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 microM inhibited I(sus) with an IC(50) 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 (AT(1)) 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 microM) significantly enhanced the suppression of I(sus) by 1 microM Ang II: (33.7+/-5.1% vs. control 17.1+/-2.3%). These results indicate that Ang II inhibits I(sus) via the AT(1) receptor and activation of PKC. Ang II significantly prolonged action potential duration (APD) when the control APD was lengthened by a Ca(2+) channel activator, BAY K8644. In myocytes with a relatively long APD, Ang II may prolong APD by inhibiting I(sus).
Matsuda
Hiroyuki
H
Department of Physiology, Kanazawa Medical University, 1-1 Daigaku, Uchinada-machi, Kahoku-gun, 920-0293 Ishikawa, Japan.
Kurata
Yasutaka
Y
Imanishi
Sunao
S
Sato
Ryoichi
R
Shibamoto
Toshishige
T
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D002120:Calcium Channel Agonists / Q000494:pharmacology; D006352:Heart Ventricles / Q000166:cytology*; D020128:Inhibitory Concentration 50; D008297:Male; D032342:Muscle Cells / Q000502:physiology*; D018408:Patch-Clamp Techniques; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D000959:Antihypertensive Agents; D002120:Calcium Channel Agonists; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D000068756:Valsartan; D011493:Protein Kinase C; D014633:Valine