Angiotensin II inhibited isoproterenol-induced protein kinase A-dependent Cl- conductance in guinea pig ventricular cells with an IC50 of 0.24 nmol/L via pertussis toxin-sensitive G proteins.
Does angiotensin II inhibit protein kinase A-dependent Cl- conductance in guinea pig ventricular cells?
Angiotensin II inhibits cardiac protein kinase A-dependent Cl- conductance by negatively coupling to adenylate cyclase via pertussis toxin-sensitive G proteins.
Effect estimate: IC50 0.24 nmol/L
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 degrees 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 mumol/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 GTP gamma S (100 mumol/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.
Obayashi et al. (1997) studied this question. Angiotensin II vs. Isoproterenol alone was evaluated on Cl- conductance activated by cAMP-dependent protein kinase (IC50 0.24 nmol/L). Angiotensin II inhibited isoproterenol-induced protein kinase A-dependent Cl- conductance in guinea pig ventricular cells with an IC50 of 0.24 nmol/L via pertussis toxin-sensitive G proteins.