Heterogeneity of the early outward current in ventricular cells isolated from normal and hypertrophied rat hearts.

Abstract

SUMMARY1. The nature, magnitude and kinetics of the 4-aminopyridine-sensitive early outward current (Ito) were analysed in isolated ventricular myocytes from the septum, the apex and the left ventricular free wall of rat ventricles using the wholecell voltage clamp method. The modulatory effect of pressure overload-induced cardiac hypertrophy on the regional variations of Ito was assessed in each topographical class of cells.2. Voltage clamp experiments were performed at room temperature (20-25°C) in the absence of Na+ on both sides of the membrane and in the presence of 3 mM CoCl2.Ito was studied from a holding potential of -80 mV and determined by subtraction of total outward currents elicited by the same protocols in the presence of 3 mm 4-aminopyridine (4-AP) from those obtained in its absence.3. In normal hearts, membrane passive properties were very similar in each topographical class of cells. Our results confirmed that the predominant early outward current in rat ventricular cells was 4-AP-sensitive, time and voltage dependent, and demonstrated that the magnitude of the current varied on a regional basis: current density of Ito in left ventricular free wall cells (30-1 +9-2 pA/pF at + 60 mV) was larger than in apex cells (20-2 + 1-7 pA/pF) or in septum cells (1 1-9 + 3-3 pA/pF). We noticed a larger variability in data from left ventricular free wall compared with other regions.4 magnitude appeared not to be modified, the current density-voltage curves were slightly shifted to more positive potentials and significantly decreased as compared to normal cells (in pA/pF, at + 60 mV): 8-4 + 5-0 in the left free wall group, 1 1-6 + 2-0 in the apex group, and 3-8+ 1-5 in the septum group. Steady-state activation and inactivation parameters were not clearly modified, but kinetics were slowed down.7. We conclude, therefore, that Ito is differentially distributed among different regions of the normal rat ventricle and we propose that this regional heterogeneity may be related to different distributions of functional channel densities, rather than alterations in whole-cell kinetics or single-channel properties. Pressure overloadinduced hypertrophy reduces Ito current availability by decreasing current densities without any significant change of whole-cell kinetics, while a homogenizing tendency of the ionic profile is observed among the studied regions. One possible explanation for the hypertrophy-induced variations may be an absence of Ito channel neosynthesis, leading to a decrease of channel density per surface area unit.

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

“…Similar effects on the normal regional electrical heterogeneity in rat hearts have been reported after MI (55) and other disease models (11,22,49). On the other hand, more uniform changes in the electrical properties between different regions in heart have also been reported previously (5,13). These published discrepancies in the regional response of the myocardium may be related to differences in the type, severity or duration of the disease model under investigation.…”

“…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).…”

“…right ventricle; septum; heart disease; contraction THERE ARE MARKED DIFFERENCES in the action potential duration (APD) in different regions of the mammalian ventricle (4,15,18,39,58). 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).…”

“…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).…”

Ca2+ Controls Functional Expression of the Cardiac K+ Transient Outward Current via the Calcineurin Pathway

“…In cardiac cells, Ca 2ϩ -sensitive transcription factors may play a key role in maintaining the contractile phenotype and contribute to adaptive or pathological changes in the structural or functional properties of the heart (10 perfusion method described previously (13). Taking into account the electrical heterogeneity, only the right ventricle was selected (14). Myocytes were incubated for 24 h at 37°C in Tyrode's solution supplemented with 100 IU/ml penicillin and 0.1 g/ml streptomycin as described previously (13).…”