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(Circulation. 1997;95:197-204.)
© 1997 American Heart Association, Inc.

Articles

Angiotensin II Inhibits Protein Kinase A–Dependent Chloride Conductance in Heart via Pertussis Toxin–Sensitive G Proteins

Kazuhiko Obayashi, MD; Minoru Horie, MD, PhD; Lai-Hua Xie, MS; Kunihiko Tsuchiya, MD; Akira Kubota, MD; Hitoshi Ishida, MD, PhD; Shigetake Sasayama, MD, PhD

the Department of Cardiovascular Medicine and Department of Metabolism and Clinical Nutrition (A.K., H.I.), Faculty of Medicine, Kyoto University, Japan.

Correspondence to Minoru Horie, Division of Cardiac Electrophysiology, Department of Cardiovascular Medicine, Faculty of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto 606-01, Japan. E-mail horie@kuhp.kyoto-u.ac.jp.

Background Angiotensin II receptors are reported to be abundant in the guinea pig ventricle; their coupling to adenylate cyclase in the heart, however, remains controversial. Therefore, we investigated the effect of angiotensin II on Cl^- conductance activated by cAMP-dependent protein kinase.

Methods and Results After minimizing the contribution of other ionic currents, exposure of single guinea pig ventricular cells to isoproterenol (40 to 50 nmol/L; 36°C) elicited a typical protein kinase A–dependent Cl^- conductance. Subsequent application of angiotensin II reduced the isoproterenol-induced conductance with an IC₅₀ of 0.24±0.08 nmol/L. Angiotensin II also inhibited the Cl^- currents, which were activated through stimulation of adenylate cyclase by forskolin and histamine receptors. CV-11974 (1 µmol/L), an antagonist selective for the angiotensin type 1 receptor, prevented the effect of angiotensin II. Angiotensin II did not inhibit the current that had been persistently activated by intracellular GTPS (100 µmol/L), a nonhydrolyzable guanine nucleotide, plus isoproterenol. In addition, prior incubation of myocytes with pertussis toxin prevented the angiotensin II inhibitory action. Cl^- conductance, when activated directly by intracellular dialysis with cAMP (1 mmol/L), was not affected by angiotensin II. Radioimmunologic measurement of cellular cAMP in the dissociated myocytes showed that angiotensin II inhibited the isoproterenol-induced increase of cAMP.

Conclusions Angiotensin II receptors negatively couple to adenylate cyclase via pertussis toxin–sensitive G proteins, thereby inhibiting cardiac protein kinase A–dependent Cl^- conductance.

Key Words: angiotensin • signal transduction • ions • heart failure

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