Shimizu, Kiyokazu, Muramatsu, Masahito, Kakegawa, Yoshio, Asano, Hiroshi, Toki, Yukio, Miyazaki, Yutaka, Okumura, Kenji, Hashimoto, Hidekazu, and Ito, Takayuki
This study investigated the possible involvement of prostaglandin [H.sub.2], an acetylcholine-induced ondothelium-derived contracting factor in rat aorta, in the development of abnormality of the vasculature in diabetes. Rings of thoracic aorta were prepared from control Wistar-Kyoto and STZ-induced diabetic rats to examine the changes in isometric tension. In [10.sup.-7] M norepinephrine-precontracted rings, acetylcholine induced relaxations, which were significantly impaired in diabetic rats. Inhibition of thromboxane [A.sub.2]-prostaglandin [H.sub.2] receptors with ONO-3708 ([10.sup.-6] m) prevented the development of the impairment of relaxation in diabetic rats. Thromboxane [A.sub.2] synthesis inhibition with OKY-046 ([10.sup.-5] m) did not affect the acetylcholine-induced relaxation in both control and diabetic rats. In aortic rings under resting tension, acetylcholine induced a contraction that was greater in diabetic than control rate, when the nitric oxide production was inhibited by [N.sup.g]-nitro-L-arginine methylester ([10.sup.-4] M). This acetylcholine-induced contraction was observed only in the rings with intact endathelium and was completely abolished by ONO-3708 ([10.sup.-6] M). The concentration of 6-keto-prostaglandin [F.sub.alpha] in the solution bathing diabetic rat aortic rings increased significantly after acetylcholine ([10.sup.-15] M) administration. Prostacyclin ([10.sup.-9]-[10.sup.-6] M) did not induce contractions at all. Prostacyclin is unlikely to mediate contractions because of its low contractile potency. These findings suggest that the impairment of acetylcholine-induced relaxation in the diabetic state is not caused by the diminished production of an endethelium-derived relaxing factor or nitric oxide but rather by the increased endothellum-derived contracting factor or postaglandin [H.sub.2], which may be responsible for abnormalities of the vasculature in diabetes. Diabetes, Control of vascular tone has been shown to be modulated by various vasoactive substances produced by the endothelium such as EDRFs (1-3) and EDCFs (4) in response to various stimuli. [...]