Relationship between endothelin and thromboxane A2 in rat liver microcirculation.
In our previous study, we determined changes in hepatic blood flow using a Laser Doppler blood flow meter after i.v. injection of endothelin-1 (ET-1) or endothelin-3 (ET-3) at 2 nmol/kg in rats and found that ET-3 caused greater decreases in blood flow than ET-1. In the present study, we determined how the arachidonic acid cascade, mainly thromboxane A2 (TXA2), is related to ET-1 and ET-3 using indomethacin (INDO), which inhibits the biosynthesis of prostaglandin (PG), and OKY-046, a selective inhibitor of TXA2 synthesis. In the first series of experiments, ET-1 and ET-3 were administered after inhibiting the biosynthesis of PG by s.c. injection of 2 mg/kg of INDO. While INDO failed to inhibit the slight decrease in hepatic blood flow induced by ET-1, it significantly inhibited the marked decrease in hepatic blood flow elicited by ET-3. In the next series of experiments, ET-1 and ET-3 were administered after administration of 20 mg/kg of OKY-046. OKY-046 showed no effects in animals treated with ET-1, as in those pre-treated with INDO, while it significantly inhibited the decreases in hepatic blood flow induced by ET-3. These findings suggest that ET-1 decreases hepatic blood flow due to its direct effects although to a lesser extent than ET-3, while ET-3 does so due not only to its direct effects but also to TXA2-mediated effects. It is therefore likely that in addition to ET family peptides, PG-mediated mechanisms are involved in the regulation of hepatic microcirculation by ETs.
Kurihara
T
T
Institute of Geriatrics, Tokyo Women's Medical College, Japan.
Akimoto
M
M
Kurokawa
K
K
Ishiguro
H
H
Niimi
A
A
Maeda
A
A
Sigemoto
M
M
Yamashita
K
K
Yokoyama
I
I
Hirayama
Y
Y
D000818:Animals; D016232:Endothelins / Q000494:pharmacology*; D007213:Indomethacin / Q000008:administration & dosage; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008099:Liver / Q000098:blood supply*; D008297:Male; D008689:Methacrylates / Q000008:administration & dosage; D008833:Microcirculation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013928:Thromboxane A2 / Q000502:physiology*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors; D014661:Vasoconstriction / Q000187:drug effects
D016232:Endothelins; D008689:Methacrylates; D013928:Thromboxane A2; D013930:Thromboxane-A Synthase; C034364:ozagrel; D007213:Indomethacin