Brazilian Journal of Anesthesiology
https://bjan-sba.org/article/doi/10.1016/j.bjane.2022.05.004
Brazilian Journal of Anesthesiology
Original Investigation

Changes in gap junction proteins Connexin30.2 and Connexin40 expression in the sinoatrial node of rats with dexmedetomidine-induced sinus bradycardia

Alterações na expressão das proteínas de junção comunicante Connexin30.2 e Connexin40 no nó sinoatrial de ratos com bradicardia sinusal induzida por dexmedetomidina

Yong-Qiang Yin, Yi Zhong, Yu Zhu, Lei Tian

Downloads: 0
Views: 111

Abstract

Background
Dexmedetomidine (Dex) is widely used, and its most common side effect is bradycardia. The complete mechanism through which Dex induces bradycardia has not been elucidated. This research investigates the expression of gap junction proteins Connexin30.2 (Cx30.2) and Connexin40 (Cx40) within the sinoatrial node of rats with Dex-induced sinus bradycardia.

Methods
Eighty rats were randomly assigned to five groups. Saline was administered to rats in Group C. In the other four groups, the rats were administered Dex to induce bradycardia. In groups D1 and D2, the rats were administered Dex at a loading dose of 30 μg.kg−1 and 100 μg.kg−1 for 10 min, then at 15 μg.kg−1.h−1 and 50 μg.kg−1.h−1 for 120 min separately. The rats in group D1A and D2A were administered Dex in the same way as in group D1 and D2; however, immediately after the administration of the loading dose, 0.5 mg atropine was administered intravenously, and then at 0.5 mg.kg−1.h−1 for 120 min. The sinoatrial node was acquired after intravenous infusion was completed. Quantitative real-time polymerase chain reaction and western blot analyses were performed to measure mRNA and protein expression of Cx30.2 and Cx40, respectively.

Results
The expression of Cx30.2 increased, whereas the expression of Cx40 decreased within the sinoatrial node of rats with Dex-induced sinus bradycardia. Atropine reversed the effects of Dex on the expression of gap junction proteins.

Conclusion
Dex possibly altered the expression of gap junction proteins to slow down cardiac conduction velocity in the sinoatrial node.

Keywords

Autonomic nerve system;  Connexins;  Dexmedetomidine;  Sinus bradycardia  

Resumo

Justificativa: A dexmedetomidina (Dex) é amplamente utilizada e seu efeito colateral mais comum é a bradicardia. O mecanismo completo pelo qual Dex induz bradicardia não foi elucidado. Esta pesquisa investiga a expressão das proteínas de junção comunicante Connexin30.2 (Cx30.2) e Connexin40 (Cx40) no nodo sinoatrial de ratos com bradicardia sinusal induzida por Dex. Métodos: Oitenta ratos foram distribuídos aleatoriamente em cinco grupos. A solução salina foi administrada aos ratos do Grupo C. Nos outros quatro grupos, os ratos receberam Dex para induzir bradicardia. Nos grupos D1 e D2, os ratos receberam Dex em uma dose de ataque de 30 μg/kg-1 e 100 μg/kg-1 por 10 min, depois a 15 μg/kg-1/he 50 μg/kg-1/h-1 por 120 min separadamente. Os ratos do grupo D1A e D2A receberam Dex da mesma forma que no grupo D1 e D2; entretanto, imediatamente após a administração da dose de ataque, foi administrado 0,5 mg de atropina por via intravenosa e, em seguida, 0,5 mg/kg-1/h-1 por 120 min. O nó sinoatrial foi adquirido após o término da infusão intravenosa. A reação em cadeia da polimerase quantitativa em tempo real e análises de Western blot foram realizadas para medir a expressão de mRNA e proteína de Cx30.2 e Cx40, respectivamente. Resultados: A expressão de Cx30.2 aumentou, enquanto a expressão de Cx40 diminuiu dentro do nó sinoatrial de ratos com bradicardia sinusal induzida por Dex. A atropina reverteu os efeitos de Dex na expressão de proteínas de junções comunicantes. Conclusão: Dex possivelmente alterou a expressão de proteínas de junções comunicantes para diminuir a velocidade de condução cardíaca no nó sinoatrial.

