Effects of the Renin-Angiotensin System on the Current I _to in Epicardial and Endocardial Ventricular Myocytes From the Canine Heart

Abstract

The Ca(2+)-independent portion of transient outward K(+) current (I(to)) exhibits a transmural gradient in ventricle. To investigate control mechanisms for this gradient, we studied canine epicardial and endocardial ventricular myocytes with use of the whole-cell patch-clamp technique. I(to) was larger in amplitude, had a more negative voltage threshold for activation, and had a more negative midpoint of inactivation in epicardium. Recovery from inactivation was >10-fold slower in endocardium. Incubation of epicardial myocytes with angiotensin II for 2 to 52 hours altered I(to) to resemble unincubated endocardium and reduced the amplitude of the phase 1 notch of the action potential. In contrast, incubation of endocardial myocytes with losartan for 2 to 52 hours altered I(to) to resemble unincubated epicardium and induced a phase 1 notch in the action potential. With RNase protection assays, we determined that incubations with angiotensin II or losartan did not alter mRNA levels for either Kv4.3 or Kv1.4; thus, a change in the alpha subunit for I(to) is unlikely to be responsible. To test whether posttranslational modification produced the effects of angiotensin II, we coexpressed Kv4.3 and the angiotensin II type 1a receptor in Xenopus oocytes. Incubation with angiotensin II increased the time constant for recovery from inactivation of the expressed current by 2-fold with an incubation time constant of 3.7 hours. No effect on activation or inactivation voltage dependence was observed. These results demonstrate that the properties of I(to) in endocardium and epicardium are plastic and likely under the tonic-differing influence of the renin-angiotensin system.

Angiotensin Receptor Type 1 Forms a Complex with the Transient Outward Potassium Channel Kv4.3 and Regulates Its Gating Properties and Intracellular Localization

“…The down-regulation of I to might be, at least in part, responsible for the arrhythmogenic potential of angiotensin II. Experiments with isolated cardiomyocytes demonstrated that angiotensin II inhibits I to in rat and canine myocytes (15,16). As with other G q -coupled receptors (e.g.…”

“…One important difference between protein kinase C-dependent inhibition of I to in Xenopus oocytes and the angiotensin II-dependent inhibition of I to in canine cardiomyocytes (16) or HEK 293 cells is the change in the activation voltage threshold of Kv4. 3.…”

“…Therefore, locally produced angiotensin II could act in a paracrine and/or autocrine manner to regulate I to . Experiments in vitro show that losartan stimulates I to in canine cardiomyocytes isolated from endocardium and converts the configuration of the action potential of endocardial myocytes to that found in epicardium (16).…”

“…In this animal model I to is inhibited and can be recovered by treatment with the AT1 receptor specific antagonist losartan (14). Experiments with isolated cardiomyocytes show that stimulation of the AT1 receptor results in the inhibition of I to in myocytes from rat or canine ventricle (15,16). In large mammals such as dogs or humans with substantial ventricular wall thickness, I to exhibits a transmural gradient that is vital for normal electrical activity (17,18).…”

Mechanisms linking short- and long-term electrical remodeling in the heart .....is it a stretch?

“…1B); additionally, I to is sensitive to 4-AP. 15 Pursuing the hypothesis that stretch-activated angiotensin II release occurs in cardiac memory, Yu and colleagues 16 demonstrated that application of angiotensin II to epicardial myocytes resulted in a marked reduction in I to density, a shift in current activation to more depolarized potentials, and a slowing of recovery from inactivation, all of which resulted in an electrical phenotype (in epicardial cells) more similar to endocardial cells. No changes in the expression levels of the transcripts encoding the K V 4.3 (KCND3) or K V 1.4 (KCNA4) subunits which encode I to channels (Fig.…”