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Individual Features of Induced by
Oral Pirenzepine Vagomimetic
Effect in Healthy Subjects

Melezhik Yelena Petrovna, Isaeva Anna Sergeevna,
Yabluchansky Nikolay Ivanvich

Faculty of Fundamental Medicine, Karazin Kharkov National University, Kharkov, Ukraine

SUMMARY
Introduction: Analysis of heart rate variability as an uninvasive marker of the neuro - humoral regulatory systems state allowed to reveal a paradoxical vagomimetic effect of pirenzepine in healthy subjects and in chronic heart failure patients.
Objectives: Evaluation of individual features of pirezepine vagomimetic effect in healthy subjects hav-ing different initial states of sympatho - vagal balance.
Materials and Methods: 17 healthy volunteers (13 female and 4 male) 23±5 years of age were included in the study. HRV parameters were studied on the basis of two series of ECG recording in su-pine and upright positions before and 60 min after single pirenzepine intake (25 mg per os). According to LF/HF index values obtained in the supine position prior the recording two groups of subjects with 1) initial sympathetic (LF/HF>1) and 2) initial parasympathetic (LF/HF<1) prevalence were formed.
Results: When comparing the values obtained in supine and upright positions before and after pirenzepine intake, it was evaluated that the medication induced rMSSD, pNN50, HF, HFnorm augmentation and mRR prolongation in both groups. Statistically significant LF/HF index lowering was recorded only in group 1. In supine position QT interval prolon-gation was recorded in both groups. In upright posture QT interval remained prolonged in group 1 only.
Discussion: The paradoxical vagomimetic effect was obtained in both groups but only in group with ini-tial sympathetic prevalence it was accompanied by significant shift in autonomic balance. Induced by low doses of pirenzepine parasympathetic activation resulted in QT interval prolongation.
Conclusion: As a substance appearing to be tropic to autonomic nervous system, pirenzepine may be used in patients with reduction of the total power of regulation and sympathetic distress. Oral pirenzepine in doses widely used may prolong QT interval.

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BACKGROUND
   Recent studies have evaluated that along with its main cholinolitic action some cholinoblockers in low doses show paradoxical vagomimetic effect. The above effect was obtained for scopolamine in healthy subjects [1] and in various groups of patients [2, 3, 4, 5, 6, 7] and for selective M1 - choli-noblocker pirenzepine. The vagotonic effect of pirenzepine seemed to be bound up with peripheral mechanism, which lied in blockade of the presynaptic muscarinic modulation of acetylcholine re-lease [8, 9]. Pirenzepine also appeared to decrease heart rate without affecting contractility in healthy subjects [10].

   Most of former investigations were focused on evaluation of basic patterns of pirenzepine vagomi-metic action. At the same time individual reactions of subjects having different initial state of auto-nomic balance and specific targets of vagotonic action of the drug were not studied enough. One of the best noninvasive methods of obtaining the state of neuro - humoral regulative systems is analy-sis of heart rate variability (HRV). With the help of HRV methods different reactions to various medications intake in particular propranolol were obtained in two groups of healthy subjects with initial sympathetic or parasympathetic system prevalence as it was determined by LF/HF index be-ing above or below the level of 1 [11].

OBJECTIVES
   The aim of the study was to evaluate individual features of pirezepine vagomimetic effect in healthy subjects having different initial states of sympatho - vagal balance in order to create conditions for its more rational use.

MATERIALS AND METHODS
Subjects
   17 volunteers (12 female and 5 male) 23±5 years of age were included in the study. All the subjects were healthy as determined by their medical history and a brief examination; none received any medications.

The Experimental Protocol
   Subjects were instructed to abstain from smoking or coffee and alcohol consumption for 24 h before the study. All recordings were made in a certain time in the morning in quiet surroundings.

   The neuro -humoral regulation state was evaluated on the basis of HRV parameters, and electrical phase structure of the heart cycle.

   HRV parameters were studied on the basis of two series of 5 - min ECG recording in supine and upright positions with free breathing before and 60 min after single pirenzepine intake (25 mg per os). The recordings were made using software "CardioLab 2000" (discretization rate 500). The time and frequency domain parameters of HRV we analyzed were those recommended by The Task Force of The European Society of Cardiology and The North American Society of Pacing and Electrophysiology [12 ]: HR (beats per min), mRR (ms), sdRR (ms), rMSSD (ms), pNN50 (%), HRVTi, Total Power, (ms2), VLF (ms2), LF (ms2), HF (ms2), LF/HF. The two normalized parameters LFnorm and HFnorm were not analysed because they provide essentially the same information as the ratio LF/HF [13].

