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Nonselective b -blockers, Autonomic Regulation and Phases of the Heart Cycle

Melezhik Yelena Petrovna; Isaeva Anna Vladimirovna; Yabluchansky Nikolay Ivanovich.

Faculty of Fundamental Medicine, Kharkov State University
Kharkov. Ukraine.

Abstract
Introduction
Objetives
Materials and Methods
Results
Discussion
Conclusions

Abstract:
Introduction: Analysis of heart rate variability (HRV) provides a noninvasive index of autonomic nervous system (ANS) activity and reveals different types of the heart rate autonomic regulation (HRAR) according to sympathetic or parasympathetic prevalence.
Objectives: Our study examined the changes in autonomic balance (AB) and heart cycle phases under non-selective beta-blocker propranolol in subjects having different types of HRAR.
Materials and Methods: 13 healthy volunteers (mean age 24± 4 years) received single doses of propranolol (0,8 mg/kg per os) The short term recording (5 min) of ECG was performed before and 90 min after the medicine intake. HRV was analyzed using frequency domain methods. According to the frequency spectral components obtained in the baseline the volunteers were divided into groups with sympathetic (group A, LF=1,7± 0,16 msec2) and parasympathetic (group B, LF=0,5± 0,4 msec2) prevalence.
Results: The total power of spectrum (TP) increased in both groups on the average in 1,9 times. In group A sympathetic activity decreased and parasympathetic increased, LF/HF ratio reached 0,6. In group B sympathetic influences amplified and parasympathetic weakened, ratio LF/HF enlarged to 0,6. Most of the heart cycle phases were prolonged by propranolol but QRS extended only in group A (from 95,3± 8,2 to 95,7± 0,8 ms) and shortened in group B (from 101,2± 3,8 to 96,8± 0,8 ms).
Discussion: Propranolol intake always resulted in increasing of TP, but the mechanism of it depended on the type of HRAR. The initially depressed branch of ANS activated so that AB became equal in all healthy individuals. Changes in AB were reflected in QRS duration, as it became closer in subjects with different types of HRAR after propranolol than it was in the baseline.
Conclusion: We propose that the protective effect of beta-blockers is referred to increasing of TP and normalizing of AB and QRS durations in subjects with both types of HRAR.

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Introducción: The autonomic nervous system (ANS) plays the leading part in regulating the cardiac activity. The parasympathetic nervous system (PSNS) is responsible for maintaining the basal level of cardiac activity, but the timeliness of adaptation of heart, vessels and organism as a whole in response to variable irritants from surrounding and own organism is believed to be related to the sympathetic nervous system (SNS). The receptors facilitating the sympathetic outflow to the heart are beta-adrenoreceptors, thus resulting in changes in the heart cycle phases. It was shown in [1] that beta-blockers reduce the sympathetic cardiac stimulation and they also have vagotonic activity [2] and cause prolongation of R-R intervals [3,4]. According to the dominance of SNS or PSNS several types of heart rate autonomic regulation (HRAR) may be defined [5,6,7]. For example, according to [8], it is expedient to distinguish two extreme types, with maximum activity of SNS or PSNS and three intermediate types. The noninvasive index of ANS activity is provided by analyzis of heart rate variability (HRV), which makes it possible to study discrepancies in ANS responses in subjects having different types of HRAR [9].

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Objetives: The aim of the study was to examine the effects of non-selective beta-blocker propranolol on the autonomic balance in subjects with different types of HRAR and its connection with changes in the heart cycle phases.

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Materials y Methods: 13 healthy volunteers, 10 women and 3 men (mean age 24± 4 years) received single doses of propranolol 0.8 mg/kg per os. Within a period of no less then 24 hours prior the recording the volunteers did not take alcohol, coffee and any medicine. The recording was carried out at 11 a. m., following 10-min rest in a supine posture. The short - term recording of ECG (5 min) was performed using the "CardioLab 2000" system (discretization rate 500) before propranolol intake and 90 minutes after it in supine posture and free breathing. The following parameters of the phase structure of the cardiac cycle were studied: the ? wave, interval PQ, complex QRS, interval QT (electrical systole) and interval TQ (electrical diastole) duration in msec. HRV was analyzed using frequency domain methods. The parameters of HRV we analyzed (Table 1) were those recommended by The Task Force of The European Society of Cardiology and The North American Society of Pacing and Electrophysiology [10]. Mathematical expectation M and standard deviation s were calculated using Microsoft Excel. The reliability of discrepancies between groups was estimated by using of the Student criterion.

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Based on the frequency spectral components obtained in the baseline the volunteers were divided into groups with sympathetic (group A, LF/HF = 1.7± 0.16) and parasympathetic (group B, LF/HF = 0.5± 0.4) predominance.

