Inhibition of the rapid component of the delayed rectifier potassium current in ventricular myocytes by angiotensin II via the AT1 receptor.
OBJECTIVE
There is increasing evidence that angiotensin II (Ang II) is associated with the occurrence of ventricular arrhythmias. However, little is known about the electrophysiological effects of Ang II on ventricular repolarization. The rapid component of the delayed rectifier K(+) current (I(Kr)) plays a critical role in cardiac repolarization. Hence, the aim of this study was to assess the effect of Ang II on I(Kr) in guinea-pig ventricular myocytes.


METHODS
The whole-cell patch-clamp technique was used to record I(Kr) in native cardiocytes and in human embryonic kidney (HEK) 293 cells, co-transfected with human ether-a-go-go-related gene (hERG) encoding the alpha-subunit of I(Kr) and the human Ang II type 1 (AT(1)) receptor gene.


RESULTS
Ang II decreased the amplitude of I(Kr) in a concentration-dependent manner with an IC(50) of 8.9 nM. Action potential durations at 50% (APD(50)) and 90% (APD(90)) repolarization were prolonged 20% and 16%, respectively by Ang II (100 nM). Ang II-induced inhibition of the I(Kr) was abolished by the AT(1) receptor blocker, losartan (1 muM). Ang II decreased hERG current in HEK293 cells and significantly delayed channel activation, deactivation and recovery from inactivation. Moreover, PKC inhibitors, stausporine and Bis-1, significantly attenuated Ang II-induced inhibition of I(Kr).


CONCLUSIONS
Ang II produces an inhibitory effect on I(Kr)/hERG currents via AT(1) receptors linked to the PKC pathway in ventricular myocytes. This is a potential mechanism by which elevated levels of Ang II are involved in the occurrence of arrhythmias in cardiac hypertrophy and failure.
Wang
Y H
YH
Department of Pharmacology, Hebei Medical University, Shijiazhuang, China.
Shi
C X
CX
Dong
F
F
Sheng
J W
JW
Xu
Y F
YF
D000200:Action Potentials; D000804:Angiotensin II / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism / Q000503:physiopathology; D002460:Cell Line; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects; D019808:Losartan / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D019311:Staurosporine / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection
D047228:Angiotensin II Type 1 Receptor Blockers; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D007211:Indoles; C000606913:KCNH2 protein, human; D008301:Maleimides; D047428:Protein Kinase Inhibitors; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D011493:Protein Kinase C; D019311:Staurosporine; D019808:Losartan; C070515:bisindolylmaleimide I; D011188:Potassium