Differential autocrine modulation of atrial and ventricular potassium currents and of oxidative stress in diabetic rats

Abstract

. Differential autocrine modulation of atrial and ventricular potassium currents and of oxidative stress in diabetic rats. Am J Physiol Heart Circ Physiol 290: H1879 -H1888, 2006. First published December 9, 2005 doi:10.1152/ajpheart.01045.2005The autocrine modulation of cardiac K ϩ currents was compared in ventricular and atrial cells (V and A cells, respectively) from Type 1 diabetic rats. K ϩ currents were measured by using whole cell voltage clamp. ANG II was measured by ELISA and immunofluorescent labeling. Oxidative stress was assessed by immunofluorescent labeling with dihydroethidium, a measure of superoxide ions. In V cells, K ϩ currents are attenuated after activation of the renin-angiotensin system (RAS) and the resulting ANG II-mediated oxidative stress. In striking contrast, these currents are not attenuated in A cells. Inhibition of the angiotensin-converting enzyme (ACE) also has no effect, in contrast to current augmentation in V cells. ANG II levels are enhanced in V, but not in A, cells. However, the high basal ANG II levels in A cells suggest that in these cells, ANG II-mediated pathways are suppressed, rather than ANG II formation. Concordantly, superoxide ion levels are lower in diabetic A than in V cells. Several findings indicate that high atrial natriuretic peptide (ANP) levels in A cells inhibit RAS activation. In male diabetic V cells, in vitro ANP (300 nM-1 M, Ͼ5 h) decreases oxidative stress and augments K ϩ currents, but not when excess ANG II is present. ANP has no effect on ventricular K ϩ currents when the RAS is not activated, as in control males, in diabetic males treated with ACE inhibitor and in diabetic females. In conclusion, the modulation of K ϩ currents and oxidative stress is significantly different in A and V cells in diabetic rat hearts. The evidence suggests that this is largely due to inhibition of RAS activation and/or action by ANP in A cells. These results may underlie chamber-specific arrhythmogenic mechanisms. diabetes; cardiac potassium currents DIABETES MELLITUS is a growing epidemic (59). Despite improved treatment, cardiovascular complications develop, becoming the leading cause of diabetes-related death (24, 59). Diabetic cardiomyopathy impairs mechanical function, (3,38) and electrical abnormalities increase the propensity for some cardiac arrhythmias (1). Cardiac action potentials are prolonged in animal models of diabetes due to attenuated transient and sustained repolarizing K ϩ currents (39,56). A reduction in current magnitude reflects downregulation of K ϩ channel expression, as determined in earlier work by us and others (33,42,43). Diminished outward currents presumably underlie the prolongation of the QT interval in the human electrocardiogram. Prolongation and dispersion of the QT interval, established predictors of arrhythmias and mortality (23), are common in diabetes (50).

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“…However, diabetes has been well documented to cause significant K + ion channel abnormalities. [35][36][37] An intriguing possibility is suggested by the observations of Shander et al, 31 who observed a hyperpolarizing shift in the voltage-dependence of steady-state inactivation of I Na in response to application of lysophosphatidylcholine (LPC). It has been demonstrated that activation of calcium-independent phospholipase A 2 in the STZdiabetic rat heart leads to accumulation of lysophopholipids, 19 thus suggesting a possible mechanism underlying alterations of the voltage-dependence of I Na gating.…”

Oxidative stress and inflammation modulate peroxisome proliferator‐activated receptors with regional discrepancy in diabetic heart

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