title: Autocrine A2 in the T-system of ventricular myocytes creates transmural gradients in ion transport: a mechanism to match contraction with load?
abstract: Transmural heterogeneities in Na/K pump current (IP), transient outward K(+)-current (Ito), and Ca(2+)-current (ICaL) 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 Ito, but the effects of A2 on IP and ICaL were unknown. In this study, myocytes were isolated from five muscle layers between epicardium and endocardium. We found a monotonic gradient in both Ip and Ito, with the lowest currents in ENDO. When AT1Rs were inhibited, EPI currents were unaffected, but ENDO currents increased, suggesting endogenous extracellular A2 inhibits both currents in ENDO. IP- and Ito-inhibition by A2 yielded essentially the same K0.5 values, so they may both be regulated by the same mechanism. A2/AT1R-mediated inhibition of IP or Ito or stimulation of ICaL persisted for hours in isolated myocytes, suggesting continuous autocrine secretion of A2 into a restricted diffusion compartment, like the T-system. Detubulation brought EPI IP 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 IP, 57-65% of Ito, and a significant fraction of ICaL reside in T-tubule membranes where they are transmurally regulated by autocrine secretion of A2 into the T-system lumen and activation of AT1Rs. Increased AT1R activation regulates each of these currents in a direction expected to increase contractility. Endogenous A2 activation of AT1Rs 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 AT1Rs, which create a contractile gradient that matches the gradient in load.
authors.affiliation: Department of Physiology & Biophysics, State University of New York at Stony Brook, Stony Brook, New York.
authors.forename: Junyuan
authors.initials: J
authors.lastname: Gao
authors.affiliation: Department of Physiology & Biophysics, State University of New York at Stony Brook, Stony Brook, New York.
authors.forename: Xiurong
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Physiology & Biophysics, State University of New York at Stony Brook, Stony Brook, New York.
authors.forename: Irina A
authors.initials: IA
authors.lastname: Potapova
authors.affiliation: Department of Physiology & Biophysics, State University of New York at Stony Brook, Stony Brook, New York.
authors.forename: Ira S
authors.initials: IS
authors.lastname: Cohen
authors.affiliation: Department of Physiology & Biophysics, State University of New York at Stony Brook, Stony Brook, New York. Electronic address: richard.mathias@stonybrook.edu.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Mathias
authors.affiliation: Department of Physiology & Biophysics, State University of New York at Stony Brook, Stony Brook, New York.
authors.forename: Jeremy H
authors.initials: JH
authors.lastname: Kim
mesh_terms: D000200:Action Potentials; D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D004285:Dogs; D004699:Endocardium / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism*; D017136:Ion Transport; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D010496:Pericardium / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D011188:Potassium / Q000378:metabolism*; D015221:Potassium Channels / Q000378:metabolism; D012508:Sarcolemma / Q000378:metabolism; D016276:Ventricular Function
chemical_list: D015221:Potassium Channels; D000804:Angiotensin II; D011188:Potassium