Makino A, Kamata K
Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Tokyo, Japan.
Diabetologia. 1998 Dec;41(12):1410-8. doi: 10.1007/s001250051086.
We hypothesized that in diabetes arterial reactivity to constrictors is attenuated by certain endothelium-derived substances. We examined the vasoconstriction induced by methoxamine (alpha1-agonist) in isolated mesenteric arterial beds from streptozotocin (STZ)-induced diabetic rats and age-matched control rats. The dose-response curve for methoxamine was shifted to the right and the maximum contractile response was impaired in mesenteric arterial beds from diabetic rats. The methoxamine vasoconstriction was reduced in endothelium-denuded preparations from controls rats, but increased in those from diabetic rats. Treatment with the nitric oxide synthase inhibitor NG-nitro-L-arginine enhanced the vasoconstrictions induced by methoxamine in both control and diabetic rats. Indomethacin had no effect on the methoxamine vasoconstriction in control rats, but it shifted the dose-response curve to the left in diabetic rats. Whether given with or without indomethacin, BQ-123, (an ET(A)-receptor antagonist) plus BQ-788 (an ET(B)-receptor antagonist) shifted the dose-response curve for methoxamine to the right in control rats (while reducing the maximum response) but to the left in diabetic rats. The methoxamine-stimulated release of 6-keto-prostaglandin F1alpha from the mesenteric arterial bed in diabetic rats was approximately four times that seen in the control rats, while the methoxamine-induced release of thromboxane B2 (TXB2), a metabolite of thromboxane A2 (TXA2), was less in diabetic rats than in the control animals. These results suggest that an increased production of prostaglandin I2 (PGI2) and decreased formation of TXA2 could be responsible for the attenuation of the methoxamine-induced mesenteric vasoconstriction seen in diabetic rats, and these changes in the diabetic state could be partly responsible for the lower blood pressure seen in our diabetic rats.
我们假设，在糖尿病状态下，动脉对缩血管物质的反应性会被某些内皮衍生物质减弱。我们研究了甲氧明（一种α1肾上腺素能激动剂）在链脲佐菌素（STZ）诱导的糖尿病大鼠和年龄匹配的对照大鼠分离的肠系膜动脉床中所诱导的血管收缩情况。糖尿病大鼠肠系膜动脉床中，甲氧明的剂量 - 反应曲线向右移动，且最大收缩反应受损。在对照大鼠去内皮的制剂中，甲氧明诱导的血管收缩减弱，但在糖尿病大鼠的去内皮制剂中却增强。用一氧化氮合酶抑制剂NG - 硝基 - L - 精氨酸处理可增强对照大鼠和糖尿病大鼠中由甲氧明诱导的血管收缩。吲哚美辛对对照大鼠的甲氧明血管收缩无影响，但在糖尿病大鼠中它使剂量 - 反应曲线向左移动。无论是否与吲哚美辛一起给予，BQ - 123（一种ET(A)受体拮抗剂）加BQ - 788（一种ET(B)受体拮抗剂）在对照大鼠中使甲氧明的剂量 - 反应曲线向右移动（同时降低最大反应），但在糖尿病大鼠中却向左移动。糖尿病大鼠肠系膜动脉床中，甲氧明刺激产生的6 - 酮 - 前列腺素F1α约为对照大鼠的四倍，而甲氧明诱导产生的血栓素B2（TXB2，血栓素A2（TXA2）的代谢产物）在糖尿病大鼠中比对照动物少。这些结果表明，前列腺素I2（PGI2）生成增加和TXA2生成减少可能是糖尿病大鼠中甲氧明诱导的肠系膜血管收缩减弱的原因，而糖尿病状态下的这些变化可能部分导致了我们实验中糖尿病大鼠血压较低。
