Angiotensin II inhibits and alters kinetics of voltage-gated K+ channels of rat arterial smooth muscle

The vasoconstrictor angiotensin II (ANG II) inhibits several types of K+ channels. We examined the inhibitory mechanism of ANG II on voltage-gated K+ (K-V) currents (I-K V) recorded from isolated rat arterial smooth muscle using patch-clamp techniques. Application of 100 nM ANG II accelerated the activation of I-K V but also caused inactivation. These effects were abolished by the AT(1) receptor antagonist losartan. The protein kinase A (PKA) inhibitor Rp-cyclic 3',5'-hydrogen phosphothioate adenosine (100 muM) and an analog of diacylglycerol, 1,2-dioctanyoyl-rac-glycerol (2 muM), caused a significant reduction of I-K V. Furthermore, the combination of 5 muM PKA inhibitor peptide 5-24 (PKA-IP) and 100 muM protein kinase C (PKC) inhibitor peptide 19-27 (PKC-IP) prevented the inhibition by ANG II, although neither alone was effective. The ANG II effect seen in the presence of PKA-IP remained during addition of the Ca2+-dependent PKC inhibitor Go6976 (1 muM) but was abolished in the presence of 40 muM PKC-epsilon translocation inhibitor peptide. These results demonstrate that ANG II inhibits K-V channels through both activation of PKC-epsilon and inhibition of PKA.