Molecular and Electrical Remodeling of L- and T-Type Ca2+ Channels in Rat Right Atrium With Monocrotaline-Induced Pulmonary Hypertension

Abstract

t is well known that fibrillating or hemodynamically overloaded atria are subject to cellular electrical remodeling, which is characterized by shortening of the action potential 1 and often contributes to the occurrence and persistence of atrial fibrillation (AF). AF and chronic obstructive pulmonary disease (COPD) frequently coexist and complicate treatment of both clinical conditions. 2,3 COPD patients are susceptible to secondary pulmonary hypertension (PH), and the resulting hemodynamic changes, and in addition hypoxia, hypercapnia, acid-base disorders, disturbed sympathovagal balance, and medication can lead to the development of AF. 2,3 Recent studies demonstrated that the densities of the L-type calcium (Ca 2+ ) current (ICaL), transient outward current (Ito), and voltage-dependent Na + current (INa) are decreased in experimental animal models of atrial tachycardia-related AF. [4][5][6] In contrast to tachycardia-induced ionic remodeling, several clinical and experimental studies have indicated a decrease, no change, or even an increase in the ICaL density in chronic heart failure (CHF), 1,7,8 depending on the experimental conditions. Nonetheless, it is generally agreed that a possible change in ICaL is a key factor in electrical remodeling of cardiac myocytes in CHF and/or hypertrophy. In addition, the T-type Ca 2+ channel is involved in electrical remodeling during CHF or hypertrophy. The T-type Ca 2+ channel is normally expressed in embryonic and neonatal myocytes, and in the conducting system of the adult heart, 9 and in rats it is re-expressed in pathologic conditions such as ventricular hypertrophy and post-myocardial infarction. 10 In the present study, the electrical properties of ICaL and ICaT were characterized in rat right atrial cells with monocrotaline (MCT)-induced PH, and the possible causes are discussed in relation to changes in the expression and function of Ca 2+ channel subunits. Methods AnimalsThe Animal Ethics Committee of Akita University School of Medicine, Japan, approved the study protocol. Four-week-old Wistar rats (CLEA Japan, Tokyo, Japan), weighing 140-150 g each, were treated with 500 mg MCT (Crotaline; Sigma, St Louis, MO, USA) to produce PH. A single dose of MCT 60 mg/kg was injected subcutaneously in the interscapular region. Measurement of Hemodynamic Parameters and Assessment of Right Ventricular (RV) HypertrophyRV pressure and heart rate were measured, using a pressure transducer connected to a monitor (DynaScope 5100E; Fukuda Denshi, Tokyo, Japan). Right atrial (RA) and RV hypertrophy were evaluated by measuring the ratio of the RA weight to body weight (BW), the ratio of the RV free wall weight to BW, and the ratio of the RV weight to the left ventricular free wall plus septum (LV + IVS) weight. (Received June 19, 2008; revised manuscript received September 8, 2008; accepted September 24, 2008; released online December 26, 2008) Departments of Cardiology, *Physiology, Akita University School of Medicine, Akita, Japan Mailing address: Hiroshi Ito, Department of Ca...

Tetrodotoxin-sensitive Ca2+ Currents, but No T-type Currents in Normal, Hypertrophied, and Failing Mouse Cardiomyocytes

“…It has been reported by Santana et al 35 that ouabain can activate I Ca(TTX) and might contribute to the ouabain-induced increase in the cardiac [Ca 2+ ] i transient. Of note, Koyama et al 45 also showed the reappearance of I Ca,T in the presence of 10μmol/L TTX in rat atrial myocytes after monocrotaline-induced pulmonary hypertrophy. However, it is peculiar that the recorded I Ca,T current was insensitive to 100μmol/L NiCl 2 which eliminates the possibility that the recorded current was indeed I Ca,T .…”

Impact of Pulmonary Hypertension Hemodynamic Phenotype on Incident Atrial Fibrillation

“…Although AF is frequently recognized as a marker of postcapillary PH or clinical group 2 PH [19], we found that PH hemodynamic phenotype was not independently associated with incident AF. The pathophysiology of atrial arrhythmias in PH has been linked to right atrial fibrosis [20] as a result of chronic hypoxia and structural remodeling from chronic right atrial pressure overload [21], stretching [16], and remodeling with electrophysiological alterations in calcium channels [22]. Specifically, isthmus-dependent or typical atrial flutter has been described as a potentially separate entity in patients with PH given that right-sided cardiac chambers are implicated in its pathophysiology [6].…”

Mechanisms of pulmonary arterial hypertension-induced atrial fibrillation: insights from multi-scale models of the human atria

“…To investigate the effects of PAH-induced remodelling on atrial electrical activity, we identified relative changes in atrial remodelling from experimental data in MCT-induced PAH rats [18,[25][26][27][28], dogs [20,29], rabbits [11] and humans [7][8][9][30][31][32][33][34][35][36][37][38][39]. These experimental data encompass changes in the expression of ion channel-related genes, Ca 2+ -handling-related genes, connexin genes, fibrosis-related genes and inflammasome-related genes [9,[12][13][14][15]18,19,40] (figure 1a).…”

“…Prolonged APD/ERP has been consistently observed in the RA of animals and humans [7][8][9]18,[25][26][27][28][30][31][32][33][34][35][36][37][38][39]. The prolonged APD can be attributed to PAH-induced remodelling of atrial potassium (K + ) currents, including reductions in Kcnj2, Kcna5 and Kcnq1.…”