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. 2023 Feb 1;85(2):175-179.
doi: 10.1292/jvms.22-0494. Epub 2022 Dec 29.

Amitriptyline intoxication in bullfrogs causes widening of QRS complexes in electrocardiogram

Affiliations

Amitriptyline intoxication in bullfrogs causes widening of QRS complexes in electrocardiogram

Amu Nagano et al. J Vet Med Sci. .

Abstract

Amitriptyline intoxication is caused by its suicidal or accidental overdose. In the present study, by intravenously injecting 1.5 or 3.0 mg/kg amitriptyline into bullfrogs, we actually revealed that amitriptyline causes the widening of QRS complexes in electrocardiogram (ECG). In simultaneous recordings of the cardiac action potential, amitriptyline decreased the slope of phase 0 in the action potential, indicating the inhibition of the inward sodium currents during this phase. The following treatment with sodium bicarbonate quickly restored the widened QRS complexes in the ECG, demonstrating the counteraction with the sodium channel blockade caused by amitriptyline. The dual recordings of ECG waveforms and the action potential in cardiomyocytes enabled us to demonstrate the mechanisms of characteristic ECG abnormalities caused by amitriptyline intoxication.

Keywords: amitriptyline; bullfrog heart; cardiac action potential; electrocardiogram (ECG); widening of QRS complexes.

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Conflict of interest statement

The authors have nothing to disclose.

Figures

Fig. 1.
Fig. 1.
Intravenous injection of amitriptyline or paroxetine solutions and the simultaneous recording of electrocardiogram (ECG) waveforms and the transmembrane action potential. To induce amitriptyline or paroxetine intoxication, amitriptyline (1.5 or 3 mg/kg) or paroxetine (3 mg/kg) solutions were separately injected into the venous sinus located on the back of frog hearts. Immediately after each injection, ECG waveforms and the action potential of ventricular cardiomyocytes were simultaneously recorded, using ECG- and suction- electrodes.
Fig. 2.
Fig. 2.
Effects of 3 mg/kg amitriptyline and paroxetine on electrocardiogram (ECG) and the transmembrane action potential. Bullfrogs were intravenously injected with 3 mg/kg amitriptyline (n=3) (A) and paroxetine (n=3) (B). Then the ECG waveforms (top) and the action potential of cardiomyocytes (bottom) were simultaneously recorded 0 and 2 min after each injection.
Fig. 3.
Fig. 3.
Effects of sodium bicarbonate on 1.5 mg/kg amitriptyline-induced changes in electrocardiogram (ECG) and the transmembrane action potential. (A) Bullfrogs were intravenously injected with 1.5 mg/kg amitriptyline, followed by 1 M sodium bicarbonate. The ECG waveforms (top) and the action potential of cardiomyocytes (bottom) were simultaneously recorded after the injection. The numerical changes in the QRS duration in ECG (B) and the slope of phase 0 in the cardiac action potential (C) were continuously measured for 2 min after 1.5 mg/kg amitriptyline injection, followed by 1 M sodium bicarbonate injection. #P<0.05 vs. before amitriptyline injection. Values are means ± SEM (n=5). Differences were analyzed by ANOVA followed by Student’s t test.
Fig. 4.
Fig. 4.
Nav1.5 expression and the mechanisms of amitriptyline-induced ECG changes. (A) left: Masson’s trichrome staining in normal ventricular cardiomyocytes. right: Immunohistochemistry using an antibody for Nav1.5 (brown), counterstained with hematoxylin in normal ventricular cardiomyocytes. Magnification × 20. (B) Amitriptyline, which blocks the Nav1.5-channel currents in isolated rat cardiomyocytes [5], inhibited the inward sodium (Na+) entry into cardiomyocytes in bullfrog hearts and slowed the rate of rapid depolarization during phase 0 of the cardiac action potential. Consequently, such morphological changes in the action potential manifested as the widening of QRS complexes in the ECG. Sodium bicarbonate, which provides additional Na+ ions, counteracted the amitriptyline-induced inhibition of Nav1.5-channels.
Fig. 5.
Fig. 5.
Effects of 1 mg/kg flecainide on electrocardiogram (ECG) and the transmembrane action potential. Bullfrogs were intravenously injected with 1 mg/kg flecainide. Then the ECG waveforms (top) and the action potential of cardiomyocytes (bottom) were simultaneously recorded before after the injection.

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