Role of Prostaglandin H₂ as an Endothelium-Derived Contracting Factor in Diabetic State

This study investigated the possible involvement of prostaglandin H₂, an acetylcholine-induced endothelium-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 10⁻⁷ M norepinephrine-precontracted rings, acetylcholine induced relaxations, which were significantly impaired in diabetic rats. Inhibition of thromboxane A₂-prostaglandin H₂ receptors with ONO-3708 (10⁻⁶) M) prevented the development of the impairment of relaxation in diabetic rats. Thromboxane A₂ synthesis inhibition with OKY-046 (10⁻⁵ 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 rats, when the nitric oxide production was inhibited by N^Gxs-nitro-L-arginine methylester (10⁻⁴ M). This acetylcholine-induced contraction was observed only in the rings with intact endothelium and was completely abolished by ONO-3708 (10⁻⁶ M). The concentration of 6-keto-prostaglandin F_1α in the solution bathing diabetic rat aortic rings increased significantly after acetylcholine (10⁻⁵ M) administration. Prostacyclin (10⁻⁹ · 10⁻⁶ 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 endothelium-derived relaxing factor or nitric oxide but rather by the increased endothelium-derived contracting factor or prostaglandin H₂, which may be responsible for abnormalities of the vasculature in diabetes.