Stage-dependent changes in membrane currents in rats with monocrotaline-induced right ventricular hypertrophy

Abstract

Sequential changes in action potential configuration, 4-amino-pyridine-sensitive transient outward current (Ito), and L-type calcium current (ICa) in association with hypertrophy were investigated in ventricular myocytes from rats with monocrotaline (MCT)-induced pulmonary hypertension. The tissue weight ratio of right ventricle (RV) to left ventricle plus septum 14 and 28 days after a subcutaneous injection of MCT increased by 29.7 and 77.2%, respectively. Action potential duration (APD) of RV cells from MCT rats increased progressively, prolonged by 73.2 and 92.2% on days 14 and 28, respectively. The current density of Ito in RV cells from MCT rats on day 14 (32.5 +/- 4.5 pA/pF, n = 13) was significantly larger than in controls (26.8 +/- 4.5 pA/pF, n = 8; P < 0.05). On day 28, however, Ito density in MCT rats (15.3 +/- 4.6 pA/pF, n = 9) was significantly less than in controls (27.3 +/- 4.2 pA/pF, n = 10; P < 0.05). There were no differences in the voltage dependence of steady-state activation and inactivation of Ito between MCT and control rats. ICa density in MCT rats on day 14 (15.7 +/- 2.6 pA/pF, n = 10) was significantly larger than in controls (10.0 +/- 2.3 pA/pF, n = 10; P < 0.05), but there was no significant difference in Ito density between MCT rats (8.3 +/- 3.7 pA/pF, n = 10) and controls (11.6 +/- 3.0 pA/pF, n = 10) on day 28. These findings suggest that hypertrophy of mammalian hearts may cause stage-dependent changes in Ito and ICa density of ventricular myocytes. The APD prolongation in the early stage of hypertrophy may be caused mainly by an increase in ICa density, whereas the APD prolongation in the late stage may be ascribed to a reduction in Ito density.

Myocardial infarction in rat eliminates regional heterogeneity of AP profiles,ItoK+currents, and [Ca2+]itransients

“…This electrical heterogeneity in normal myocardium correlates with regional differences in the Ca 2ϩ -independent transient outward K ϩ current density (I to ) (5,15,18,34,35,43) as well as in gene expression of K ϩ channels (8,16,58). APD prolongation and reductions in I to density occur in rat heart after left anterior descending coronary artery ligation (2,43,58), aortic banding (5,22,55), as well as after treatment with either catecholamine (11) or monocrotaline (32,33). Depending on the model, the extent of I to density changes in disease may not be uniform throughout the ventricle (2,5,11,22,55), thereby leading to possible losses of electrical heterogeneity and increased susceptibility to arrhythmias (3).…”

Time- and Subunit-dependent Differential mRNA Expression of L-type Ca2+ Channel during Progression of Right Ventricular Hypertrophy.

“…22) Although little is known about the functions of β2 and β3 that are known to compose the L-type calcium channel in the myocardium, it would be very interesting if the time-course of the ratio of β3 to α1c could be correlated with that of the electrophysiologic results on the stage-dependent Ica density that were reported previously. 11) There are some limitations in the present study. (1) The mRNA level is not always parallel to the protein level, and (2) because the precise relation ship between the expression level and the electrophysiological function of the whole channel has not yet been clarified, we cannot apply our results directly to the electrophysiological changes in Ica density.…”

“…9) In left ventricular hypertrophy, Ica density has been reported to decrease, 5) increase, 3,4) or be unchanged. 7,8) Lee, et al 11) has raised a possible comprehensive interpretation of these controversial results, suggesting that the Ica density varied according to the stage of the acquired hypertrophy. In their study, Ica density increased in the early stage of progressive hypertrophy but tended to decrease towards its terminal stage.…”

“…[7][8][9] These controversial results may be attributed to the different stages of cardiac hypertrophy investigated. 10) Actually, Lee, et al 11) showed that Ica density increased in the early stage of right ventricular hypertrophy, but decreased in its later stage.…”

“…To test this hypothesis, we investigated the mRNA expression level of not only α1c but also the auxiliary subunits, and analyzed the expression ratio of each auxiliary subunit to the main subunit α1c. To compare the time-dependent change in the mRNA level during cardiac hypertrophy with the stage-dependent change of Ica previously reported by Lee, et al 11) we used the same rat model of right ventricular hypertrophy induced by monocrotaline in the present study.…”