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Angiotensin II inhibits rat arterial KATP channels by inhibiting steady‐state protein kinase A activity and activating protein kinase Ce
Author(s) -
Hayabuchi Y.,
Davies N. W.,
Standen N. B.
Publication year - 2001
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1111/j.1469-7793.2001.0193l.x
Subject(s) - pinacidil , protein kinase c , protein kinase a , angiotensin ii , chemistry , intracellular , patch clamp , losartan , atp sensitive potassium channel , antagonist , medicine , endocrinology , pharmacology , phosphorylation , receptor , biochemistry , biology , glibenclamide , diabetes mellitus
1 We used whole‐cell patch clamp to investigate steady‐state activation of ATP‐sensitive K + channels (K ATP ) of rat arterial smooth muscle by protein kinase A (PKA) and the pathway by which angiotensin II (Ang II) inhibits these channels. 2 Rp‐cAMPS, an inhibitor of PKA, did not affect K ATP currents activated by pinacidil when the intracellular solution contained 0.1 mM ATP. However, when ATP was increased to 1.0 mM, inhibition of PKA reduced K ATP current, while the phosphatase inhibitor calyculin A caused a small increase in current. 3 Ang II (100 nM) inhibited K ATP current activated by the K + channel opener pinacidil. The degree of inhibition was greater with 1.0 mM than with 0.1 mM intracellular ATP. The effect of Ang II was abolished by the AT 1 receptor antagonist losartan. 4 The inhibition of K ATP currents by Ang II was abolished by a combination of PKA inhibitor peptide 5‐24 (5 μM) and PKC inhibitor peptide 19‐27 (100 μM), while either alone caused only partial block of the effect. 5 In the presence of PKA inhibitor peptide, the inhibitory effect of Ang II was unaffected by the PKC inhibitor Gö 6976, which is selective for Ca 2+ ‐dependent isoforms of PKC, but was abolished by a selective peptide inhibitor of the translocation of the ε isoform of PKC. 6 Our results indicate that K ATP channels are activated by steady‐state phosphorylation by PKA at normal intracellular ATP levels, and that Ang II inhibits the channels both through activation of PKCε and inhibition of PKA.