Autocrine A2 in the T-System of Ventricular Myocytes Creates Transmural Gradients in Ion Transport: A Mechanism to Match Contraction with Load?

作者：Gao Junyuan; Sun Xiurong; Potapova Irina A; Cohen Ira S; Mathias Richard T^*; Kim Jeremy H

来源：Biophysical Journal, 2014, 106(11): 2364-2374.

DOI：10.1016/j.bpj.2014.04.042

Transmural heterogeneities in Na/K pump current (l(p)), transient outward K+-current (I-to), and Ca2+-current (I-CaL) play an important role in regulating electrical and contractile activities in the ventricular myocardium. Prior studies indicated angiotensin II (A2) may determine the transmural gradient in I-to, but the effects of A2 on I, and I-caL were unknown. In this study, myocytes were isolated. from five muscle layers between epicardium and. endocardium. We found a monotonic gradient in both I-p and Ito, with the lowest currents in ENDO. When AT(1)Rs were inhibited, EPI currents were unaffected, but ENDO currents increased, suggesting endogenous extracellular A2 inhibits both currents in ENDO. I-p-and I-to-inhibition by A2 yielded essentially the same K-0.5 values, so they may both be regulated by the same mechanism. A2/AT(1) R-mediated inhibition of I-p or I-to or stimulation of I-caL persisted for hours in isolated myocytes, suggesting continuous autocrine secretion of A2 into a restricted diffusion compartment, like the T-system. Detubulation brought EPI I-p to its low ENDO value and eliminated A2 sensitivity, so the T-system lumen may indeed be the restricted diffusion compartment. These studies showed that 33-50% of IF, 57-65% of I-to, and a significant fraction of I-caL reside in T-tubule membranes where they are transmurally regulated by autocrine secretion of A2 into the T-system lumen and activation of AT(1)Rs. Increased AT(1)R activation regulates each of these currents in a direction expected to increase contractility. Endogenous A2 activation of AT(1)Rs increases monotonically from EPI to ENDO in a manner similar to reported increases in passive tension when the ventricular chamber fills with blood. We therefore hypothesize load is the signal that regulates A2-activation of AT(1)Rs, which create a contractile gradient that matches the gradient in load.

• 出版日期2014-6-3