Sleep, 14(1):43-47
© 1991 American Sleep Disorders Association
Beta Blocker Effects on Heart Rate During Sleep: A Placebo-Controlled Polysomnographic Study with Normotensive Males Raymond C. Rosen, John B. Kostis, Lawrence G. Seltzer, Lynn S. Taska, and Barry C. Holzer UM.D.NJ -Robert Wood Johnson Medical School, Departments of Psychiatry and Medicine, Piscataway, New Jersey, US.A.
Summary: Although the effect of beta blockers on heart rate (HR) at rest, during exercise, and by ambulatory electrocardiography during the day and night has been studied extensively, data on the effect of these drugs on heart rate during the various stages of sleep are not available. We performed overnight polysomnography and exercise testing in a randomized, double-blind, placebo-controlled, Latin square crossover study of four beta blockers with different ancillary properties (atenolol 100 mg daily, metoprolol 100 mg, pindolol 10 mg, and propranolol 80 mg), on 30 healthy men aged 23-40 years (29.4 ± 4.3) (mean ± SD). At rest pindolol increased HR by 4.7 beats/min ± 13.1 (p < 0.05), while beta blockers without intrinsic sympathomimetic activity (ISA) decreased HR (p < 0.000 I) by 6.1 ± 8.8 (atenolol), 5.8 ± 8.4 (propranolol), and 5.0 ± 9.4 (metoprolol). Exercise at 125 W increased HR on placebo by 76.4 ± 18.4 beats. Compared to placebo all beta blockers were associated with lower (p < 0.0001) exercise HR by 18.3 ± 23.2 atenolol, 21.1 ± 15.5 metoprolol, 16.8 ± 14.1 pindolol, and 20.8 ± 13.1 propranolol [not significant (NS) among beta blockers). Thus the effect of beta blockers on heart rate was magnified during exercise. Mean and maximum HR were higher in rapid eye movement (REM) than in nonREM (NREM) sleep (p < 0.00 I). However, the effects of beta blockers on NREM and REM sleep were almost identical (atenolol 7.3 ± 5.9 deciineduringNREM and 7.4 ± 5.7 during REM, metoprolol7.7 ± 6.5 NREM and 8.0 ± 6.0 REM, propranolol 6.7 ± 5.7 NREM and 6.8 ± 6.1 REM). A differential effect of pindolo I on NREM/REM sleep analogous to rest! exercise was not observed (increase by 7.5 ± 9.3 in NREM and by 10.1 ± 8.6 in REM) (p = NS). In addition, an increase of HR in the early morning hours was not observed as long as the subjects remained asleep. These data suggest that: I) the tachycardia of REM sleep is mediated primarily through nonadrenergic (e.g., vagal) mechanisms, and 2) the increase in HR during early morning hours is probably due to awakening and the assumption of erect position. These findings may be clinically relevant in view of the circadian variation of ischemic morbid and mortal events. Key Words: Sleep-Heart rate-Beta blockers.
The effect of beta blockers on heart rate (HR) has been studied extensively at rest, during exercise, and by ambulatory electrocardiography during the day and night. The HR" is higher during exercise and in daytime hours as compared to rest and nighttime sleep. These differences have been attributed in part to changes in sympathetic tone (1-3). Beta blockers lower HR, and this effect is more pronounced during exercise (4-6) and in the daytime as compared to rest and nighttime (7,8), when subjects are presumably asleep, However, sleep is a complex and nonuniform behavioral state associated with significant HR variability (9). Studies of cardiovascular function during sleep have generally
indicated increased HR during rapid eye movement (REM) sleep (10) in association with increases in both blood pressure and HR variability (11). There are scant data on the effect of beta blockers on HR during sleep with simultaneous polysomnographic assessment of sleep architecture (12). The purpose of this investigation, an ancillary study to a previously reported investigation of the effect of beta blockers on central nervous system (eNS) function (13), was to examine the effects of four beta blockers with different ancillary properties on HR during sleep studied by polysomnography. METHOD
Accepted for publication October 1990. Address correspondence and reprint requests to Dr. Raymond C. Rosen, U.M.D.N.J.-Robert Wood Johnson Medical School, DepartmentofPsychiatry, 675 Hoes Lane, Piscataway, NJ 08854, U.S.A.