Palavras-chave

Sistema nervoso autônomo; Conexinas; Dexmedetomidina; Bradicardia sinusal

References

1 Y Ergul, S Unsal, I Ozyilmaz, et al. Electrocardiographic and electrophysiologic effects of dexmedetomidine on children Pacing Clin Electrophysiol, 38 (2015), pp. 682-687

2 K Takata, YU Adachi, K Suzuki, et al. Dexmedetomidine-induced atrioventricular block followed by cardiac arrest during atrial pacing: A case report and review of the literature J Anesth, 28 (2014), pp. 116-120

3 X Zhang, U Schmidt, JC Wain, et al. Bradycardia leading to asystole during dexmedetomidine infusion in an 18 year-old double-lung transplant recipient J Clin Anesth, 22 (2010), pp. 45-49

4 CW. Lo Role of gap junctions in cardiac conduction and development: Insights from the connexin knockout mice Circ Res, 87 (2000), pp. 346-348

5 JA Jansen, TA van Veen, JM de Bakker, et al. Cardiac connexins and impulse propagation J Mol Cell Cardiol, 48 (2010), pp. 76-82

6 NV Munshi, J McAnally, S Bezprozvannaya, et al. Cx30.2 enhancer analysis identifies gata4 as a novel regulator of atrioventricular delay Development, 136 (2009), pp. 2665-2674

7 MM Kreuzberg, G Sohl, JS Kim, et al. Functional properties of mouse connexin30.2 expressed in the conduction system of the heart Circ Res, 96 (2005), pp. 1169-1177

8 S Shimizu, T Akiyama, T Kawada, et al. Medetomidine, an alpha(2)-adrenergic agonist, activates cardiac vagal nerve through modulation of baroreflex control Circ J, 76 (2012), pp. 152-159

9 T Kawada, T Akiyama, S Shimizu, et al. Sympathetic afferent stimulation inhibits central vagal activation induced by intravenous medetomidine in rats Acta Physiol, 209 (2013), pp. 55-61

10 S Kapa, KL Venkatachalam, SJ. Asirvatham The autonomic nervous system in cardiac electrophysiology: An elegant interaction and emerging concepts Cardiol Rev, 18 (2010), pp. 275-284

11 TJ Ebert, JE Hall, JA Barney, et al. The effects of increasing plasma concentrations of dexmedetomidine in humans Anesthesiology, 93 (2000), pp. 382-394

12 A Snapir, J Posti, E Kentala, et al. Effects of low and high plasma concentrations of dexmedetomidine on myocardial perfusion and cardiac function in healthy male subjects Anesthesiology, 105 (2006), pp. 902-910

13 JA Tan, KM. Ho Use of dexmedetomidine as a sedative and analgesic agent in critically ill adult patients: A meta-analysis Intensive Care Med, 36 (2010), pp. 926-939

14 DB Sharp, X Wang, D Mendelowitz Dexmedetomidine decreases inhibitory but not excitatory neurotransmission to cardiac vagal neurons in the nucleus ambiguus Brain Res, 1574 (2014), pp. 1-5

15 S Shimizu, T Akiyama, T Kawada, et al. Medetomidine suppresses cardiac and gastric sympathetic nerve activities but selectively activates cardiac vagus nerve Circ J, 78 (2014), pp. 1405-1413

16 Y Li, X Fu, Z Zhang, et al. Knockdown of cardiac kir3.1 gene with sirna can improve bradycardia in an experimental sinus bradycardia rat model Mol Cell Biochem, 429 (2017), pp. 103-111

17 MM Kreuzberg, JW Schrickel, A Ghanem, et al. Connexin30.2 containing gap junction channels decelerate impulse propagation through the atrioventricular node Proc Natl Acad, 103 (2006), pp. 5959-5964

18 M Stein, TA van Veen, CA Remme, et al. Combined reduction of intercellular coupling and membrane excitability differentially affects transverse and longitudinal cardiac conduction Cardiovasc Res, 83 (2009), pp. 52-60

19 S Kirchhoff, E Nelles, A Hagendorff, et al. Reduced cardiac conduction velocity and predisposition to arrhythmias in connexin40-deficient mice Curr Biol, 8 (1998), pp. 299-302

20 JW Schrickel, MM Kreuzberg, A Ghanem, et al. Normal impulse propagation in the atrioventricular conduction system of cx30.2/cx40 double deficient mice J Mol Cell Cardiol, 46 (2009), pp. 644-652

21 Y Jammes, F Joulia, JG Steinberg, et al. Endogenous adenosine release is involved in the control of heart rate in rats Can J Physiol Pharmacol, 93 (2015), pp. 667-675

22 K Monzen, R Nagai, I. Komuro A role for bone morphogenetic protein signaling in cardiomyocyte differentiation Trends Cardiovasc Med, 12 (2002), pp. 263-269

23 NJ Severs, AF Bruce, E Dupont, et al. RemodeUing of gap junctions and connexin expression in diseased myocardium Cardiovasc Res, 80 (2008), pp. 9-19

62bdae00a953953ded088a22 rba Articles
Links & Downloads

Braz J Anesthesiol

Share this page
Page Sections