 

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Results: It was found that all the investigated subjects divided into the two groups with initial prevalence of SNS or PSNS in the equal proportions. Group A included 6 and group B comprised 7 subjects (Table 2).

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In response to a single propranolol intake the total power of spectrum showed an increase in every single individual of both groups on the average by 1.9 times. At the same time the mechanisms of ?? growth in group A and B were totally different. In all subjects from group A ?? increased due to growing of HF component of the spectrum and the reactions of LF part exhibited individual discrepancies (reduction of LF for 3 subjects and augment for 3 ones). In group B the effect was just the opposite, i.e. the sympathetic activity increased and the parasympathetic activity showed individual changes (excitation of HF for 4 subjects and slight decrease for 3 ones). The cardiac cycle duration in both groups was extended (on the average by 1.32 times in group A and by 1.24 times in group B) chiefly by lengthening the interval TQ (by 1.69 times in group A and by 1.38 times in group B). The extension of the interval QT was less pronounced (by 1.09 times in group A and by 1.05 times in group B). The ? wave and interval PQ duration in both groups increased (by 1.04 and 1.03 times in group A and by 1.15 and 1.13 times in group B respectively). The duration of the complex QRS showed an insignificant increas in group A (by 1.01 times), and decreased in group B (by 1.05 times).

We have examined the propranolol – induced LF and HF changes in each particular case. It was established that the above – mentioned changes tended to show different directions in group A and B thus, resulting in sympatho/vagal balance becoming equal in all subjects (LF/HF reached 0.6 in both groups). The duration of complex QRS in group A and B changed in the similar fashion, i. e. it showed the tendency towards becoming closer after propranolol as compared to the data obtained in those groups in the baseline. It is quite easy to show the relation between the sympatho/vagal balance (LF/HF ratio) and the duration of ventricle depolarization (complex QRS) using a phase portrait method (fig. 1). The substantial spreading in values of the complex QRS duration and LF/HF ratio in the baseline was replaced by close location of these values in the neighborhood of a single point. Propranolol has similar effects on autonomic regulation of the heart cycle and the ventricle depolarization time thereby bringing these indexes up to the same level of values.

Figure 1. Sympatho/vagal balance (LH/HF) and time of ventricle depolarization (complex QRS, msec)
before propranolol intake and 90 min after it on the phase portrait. Every point of the diagram reflects values
of the LH/HF ratio (ordinate) and the duration of QRS complex (absciss) for every subject from both groups
before (*) and 90 minutes after ( · ) propranolol.
Image76.gif (2723 bytes)

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Discussion: Our findings highlight different mechanisms of adaptations that occur in sympatho/vagal balance under nonselective beta – adrenergic blockade in initially sympathotonic and parasympathotonic subjects. As well as in [11] we revealed that in case of the sympathetic activity predominance in the baseline beta – blockers would lead to its reduction. This phenomenon was accompanied by an increase in HRV parameters related to parasympathetic activity, which may be due to the vagotonic activity of propranolol also described in [2]. In the case of initial high parasympathetic activity the effect of beta – adrenergic was just the opposite i.e. SNS activity was increased and PSNS decreased. In [12] was shown that in some cases beta – blockers caused hyperreactive type of response due to a reflex catecholamine release. Thus, the total stimulating effect of catecholamines had exceeded the blocker effects. Our research enables one to relate this type of a response to initial predominance of PSNS activity. According to our data beta – blockers activate initially depressed ANS branch bringing the sympatho/vagal balance to the same level of values irrespective of the HRAR type. It was shown in a series of studies [1,9,13] that beta - blockers may prolong the span of life and have beneficial effects on the prognosis in patients after miocardial infarction and heart failure, therefore we assume that this level of sympatho/vagal balance is optimum for an organism.

We find it important to emphasize once again that according to the data obtained the point of application of sympatho/vagal balance to the phase structure of a heart cycle is only the ventricle depolarization period. According to the hypothesis of the normalizing effect of beta – adrenergic blockade on the sympatho/vagal balance we assume its identical significance in organizing the temporal processes in cardiac activity.

The extension of the cardiac cycle as a whole and electrical systole and diastole particularly testified to the negative chronotropic effect of beta - blockers that was described in numerous studies [14,15]. Besides our findings also showed that the propranolol intake resulted in a greater extend of electrical systole (interval QT) as compared to diastole (interval TQ).

The changes in the duration of above - listed intervals and of complex QRS were more pronounced in subjects with an initial SNS prevalence that corresponds to their greater reactivity described in [13]. However, the time of atrial depolarization and AV – conduction was more variable in subjects with initially high PSNS activity. Such an effect of the beta- adrenergic blockade was found in some other studies [16], where was also demonstrated that propranolol led to prolongation of the effective refractory period during sinus rhythm, but it did not affect it during atrial pacing.

