Effects of Angiotensin II on sustained outward currents in rat ventricular myocytes

We investigated the effects of angiotensin II (Ang II) on the sustained outward current (I _sus) and action potential of rat ventricular myocytes using the whole-cell patch-clamp technique. Ang II at 30 nM~3 µM inhibited I _sus with an IC₅₀ of 240 nM, a Hill coefficient of 1.0 and maximum inhibition of 19.4%. Ang II-mediated inhibition of I _sus was voltage independent, was due to a decrease in the K⁺ current and was abolished by the Ang II type-I (AT₁) receptor blocker, valsartan. The protein kinase C (PKC) inhibitors PKC19–36 or calphostin C, abolished Ang II-mediated inhibition of I _sus. In contrast, pretreatment with the protein kinase A (PKA) inhibitor PKA6–22 (100 µM) significantly enhanced the suppression of I _sus by 1 µM Ang II: (33.7±5.1% vs. control 17.1±2.3%). These results indicate that Ang II inhibits I _sus via the AT₁ receptor and activation of PKC. Ang II significantly prolonged action potential duration (APD) when the control APD was lengthened by a Ca²⁺ channel activator, BAY K8644. In myocytes with a relatively long APD, Ang II may prolong APD by inhibiting I _sus.