Angiotensin II inhibits protein kinase A-dependent chloride conductance in heart via pertussis toxin-sensitive G proteins

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 GTPγS (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.