Four beta blockers with different ancillary properties were chosen for this study: atenolol, a hydrophilic beta-1 selective beta blocker; metoprolol, a lipophilic 43
Downloaded from https://academic.oup.com/sleep/article-abstract/14/1/43/2742782 by guest on 01 June 2018
44
R. C. ROSEN ET AL.
beta-l selective beta blocker; propranolol, a lipophilic nonselective beta blocker; and pindolol, a lipophilic nonselective beta blocker that, unlike the other three, possesses a significant degree of intrinsic sympathomimetic (partial agonist) activity. The effects of beta blockers on CNS function were presented in a previous report (13). Study design This was a placebo-controlled, Latin square design (14), double-blind study with five treatment periods of 1 week each separated by 2-week drug-free washout periods. The following medications were administered in counterbalanced order: 100 mg atenolol at 8 a.m. and placebo at 7 p.m., 100 mg metoprolol at 8 a.m. and 100 mg at 7 p.m., 10 mg pindolol at 8 a.m. and 10 mg at 7 p.m., 80 mg propranolol at 8 a.m. and 80 mg at 7 p.m., and placebo both at 8 a.m. and at 7 p.m. Subjects were instructed to take the medications for 7 days from prepackaged blind blister cards. Exercise stress test and polysomnographic evaluations were performed at the end of the seventh day ofadministration of drug (14 tablets ingested), beginning 1 h after the ingestion of the 7-p.m. dose. After each 7-day treatment period, the subjects entered a drug-free washout period for 14 days. Compliance was ascertained by pill count of the blister cards, and time of ingestion of each dose was monitored via daily medication logs kept by all participants. Subjects had strict instructions to contact the study coordinator with any questions or difficulties in taking the medication. According to the:se measures of compliance only 1 of 1,050 tablets was missed, and no tablet was missed on a sleep study day.
Exercise measurements Multistage exercise stress testing on a bicycle was performed as follows: 50 W for 3 min, 75 W for 3 min, 125 W for 3 min, 100 W for 3 min, and ISO W for 3 min. The bicycle was calibrated by means of kilogram weights. HR was measured in subjects at supine and sitting rest, at the end of each exercise level, and immediately on completion of the exercise test. The data obtained during exercise at 125 Ware reported here. The suppression of exercise HR compared with that after placebo was used as a measure of equipotency of the beta blockers (15). Sleep laboratory (polysomnographic) evaluation
After exercise testing, subjects were prepared for overnight sleep laboratory assessment. All sleep studies were conducted in a soundproofed and electrically shielded chamber, and standardized sleep laboratory techniques were used for the recording and scoring of all sleep records (16). Specific measures included the following: Electroencephalogram (EEG). Electrode sites for bilateral recording of the EEG were standard C4-C3, with AI-A2 reference sites. Gold-plated cup electrodes were secured by means of collodion, and signals were displayed on a Beckman-type RM polygraph. Electrooculogram (EOG). Recordings of eye movement were obtained by means of monopolar silver chloride electrodes placed over the outer canthi of the right and left eye and referenced to A2. Eye movements during REM sleep and phasic REM activity were scored according to the Pittsburgh criteria (17). Electromyogram (EMG). Two silver chloride electrodes were attached to the subject's chin for continSubjects uous recording ofthe EMG. Reduction in electromyoThirty healthy men 23-40 years old (29.4 ± 4.3) graphic levels was used as an additional criterion for were enrolled in the study. All subjects were screened the onset of REM sleep. Electrocardiogram (EKG). Recordings were obfor the following exclusion criteria: any acute illness or chronic disease, acute or chronic alcoholism, psy- . tained by placement of three self-adhesive electrodes chiatric disorders, chronic use of any prescribed and on the precordium to obtain "modified lead V5." In unprescribed medications or drugs, sinus bradycardia addition, a cardiotachometer was used to convert EKG (pulse
© 1991 American Sleep Disorders Association
Beta Blocker Effects on Heart Rate During Sleep: A Placebo-Controlled Polysomnographic Study with Normotensive Males Raymond C. Rosen, John B. Kostis, Lawrence G. Seltzer, Lynn S. Taska, and Barry C. Holzer UM.D.NJ -Robert Wood Johnson Medical School, Departments of Psychiatry and Medicine, Piscataway, New Jersey, US.A.
Summary: Although the effect of beta blockers on heart rate (HR) at rest, during exercise, and by ambulatory electrocardiography during the day and night has been studied extensively, data on the effect of these drugs on heart rate during the various stages of sleep are not available. We performed overnight polysomnography and exercise testing in a randomized, double-blind, placebo-controlled, Latin square crossover study of four beta blockers with different ancillary properties (atenolol 100 mg daily, metoprolol 100 mg, pindolol 10 mg, and propranolol 80 mg), on 30 healthy men aged 23-40 years (29.4 ± 4.3) (mean ± SD). At rest pindolol increased HR by 4.7 beats/min ± 13.1 (p < 0.05), while beta blockers without intrinsic sympathomimetic activity (ISA) decreased HR (p < 0.000 I) by 6.1 ± 8.8 (atenolol), 5.8 ± 8.4 (propranolol), and 5.0 ± 9.4 (metoprolol). Exercise at 125 W increased HR on placebo by 76.4 ± 18.4 beats. Compared to placebo all beta blockers were associated with lower (p < 0.0001) exercise HR by 18.3 ± 23.2 atenolol, 21.1 ± 15.5 metoprolol, 16.8 ± 14.1 pindolol, and 20.8 ± 13.1 propranolol [not significant (NS) among beta blockers). Thus the effect of beta blockers on heart rate was magnified during exercise. Mean and maximum HR were higher in rapid eye movement (REM) than in nonREM (NREM) sleep (p < 0.00 I). However, the effects of beta blockers on NREM and REM sleep were almost identical (atenolol 7.3 ± 5.9 deciineduringNREM and 7.4 ± 5.7 during REM, metoprolol7.7 ± 6.5 NREM and 8.0 ± 6.0 REM, propranolol 6.7 ± 5.7 NREM and 6.8 ± 6.1 REM). A differential effect of pindolo I on NREM/REM sleep analogous to rest! exercise was not observed (increase by 7.5 ± 9.3 in NREM and by 10.1 ± 8.6 in REM) (p = NS). In addition, an increase of HR in the early morning hours was not observed as long as the subjects remained asleep. These data suggest that: I) the tachycardia of REM sleep is mediated primarily through nonadrenergic (e.g., vagal) mechanisms, and 2) the increase in HR during early morning hours is probably due to awakening and the assumption of erect position. These findings may be clinically relevant in view of the circadian variation of ischemic morbid and mortal events. Key Words: Sleep-Heart rate-Beta blockers.
The effect of beta blockers on heart rate (HR) has been studied extensively at rest, during exercise, and by ambulatory electrocardiography during the day and night. The HR" is higher during exercise and in daytime hours as compared to rest and nighttime sleep. These differences have been attributed in part to changes in sympathetic tone (1-3). Beta blockers lower HR, and this effect is more pronounced during exercise (4-6) and in the daytime as compared to rest and nighttime (7,8), when subjects are presumably asleep, However, sleep is a complex and nonuniform behavioral state associated with significant HR variability (9). Studies of cardiovascular function during sleep have generally
indicated increased HR during rapid eye movement (REM) sleep (10) in association with increases in both blood pressure and HR variability (11). There are scant data on the effect of beta blockers on HR during sleep with simultaneous polysomnographic assessment of sleep architecture (12). The purpose of this investigation, an ancillary study to a previously reported investigation of the effect of beta blockers on central nervous system (eNS) function (13), was to examine the effects of four beta blockers with different ancillary properties on HR during sleep studied by polysomnography. METHOD
Accepted for publication October 1990. Address correspondence and reprint requests to Dr. Raymond C. Rosen, U.M.D.N.J.-Robert Wood Johnson Medical School, DepartmentofPsychiatry, 675 Hoes Lane, Piscataway, NJ 08854, U.S.A.
