Modulation of the transient outward K+ current by inhibition of endothelin-A receptors in normal and hypertrophied rat hearts.
Inhibition of endothelin-A (ET(A)) receptors has been shown to reduce ventricular electrical abnormalities associated with cardiac failure. In this study, we investigate the effect of ET(A)-receptor inhibition on the development of regional alterations of the transient outward K(+) current (I (to)) in the setting of pressure-induced left ventricular (LV) hypertrophy. Cardiac hypertrophy was induced in female Sprague-Dawley rats by stenosis of the ascending aorta (AS) for 7 days. Treatment with the selective ET(A)-receptor antagonist darusentan (LU135252, 35 mg [kg body weight](-1) day(-1)) was started 1 day before the surgery. AS induced a 46% increase in the relative LV weight (p < 0.001) and caused a significant reduction in I (to) (at +40 mV) in epicardial myocytes (19.5 +/- 1.2 pA pF(-1), n = 32 vs 23.2 +/- 1.2 pA pF(-1), n = 35, p < 0.05). Darusentan further reduced I (to) in AS (15.4 +/- 1.3 pA pF(-1), n = 37, p < 0.05) and sham-operated animals (19.8 +/- 1.6 pA pF(-1), n = 48, ns.). The effects of AS and darusentan on I (to) were significant and independent as tested by two-way analysis of variance. I (to) was not affected in endocardial myocytes. These results indicate that endothelin-1 may exert a tonic effect on the magnitude of I (to) in the epicardial region of the left ventricle but that ET(A)-receptor activation is not necessary for the development of electrical alterations associated with pressure-induced hypertrophy.
Wagner
Michael
M
Institut für Vegetative Physiologie und Pathophysiologie, Universitätsklinikum Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
Goltz
Diane
D
Stucke
Carolin
C
Schwoerer
Alexander Peter
AP
Ehmke
Heimo
H
Volk
Tilmann
T
D000818:Animals; D001024:Aortic Valve Stenosis / Q000150:complications / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004594:Electrophysiology; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation; D006321:Heart / Q000502:physiology*; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D010666:Phenylpropionates / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism*; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000187:drug effects / Q000502:physiology*
D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D010666:Phenylpropionates; D015221:Potassium Channels; D011743:Pyrimidines; D044022:Receptor, Endothelin A; C107831:darusentan; D011188:Potassium