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 microM) and an analog of diacylglycerol, 1,2-dioctanyoyl-rac-glycerol (2 microM), caused a significant reduction of I(K(V)). Furthermore, the combination of 5 microM PKA inhibitor peptide 5-24 (PKA-IP) and 100 microM 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 Ca(2+)-dependent PKC inhibitor Gö6976 (1 microM) but was abolished in the presence of 40 microM 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.
Hayabuchi
Y
Y
Ion Channel Group, Department of Cell Physiology and Pharmacology, University of Leicester, United Kingdom.
Standen
N B
NB
Davies
N W
NW
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004075:Diglycerides / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D007700:Kinetics; D019808:Losartan / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008638:Mesenteric Arteries / Q000166:cytology / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology*; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D051744:Protein Kinase C-epsilon; D051381:Rats; D017208:Rats, Wistar; D013873:Thionucleotides / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D000959:Antihypertensive Agents; D004075:Diglycerides; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D010455:Peptides; D024642:Potassium Channels, Voltage-Gated; D013873:Thionucleotides; D014662:Vasoconstrictor Agents; C044295:1,2-dioctanoylglycerol; D000804:Angiotensin II; C016957:adenosine-3',5'-cyclic phosphorothioate; C064719:iberiotoxin; D000242:Cyclic AMP; C497257:Prkce protein, rat; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D019808:Losartan