Positive inotropic and vasoconstrictive effects of endothelin-1 in in vivo and in vitro experiments: characteristics and the role of L-type calcium channels.
Cardiac and vascular effects of endothelin-1 (ET-1) were studied in hemodynamic models in vivo and in isolated artery and heart tissues. The hemodynamic changes induced by ET-1 (30-300 pmol/kg i.v.) in dogs were increases in blood pressure, cardiac output, and ventricular contractility. Ring preparations of canine coronary artery and rabbit thoracic aorta showed vasoconstrictive responses to ET-1 (10(-10) M and over) with an EC50 of 3-10 x 10(-9) M. Nifedipine 10(-5) M did not reverse these effects completely. ET-1 had positive inotropic effects from 10(-10) M in rabbit papillary muscles. It lengthened the action potential duration by 16% and increased the developed tension by 180% (10(-8) M). In contrast, Bay K 8644 (10(-7) M) produced similar lengthening (17%) in the duration with only a 37% increase in the tension. This suggests a difference in the mechanisms of the positive inotropic effects between these two agents. We conclude that ET-1 has positive inotropic and vasoconstrictive effects, and that these ET-1-induced contractions in ventricular muscles and arteries cannot be explained thoroughly by the increase in currents through voltage-dependent calcium channels.
Watanabe
T
T
Central Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan.
Kusumoto
K
K
Kitayoshi
T
T
Shimamoto
N
N
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; D000818:Animals; D015220:Calcium Channels / Q000502:physiology*; D004285:Dogs; D004558:Electric Stimulation; D016232:Endothelins; D066298:In Vitro Techniques; D008839:Microelectrodes; D009200:Myocardial Contraction / Q000187:drug effects*; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D010455:Peptides / Q000494:pharmacology*; D011817:Rabbits; D014661:Vasoconstriction / Q000187:drug effects*
D015220:Calcium Channels; D016232:Endothelins; D010455:Peptides; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester