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(Circulation. 1997;96:3129-3135.)
© 1997 American Heart Association, Inc.

Articles

Functional Compartmentalization of ATP Is Involved in Angiotensin II–Mediated Closure of Cardiac ATP-Sensitive K⁺ Channels

Kunihiko Tsuchiya, MD; Minoru Horie, MD, PhD; Masato Watanuki, MD; Carlos A. Albrecht, MD; Kazuhiko Obayashi, MD; Hisayoshi Fujiwara, MD, PhD; ; Shigetake Sasayama, MD, PhD

From the Department of Cardiovascular Medicine (K.T., M.H., M.W., C.A.A., K.O., S.S.), Kyoto University Graduate School of Medicine, Kyoto 606-01; and the Second Department of Internal Medicine (H.F.), Faculty of Medicine, Gifu University, Gifu 500, Japan.

Correspondence to Minoru Horie, MD, PhD, Division of Cardiac Electrophysiology, The Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Shogoin, Sakyo-ku, Kyoto 606-01, Japan. E-mail horie{at}kuhp.kyoto-u.ac.jp

Background The effects of angiotensin II (Ang II) on ATP-sensitive K⁺ channels (K_ATP) were investigated in ventricular myocytes enzymatically isolated from adult guinea pig heart.

Methods and Results In the whole-cell and cell-attached configurations (including open-cell-attached mode) of the patch-clamp technique, K_ATP currents (I_KATP) were activated through metabolic poisoning by the use of inhibitors of both glycolytic and oxidative ATP productions at 37°C. In the whole-cell mode, I_KATP were reversibly suppressed by increasing extracellular glucose and Ang II (1 nmol/L). In the cell-attached mode, Ang II concentration-dependently inhibited single K_ATP activities with an IC₅₀ value of 3.2±0.5 pmol/L (Hill coefficient=1.3±0.3). CV11974 (100 nmol/L), an angiotensin 1 (AT₁) receptor-selective antagonist, blocked the inhibitory action of Ang II. Preincubation of myocytes with pertussis toxin (5 µg/mL for >120 min at 37°C) virtually prevented subsequent Ang II action. The inhibitory effect of Ang II was also abolished in the open-cell–attached mode (achieved by a prior perfusion of streptolysin-O, 0.08 U/mL). In this mode, through tiny membrane holes, the intracellular ATP concentration can be controlled by bathing extracellular solutions containing a known ATP concentration.

Conclusions The inhibitory actions of Ang II on K_ATP appear to be mediated by an increase in the subsarcolemmal ATP concentration that results from the inhibition of adenylate cyclase activities via AT₁ receptors/PTX-sensitive G proteins.

Key Words: angiotensin • ischemia • potassium channels

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