Thus, in subjects having sympathetic and parasympathetic types of HRAR the different features of beta – adrenergic blockade effects on the phase structure of the heart cycle and its autonomic regulation may be observed. We suggest these features be taken into account when using beta–blockers in the cases of various cardiac pathologies.

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Conclusions: Our findings indicate that beta – adrenergic blockade in healthy individuals always results in an increase in the total power of spectrum. The mechanisms for its increase are determined by the initial state of the sympatho/vagal balance. An initially depressed ANS branch activates and the autonomic balance is brought to the same level of values for all healthy individuals. This level may be considered as optimum. The normalizing effect of beta – blockers on organizing the cardiac cycle phases is due to changing the ventricle depolarization period. Propranolol is conductive to prolongation of the heart cycle as a whole, the time of right and left atrial depolarization, AV – conduction and the time of an electrical diastole of the ventricles. The regulation of the heart cycle duration is mainly carried out by changing the prolongation of the diastole. Beta – adrenergic blockade in subjects with parasympathetic type of HRAR result in atrial depolarization time being extended.

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References

1. Eckberg DL. Beta-adrenergic blokade may prolong life in post-infar?tion patients in part by increasing vagal cardiac inhibition. Med Hypotheses 1984 Dec; 15(4):421-32

2. Pitzalis MV, Massari F, Passantino A. The effects ofchronic beta-blockers administration on respiratory sinus arrhythmia. Cardiologia 1997 Feb;42(2): 201-4

3. Craft N, Schwartz JB. Effects of age on intrinsic heart rate, heart rate variability and AV conduction in healthy humans. Am J Physiol 1995; Apr; 268(4 Pt 2): H 1441 – 52

4. Dvortsin GF, Portnoy VF, Machulin AV. Effects of different doses of propranolol on cardiac function and haemodinamics. Cardiology 1980; 20:4: 64-67 (in Russian)

5. Stankus AI, Sokolov EN. Heart rate variability is a state of informational intently. Physiol Chelov 1984; 10:5:852-858 (in Russian)

6. Valdman AV et al. Baroreflex control of the circulation in states of physical and emotional intently. In: Central and peripheral mechanisms of the autonomic nervous system. Erevan, 1980: 32-34 (in Russian)

7. Nesterov VS. Clinical features of heart and vessels diseases. Kiev: Zdorovje: 1974: 285p (inRussian)

8. Zhemaitite DI. Rhythmical pace of the impulses of sinoatrial node on the baseline and in subjects with ischemic heart diseases. Kaunas: 1965: 51 (in Russian)

9. Pousset F, Copie X, Lechat P. Effects of bisoprolol on heart rate variability in heart failure. Am J Cardiology 1996 Mar 15;77(8):612-7

10. Heart rate variability. Standarts of measurement, physiologicalinterpretation, and clinical use. Task Force of The Europian Society of Cardiology and The North American Society of Pacing and Electrophysiology (Membership of the Task Force listed in the Appendix). Europ Heart J, 1996; 17: 354-81

11. Newton GE, Parker JD, Acute effects of beta 1-selective and nonselective beta-adrenergic receptor blockade on cardiac sympathetic activity in congestive heart failure. Circulation 1996 Aug 1:94(3):353-8

12. Alperovich BR, Gorodetsky NV, Shcherbakov SS et al. The features in responses to single beta – blockers intake in accordance to functional state of the organism. Akt Vopr Clin Pharm 1982; 103-106 (in Russian)

13. Lechat P, Escolano S, Golmard JL. Prognostic value of bisoprolol-induced hemodinamic effects in heart failure during the Cardiac Insufficiency Bisoprolol Study (CIBIS). Circulation 1997 Oct7;96(7):2197-205

14. Ariphdzhanov AA, Chashimov CA, Kostko SZ. Effect of propranolol on contractive ability bioenergetic processes in myocardium. Med. J Uzbek 1975; 2: 61-62 (in Russian)

15. Korinteli MO, Metelitsa VI, Ostrovskaya TP. Screening of the single doses of the basic antihypertensive drugs on the baseline and during different tests in subjects with arterial hypertension. Cardiology 1991; 31:7:65-67 (in Russian)

16. Cheema AN, Ahmed MW, Kadish AH, Goldberger JJ. Effects of autonomic stimulation and blockade on signal-averaged P wave duration. J Am Coll Cardiol 1995 Aug;26(2):497-502

 

Questions, contributions and commentaries to the Authors: send an e-mail message (up to 15 lines, without attachments) to pharma-pcvc@pcvc.sminter.com.ar , written either in English, Spanish, or Portuguese.

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Ago/24/2000