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 hear t, however, remains controversial. Therefore, we investigated the effe ct of angiotensin II on Cl- conductance activated by cAMP-dependent pr otein 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 degrees C) elicited a typical p rotein kinase A-dependent Cl- conductance. Subsequent application of a ngiotensin II reduced the isoproterenol-induced conductance with an IC 50 of 0.24+/-0.08 nmol/L. Angiotensin II also inhibited the Cl- curren ts, which were activated through stimulation of adenylate cyclase by f orskolin and histamine receptors. CV-11974 (1 mu mol/L), an antagonist selective for the angiotensin type 1 receptor, prevented the effect o f angiotensin II. Angiotensin II did not inhibit the current that had been persistently activated by intracellular GTP gamma S (100 mu mol/L ), a nonhydrolyzable guanine nucleotide, plus isoproterenol. In additi on, prior incubation of myocytes with pertussis toxin prevented the an giotensin II inhibitory action. Cl- conductance, when activated direct ly 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 isoprote renol-induced increase of cAMP. Conclusions Angiotensin II receptors n egatively couple to adenylate cyclase via pertussis toxin-sensitive G proteins, thereby inhibiting cardiac protein kinase A-dependent Cl- co nductance.