.e.m. 3.26 6.14 3.34 6.47 Insulin (␮U/ml) Mean 9.74 16.82 Ͻ0.01 9.24 15.37 Ͻ0.01 s.e.m. 0.91 2.28 1.33 2.01 Leptin (ng/dl) Mean 7.23 6.71 NS 6.99 6.95 NS s.e.m. 1.47 1.26 1.26 1.21 Cortisol (␮g/dl) Mean 12.93 20.51 Ͻ0.001 13.73 17.48 Ͻ0.01 s.e.m. 0.96 1.27 1.78 1.46 Growth hormone (ng/ml) Mean 0.46 5.02 Ͻ0.01 0.83 4.73 Ͻ0.01 s.e.m. 0.17 1.22 0.32 1.80

treatment, maximum work capacity was 212.50 Ϯ Blood lipid profile is depicted in Table 4. Total 12.82 Watts and plasma lactate level was 6.59 Ϯ cholesterol and LDL-cholesterol before and after nebi- 0.65 mmol/l. No significant changes in submaximal volol treatment remained unchanged. In contrast, work capacity at the 4.0 mmol/l plasma lactate level HDL-cholesterol was modestly but significantly were seen with nebivolol as compared to baseline reduced after nebivolol treatment, however the (Table 1). LDL/HDL quotient was unaltered. Nebivolol treat- Free fatty acid, free glycerol, plasma adrenaline ment did not significantly alter the exercise-induced and beta-endorphins increased before and after effects on carbohydrate and lipid metabolism (Table treatment during maximal and submaximal exercise 2). In contrast, plasma ANP levels at rest were sig- and were not significantly altered by nebivolol treat- nificantly higher in the presence of nebivolol, endo- ment (Tables 2 and 3). thelin-1 levels remained unchanged (Table 3).

Table 3 Neurohormonal parameters (n = 18)

Baseline values Values after treatment

BE AE P BE AE P

Adrenaline (pg/ml) Mean 36.72 54.72 NS 33.61 48.89 NS s.e.m. 8.41 8.08 3.89 5.55 Noradrenaline (pg/ml) Mean 259.06 661.06 Ͻ0.001 275.72 796.94 Ͻ0.001 s.e.m. 25.66 65.59 29.23 87.65 Endothelin (pg/ml) n = 17 n = 17 n = 17 n = 17 Mean 4.65 4.73 NS 4.39 4.24 NS s.e.m. 0.33 0.36 0.28 0.26 Aktive renin (␮U/ml) Mean 15.14 30.13 NS 8.17 24.50 Ͻ0.05 s.e.m. 5.30 5.39 1.03 6.45 ANP (pg/ml) n = 17 n = 17 n = 17 n = 17 Mean 88.25* 199.64 Ͻ0.001 148.43* 202.03 NS s.e.m. 12.69 44.19 34.35 42.59 ␤-Endorphin (pg/ml) Mean 27.06 94.90 Ͻ0.001 27.67 101.08 Ͻ0.001 s.e.m. 3.37 9.62 2.48 15.56

*P Ͻ 0.05 ANP at rest before and after treatment.

Journal of Human Hypertension Nebivolol in physically active patients HG Predel et al 719 Table 4 Plasma concentrations of lipid at rest before and after This open pilot study, including a small but hom- = treatment (n 18) ogenous group of patients, was performed to obtain preliminary data on this important issue and to gen- Before After P treatment treatment erate hypotheses for further blinded studies includ- at rest at rest ing larger numbers of patients. Taken these limi- tations into account the results of the present study Total Cholesterol (mg/dl) demonstrate that treatment with nebivolol has a sig- Mean 211.39 210.67 0.9347 NS nificant effect on resting blood pressure and on the s.e.m. 11.44 13.09 exercise-induced increase in blood pressure during LDL Cholesterol (mg/dl) Mean 132.06 130.17 0.7751 NS dynamic maximal muscular exercise. Heart rate was s.e.m. 9.99 10.52 significantly decreased at rest and at all levels of HDL Cholesterol (mg/dl) exercise with nebivolol treatment. Mean 49.28 46.00 0.0074 Such a haemodynamic profile can be regarded as s.e.m. 2.63 2.61 favourable for physically active patients, parti- LDL/HDL Mean 2.75 2.91 0.1519 NS cularly given that premature vascular damage is s.e.m. 0.21 0.24 considered to be attributable to excessive increases Triglycerides (mg/dl) in blood pressure during exercise.28 Mean 138.83 148.56 0.3622 NS Furthermore, maximal and submaximal work s.e.m. 15.68 17.92 capacity and perceived exertion were not compro- mised by the study drug treatment. This is of impor- tance in view of strategies to implement long-term No relevant side effects developed during the exercise programmes as a fundamental element in treatment with nebivolol. antihypertensive management. The constellation of unaltered ET-1 and plasma Discussion adrenaline levels with significantly increased plasma atrial natriuretic peptide (ANP) levels at rest The present recommendations on treatment of under nebivolol treatment is a potentially beneficial essential hypertension are based on non-parmacol- neurohumoral profile in the setting of essential ogical and pharmacological strategies, which are fre- hypertension. The functional significance of the quently applied simultaneously. Among the non- increase in plasma concentrations of ANP, which pharmacological treatment options regular dynamic has vasodilating properties, at rest remains elusive, physical activity at moderate intensities plays an however, and may not be further interpreted on the important role.10,11 basis of the available data. Thus, to ensure an effective and successful long- The observation of a significant increase of beta term exercise-therapy, potential effects of the anti- endorphin plasma levels during exercise with no hypertensive medication on physical performance alteration by nebivolol treatment is an important and on exercise-associated lipid and carbohydrate finding considering the positive effects of beta metabolism must also be considered. endorphins, both in the context of exercise tolerance This pilot study investigated the effects of the and quality of life.29,30 vasodilating beta-1 selective blocker, nebivolol, on The effects of antihypertensive therapy on the physically active patients with mild essential hyper- lipid and carbohydrate metabolism are relevant for tension without secondary complications. Physical long-term prognosis.31 Nebivolol treatment did not activity was defined as a caloric expenditure of alter the metabolic profile at rest or during exercise 2000–2500 kcal per week by exercise. Sports activi- in a clinically relevant way. The modest decrease in ties at this level mediate significant reductions in HDL-cholesterol was compensated by the unaltered cardiovascular events and optimal adjustments of LDL/HDL quotient. Exercise-induced lipolysis plays the cardiovascular risk profile including lipid and a key role in energy metabolism. The fact that the carbohydrate metabolism.3,5,25 With respect to beta- FFA increase during exercise was not affected with blocking agents there is conflicting data on their nebivolol treatment suggests that the drug does not suitability in the treatment of physically active exert inhibitory effects on lipolysis. patients with EH. The beneficial haemodynamic The significant increases in insulin, cortisol and profile with marked antihypertensive effects during growth hormone plasma concentrations after exer- exercise may be counteracted by negative effects on cise were not modified by nebivol treatment and are lipid and carbohydrate metabolism as well as on in accordance with previous findings in healthy, exercise performance.26,27 normotensive subjects undergoing the same exer- Nebivolol is a third-generation beta-blocker. Pre- cise protocol.32 vious studies have shown remarkable vasodilating Further evidence of the neutral effects of nebivo- effects with minimal alterations of the metabolic lol on the various energy metabolism parameters profile.22,23 However, there is little information comes from the observation of unaltered lactate available on its pharmacological effects in physi- dynamics during maximal exercise under treatment. cally active hypertensive patients. These effects on the metabolic profile are of bene-

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