    The analysis of the electrical phase structure of the heart cycle was based on evaluation of the fol-lowing variables: P wave (ms), interval PQ (ms), interval QT (ms), interval TP (ms).

Stratification of the subjects under study
   According to the frequency spectral components obtained in the baseline the volunteers were di-vided into 2 groups: Group 1 (LF/HF>1), Group 2 (LF/HF<1). The subjects with LF/HF = 1 were randomly included into one of the groups. Group 1 consisted of 13 subjects and group 2 included 4 individuals. Physiological background of such a division laid in M. Pagani's (1986) [14] conclusion that instantaneous balance between sympathetic and vagus nerve activities could be captured by means of LF/HF ratio. The groups described should not be identified with sympathotonia and vago-tonia, because all LF/HF values in both groups were within the normal range.

Statistical Analyses
   The data obtained were analyzed using parametric and non - parametric methods. Mean (M) and standard deviation (SD) were calculated using Microsoft Excel. Inter - group differences were cal-culated by application of the Mann - Withney criterion, the significance of parameter changes in group 1 and 2 was evaluated by Wilkoxon T test and Fisher method correspondently. For statisti-cally significant variations 95% confidence interval values were provided.

RESULTS AND DISCUSSION
   In response to pirenzepine intake augmentation both of time domain parameter of HRV mirroring the total power of variability (sdRR, HRV Ti) and the ones connected with vagus nerve activity (rMSSD, pNN50) was recorded [Table 1]. The above growing being quite difference in degree was traced in both groups in the two studied positions of the subject.

   1. In supine posture the medication induced significant augmentation of sdRR, HRV Ti, rMSSD, pNN50 and prolongation of the heart cycle duration both in groups A and B.
   2. In upright posture after pirenzepine intake all above parameter of HRV (sdRR, HRV Ti, rMSSD, pNN50) in both group significantly exceeded the ones recorded in upright posture be-fore the drug intake. At the same time significant mRR prolongation was recorded in group 1 only.

    The patterns of pirenzepine vagotonic effect obtained via analysis of time domain parameters changes were also confirmed by frequency domain HRV characteristic alterations [Fig. 1]:
1. In supine posture after pirenzepine intake the total power of spectrum of RR - interval variabil-ity was significally augmented in all its frequency ranges. The most pronounced changes were obtained in the high frequency range.
2. In upright posture the above pattern remained i.e. Total Power rose at the expense of all fre-quency domains with maximal augmentation in the HF frequency range.

Fig. 1 Induced by pirenzepine changes of the total power of RR - intervals variability and contribu-tions to total power of VLF, LF, HF frequency domains in group 1 (first graph) and group 2 (second graph) in supine and upright positions of the subjects under study

    Evaluation of induced by the medication LF/HF index changes allowed to reveal significant dis-crepancies in mostly similar changes of different branches of neuro - humoral regulative systems activity in groups A and B [Fig. 2]. In supine posture pirenzepine induced significant decrease of LF/HF index in group 1 while in group 2 it was unchanged. In upright posture observed in both groups LF/HF index decrease was therefore insignificant because of high individual variability of the parameters studied.

Fig. 2 Induced by pirenzepine LF/HF index changes in group 1 and 2 in supine and upright position of the subject under study.

    In both groups pirenzepine did not alter the pattern of tilt test reactions. Thus both in basal condi-tion and after the medication intake the orthostatic reactions lied in Total Power decrease mostly at the expense of vagus nerve activity. Though pirenzepine stipulate for the tilt test decrease of HRV parameters mirroring vagus nerve activity (rMSSD, pNN50, HF) being less pronounced than the one obtained in active tilt test before the medication intake.

    After the medication intake in supine position of the subject under study significant prolongation of QT and TP intervals was obtained in group 1 and a tendency to those changes was evaluated in group 2 [Table 2]. In upright posture QT and TP intervals remained prolonged in group 1 only. At the same time P wave and PQ interval durations remained practically unchanged.

    Thus the targets of pirenzepine vagotonic action in electrical phase structure of the heart cycle are both electrical diastole and systole. It should be noted that TP interval alterations were more pro-nounced than QT duration changes. At the same time in group 1 QT intervals prolongation were quite stable.

    Quite similar pattern of pirenzepine modification of the neuro - humoral regulative systems state was obtained in former studies. In [15] vagomimetic action of the drug was obtained both in heart failure patients and in healthy controls. Vagotonic action showed itself as RR - intervals prolonga-tion and augmentation of absolute values of HF domain power. At the same time Hayano et al did not receive significant LF/HF index changes in either group under study [15].