Four beta blockers with different ancillary properties were chosen for this study: atenolol, a hydrophilic beta-1 selective beta blocker; metoprolol, a lipophilic 43
Downloaded from https://academic.oup.com/sleep/article-abstract/14/1/43/2742782 by guest on 01 June 2018
44
R. C. ROSEN ET AL.
beta-l selective beta blocker; propranolol, a lipophilic nonselective beta blocker; and pindolol, a lipophilic nonselective beta blocker that, unlike the other three, possesses a significant degree of intrinsic sympathomimetic (partial agonist) activity. The effects of beta blockers on CNS function were presented in a previous report (13). Study design This was a placebo-controlled, Latin square design (14), double-blind study with five treatment periods of 1 week each separated by 2-week drug-free washout periods. The following medications were administered in counterbalanced order: 100 mg atenolol at 8 a.m. and placebo at 7 p.m., 100 mg metoprolol at 8 a.m. and 100 mg at 7 p.m., 10 mg pindolol at 8 a.m. and 10 mg at 7 p.m., 80 mg propranolol at 8 a.m. and 80 mg at 7 p.m., and placebo both at 8 a.m. and at 7 p.m. Subjects were instructed to take the medications for 7 days from prepackaged blind blister cards. Exercise stress test and polysomnographic evaluations were performed at the end of the seventh day ofadministration of drug (14 tablets ingested), beginning 1 h after the ingestion of the 7-p.m. dose. After each 7-day treatment period, the subjects entered a drug-free washout period for 14 days. Compliance was ascertained by pill count of the blister cards, and time of ingestion of each dose was monitored via daily medication logs kept by all participants. Subjects had strict instructions to contact the study coordinator with any questions or difficulties in taking the medication. According to the:se measures of compliance only 1 of 1,050 tablets was missed, and no tablet was missed on a sleep study day.
Exercise measurements Multistage exercise stress testing on a bicycle was performed as follows: 50 W for 3 min, 75 W for 3 min, 125 W for 3 min, 100 W for 3 min, and ISO W for 3 min. The bicycle was calibrated by means of kilogram weights. HR was measured in subjects at supine and sitting rest, at the end of each exercise level, and immediately on completion of the exercise test. The data obtained during exercise at 125 Ware reported here. The suppression of exercise HR compared with that after placebo was used as a measure of equipotency of the beta blockers (15). Sleep laboratory (polysomnographic) evaluation
After exercise testing, subjects were prepared for overnight sleep laboratory assessment. All sleep studies were conducted in a soundproofed and electrically shielded chamber, and standardized sleep laboratory techniques were used for the recording and scoring of all sleep records (16). Specific measures included the following: Electroencephalogram (EEG). Electrode sites for bilateral recording of the EEG were standard C4-C3, with AI-A2 reference sites. Gold-plated cup electrodes were secured by means of collodion, and signals were displayed on a Beckman-type RM polygraph. Electrooculogram (EOG). Recordings of eye movement were obtained by means of monopolar silver chloride electrodes placed over the outer canthi of the right and left eye and referenced to A2. Eye movements during REM sleep and phasic REM activity were scored according to the Pittsburgh criteria (17). Electromyogram (EMG). Two silver chloride electrodes were attached to the subject's chin for continSubjects uous recording ofthe EMG. Reduction in electromyoThirty healthy men 23-40 years old (29.4 ± 4.3) graphic levels was used as an additional criterion for were enrolled in the study. All subjects were screened the onset of REM sleep. Electrocardiogram (EKG). Recordings were obfor the following exclusion criteria: any acute illness or chronic disease, acute or chronic alcoholism, psy- . tained by placement of three self-adhesive electrodes chiatric disorders, chronic use of any prescribed and on the precordium to obtain "modified lead V5." In unprescribed medications or drugs, sinus bradycardia addition, a cardiotachometer was used to convert EKG (pulse
