Effects of the renin-angiotensin system on the current I-to in epicardial and endocardial ventricular myocytes from the canine heart

The Ca2+-independent portion of transient outward K+ current (I-to) exhibit s a transmural gradient in ventricle. To investigate control mechanisms for this gradient, we studied canine epicardial and endocardial ventricular my ocytes with use of the whale-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 inacti vation was >10-fold slower in endocardium. Incubation of epicardial myocyte s with angiotensin II for 2 to 52 hours altered I-to to resemble unincubate d endocardium and reduced the amplitude of the phase 1 notch of the action potential. In contrast, incubation of endocardial myocytes with losartan fo r 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 m RNA levels for either Kv4.3 or Kv1.4; thus, a change in the a subunit for I -to is unlikely to be responsible. To test whether posttranslational modifi cation produced the effects of angiotensin II, we coexpressed Kv4.3 and the angiotensin II type la receptor in Xenopus oocytes. Incubation with angiot ensin 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. Th ese results demonstrate that the properties of I-to in endocardium and epic ardium are plastic and likely under the tonic-differing influence of the re nin-angiotensin system.