CONCLUSION
   M1-cholinoblocker pirenzepine has a dual influence on regulatory systems simultaneously aug-menting the total power of regulation and optimizing sympatho - vagal balance. In healthy subjects pirenzepine induces growing of the total power of spectrum and absolute powers in all domains. Maximal augmentation occurs in the high frequency domains. Statistically significant changes of the sympatho - vagal balance ratio in responce to pirenzepine are recorded in subjects with initial sympathetic prevalence only. In healthy subjects pirenzepine does not change the pattern of or-thostatic regulatory systems response but diminishes its rate. Pirenzepine has negative chronotropic effect. Pirenzepine induces prolongation of the electrical systole and diastole being more pro-nounced in subjects with sympathetic prevalence. As a substance with autonomic - tropic action, pirenzepine may be used in cases of the total power of regulation fall and sympathetic distress.

REFERENCES

1. Vesalainen RK Effects of low-dose transdermal scopolamine on autonomic cardiovascular con-trol in healthy young subjects. Clin Physiol. 1997 Mar; 17(2): 135-48.

2. Casadei B, Pipilis A, Sessa F, Conway J, Sleight P. Low doses of scopolamine increase cardiac vagal tone in acute phase of myocardial infarction. Circulation. 1993; 88:353-357.

3. Vybiral T, Glaeser DH, Morris G, Hess KR, yang K, Francis M, Pratt CM. Effects of low-does scopolamine on heart rate variability in acute myocardial infarction. J Am Coll Cardiol. 1993; 22: 1320 - 1326.

4. De Ferrari GM, Mantica M, Vanoli E, Hull SS Jr, Schwartz PJ. Scopolamine increases vagal tone and vagal reflexes in patients after myocardial infarction. J Am Coll Cardiol. 1993; 22:1327 - 1334.

5. Pedretti R, Colombo E, Sarzi Brada S, Caru B. Influence of trancdermal scopolamine on cardiac sympathovagal interaction after myocardial infarction. Am J Cardiol. 1993; 72: 384 - 392.

6. Kochiadakis GE, Rombola AT, Kanoupakis EM, Zuridakis EG, Skalidis EI, Vardas PE. Effect of transdermal scopolamine on heart rate variability in patients with severe coronary heart dis-ease. Pacing Clin Electrophysiol 1996 Nov; 19(11 Pt 2):1867-71.

7. Venkatesh G. Double blind placebo controlled trial of short term transdermal scopolamine on heart rate variability in patients with chronic heart failure. Heart. 1996 Aug; 76(2): 137-43.

8. Wetzel GT, Brown JH. Presynaptic modulation of acetylcholine release from cardiac parasym-pathetic neurons. Am J Physiol. 1985; 248:H33 - H39.

9. Pedretti RF, Colombo E, Braga SS, Ballardini L, Caru B Effects of oral pirenzepine on heart rate variability and baroreceptor reflex sensitivity after acute myocardial infarction. J. Am. Coll. Cardiol. 1995 Mar 15;25(4):915-21.

10. Jakubetz J Human cardiac beta1- or beta2-adrenergic receptor stimulation and the negative chronotropic effect of low-dose pirenzepine. Clin Pharmacol Ther - 2000 May; 67(5): 549-57.

11. Melezhik, Y. P., Isaeva, A. S., Yabluchansky, N. I. Nonselective b -blockers, autonomic regula-tion and phases of the heart cycle. 1st Virtual Congress of Cardiology [Online], 2000, Jan. Awailable from: www.fac.org.ar/svcv

12. Task Force of The Europian Society of Cardiology and The North American Society of Pacing and Electrophysiology. Heart rate variability. Standarts of measurement, physiologicalinterpre-tation, and clinical use. Europ. Heart. J 1996.. 17: 354-381.

13. Eckberg DL. Sympathovagal balance: a critical appraisal. Circulation 1997;96:3324-32.

14. Pagani M., Lombardi F., Guzzetti S., Rimoldi O., Furlan R., Pizzinelli P., Sandrone G., Mar-fatto G., Dell'Orto S., Piccaluga E., Turiel M., Baselli G., Gerutti S., Malliani A. Power spectral analysis of heart rate and arterial pressure variabilities as a marker of sympatho-vagal interac-tion in man and conscious dogs. Circ. Res. 59:178-193, 1986.

15. Hayano T, Shimizu A, Ikeda Y, Yamamoto T, Yamagata T, Ueyama T, Furutani Y, Matsuzaki M Paradoxical effects of pirenzepine on parasympathetic activity in chronic heart failure and control. Int. J. Cardiol. 1999 Jan;68(1):47-56.

 

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2nd Virtual Congress of Cardiology

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