Participation of adrenoreceptors in the mechanisms of pathologic cardiac rhythm induced in newborn rats by nickel chloride administration

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Abstract

In experiments on 3-day-old rats to identify the possible involvement of adrenoreceptors (AR) in the development of pathologic heart rhythm with high-amplitude (> 0.5 c) bradycardic complexes (PHRBC) occurring in newborn rats after NiCl2 administration, a comparative analysis of changes in heart rate variability (HRV), heart rate, and respiration after injection of nickel chloride and a high dose of the β-AR agonist isoproterenol was carried out. Injection of NiCl2, which blocks T-type voltage-dependent Ca2+ channels (T-VDCC), causes in 100% of rats the occurrence of PHRBC accompanied by a decrease in the role of neural influences and an increase in the role of neurohumoral factors in the mechanisms of heart rate regulation. Activation of β-AR causes shifts of physiological parameters qualitatively and quantitatively similar to those observed after NiCl2 poisoning in rats, but PHRBC does not occur. Pharmacological analysis with premedication of rats with β-AR antagonists (propranolol, atenolol) or α-AR antagonists (phentolamine) followed by NiCl2 administration showed that β-AR blockade with the nonselective adrenolytic propranolol prevents the development of PSRBC in half of the rats. In animals with pathologic arrhythmia occurring after NiCl2 injection, a rapid increase in the load on the sympathoadrenal system is noted, and the initial (background) instability of the mechanisms of heart rhythm regulation is revealed. Blockade of α- and β1-AR does not prevent the development of PHRBC during subsequent NiCl2 administration, which suggests the participation of β2-AR in the development of arrhythmia. Administration of the selective β2-AR agonist clenbuterol to rats leads to a decrease in HRV, including neurohumoral regulation and the appearance of low-amplitude (< 0.1 c) bradycardic complexes (BC) in 22% of rats. The results obtained by us together with the analysis of the literature suggest that β-AR plays an important role in the complex changes in the balance of regulatory influences in the occurrence of PHRBCs. Activation of β1-AR contributes to increased release of catecholamines by adrenal chromaffin cells, increased role of neurohumoral component of heart rhythm regulation and causes activation of β2-AR. Blockade of β2-AR, on the contrary, reduces the release of catecholamines and prevents the development of pathological arrhythmia. The second necessary factor leading to the development of arrhythmias with high-amplitude BCs is blockade of T-type calcium channels.

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S. V. Kuznetsov

Sechenov Institute of Evolutionary Physiology and Biochemistry Russian Academy of Sciences

Author for correspondence.
Email: ksv@iephb.ru
Russian Federation, Saint Petersburg

N. N. Kuznetsova

Sechenov Institute of Evolutionary Physiology and Biochemistry Russian Academy of Sciences

Email: ksv@iephb.ru
Russian Federation, Saint Petersburg

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2. Fig. 1. Heart rhythm disturbances in a 3-day-old rat 14 min after NiCl2 injection at a dose of 109 mg/kg. The heart rhythm periodogram (a), ECG (b) and a fragment of the ECG recording from 30 to 50 sec (c) are shown. The abscissa axis shows time (sec), the ordinate axis shows ECG amplitude (mV) and rhythm periodogram (sec).

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3. Fig. 2. Shift in HRV parameters in 3-day-old rats after injection of NiCl2 (a, b), isoproterenol (c, d) and clenbuterol (e, f), presented as % of the initial (background) level taken as 100%. The values ​​of the VLF, LF, HF, To parameters (a, c, e) are given in normalized form (the power maxima of individual spectra are taken as 1). The relative power of the VLF, LF, HF ranges (b, d, f) is presented as % of the total (To) spectrum power. The LF/HF coefficient is calculated based on the averaged individual normalized LF and HF parameters. Heart rate (HR) is presented in beats/min. *p < 0.05 – reliability of differences between the background and the experiment, presented on the basis of the data from Tables 2, 3, 8.

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4. Fig. 3. Shift of HRV indices in 3-day-old rats, presented as % of the initial (background) level taken as 100%, after NiCl2 injection without (a) and after premedication of animals with phentolamine (b), atenolol (c) and propranolol (d, e). The values ​​of absolute power indices of the VLF, LF, HF, To ranges are given in normalized form (the power maxima of individual spectra are taken as 1). Here and in Fig. 4: *p < 0.05 – reliability of differences between the background and the experiment, presented on the basis of the data from Tables 2, 4, 5, 7.

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5. Fig. 4. Shift of HRV indices in 3-day-old rats after pharmacological effects in % of the initial (background) level taken as 100%. Relative power of VLF, LF, HF ranges is presented in % of the total (To) spectrum power. The LF/HF coefficient is calculated based on averaged individual normalized LF and HF indices. Heart rate (HR) is presented in beats/min.

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6. Fig. 5. Synchronization of bradycardic complexes of the heart rhythm (a) in a 3-day-old rat with bursts of motor activity (b) in the background and after an injection of clenbuterol at a dose of 90 mg/kg (c, d). The abscissa axis shows time in seconds, the ordinate axis in (a), (c) shows the duration of RR intervals (seconds); in b, d – EMG power (V2•s).

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