Prostaglandin H2 as an endothelium-derived contracting factor modulates endothelin-1-induced contraction.
OBJECTIVE
To investigate the possible involvement of prostaglandin H2, an endothelium-derived contracting factor in the rat aorta, in the development of the contraction induced by endothelin-1.


METHODS
The aortic rings from spontaneously hypertensive rats (SHR) were prepared, and the changes of isometric tension of these rings developed by endothelin-1 were recorded with or without the treatment of several inhibitors or an antagonist. The concentrations of prostaglandins and thromboxane B2 in the bath solution with the rings contracted by endothelin-1 were measured by radioimmunoassay. The effects of a thromboxane A2/prostaglandin H2 receptor antagonist (ONO-3708) on endothelin-1-induced contraction were compared in SHR and Wistar-Kyoto (WKY) rats.


RESULTS
Indomethacin (10(-5) mol/l) and ONO-3708 (10(-6) mol/l) significantly diminished endothelin-1 (3 x 10(-8) mol/l)-induced contractions in the aortic rings from SHR with but not without endothelium. The thromboxane A2 synthetase inhibitors OKY-046 (10(-5) mol/l) and RS-5186 (10(-5) mol/l) did not attenuate the contractions either with or without endothelium. Endothelin-1 significantly increased the release of 6-keto-prostaglandin F1 alpha, which is the metabolite of prostaglandin I2 and its precursor prostaglandin H2, from rings with endothelium of SHR, but the concentration of thromboxane B2 from aortic rings was unchanged. In the rings without endothelium the endothelin-1-induced release of 6-keto-prostaglandin F1 alpha was also observed. The half-maximal effective concentration of endothelin-1 for rings from SHR was shifted to the right by ONO-3708, but that of WKY rats was not changed, and significantly greater amounts of 6-keto-prostaglandin F1 alpha were released in the rings from SHR than in those from WKY rats by endothelin-1.


CONCLUSIONS
Endothelin-1 induced the release of prostaglandin H2 from endothelial cells in the rat aorta, the effect being greater in the hypertensive state. The released prostaglandin H2, an endothelium-derived contracting factor, modulated the vasoconstriction that is induced by endothelin-1, another endothelium-derived contracting factor, in addition to the direct vasoconstrictive action of endothelin-1 on vascular smooth muscle.
Asano
H
H
Department of Internal Medicine II, Nagoya University School of Medicine, Japan.
Shimizu
K
K
Muramatsu
M
M
Iwama
Y
Y
Toki
Y
Y
Miyazaki
Y
Y
Okumura
K
K
Hashimoto
H
H
Ito
T
T
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D016232:Endothelins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000378:metabolism; D066298:In Vitro Techniques; D007537:Isometric Contraction; D008297:Male; D009638:Norepinephrine / Q000378:metabolism; D044262:Prostaglandin H2; D011453:Prostaglandins / Q000378:metabolism / Q000494:pharmacology; D011463:Prostaglandins H / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D014661:Vasoconstriction; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D016232:Endothelins; D011453:Prostaglandins; D011463:Prostaglandins H; D014662:Vasoconstrictor Agents; D044262:Prostaglandin H2; D013928:Thromboxane A2; D015121:6-Ketoprostaglandin F1 alpha; C049855:ONO 3708; D009638:Norepinephrine