Jesmin Subrina, Zaedi Sohel, Maeda Seiji, Yamaguchi Iwao, Goto Katsutoshi, Miyauchi Takashi
Department of Internal Medicine, Cardiovascular Division, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Exp Biol Med (Maywood). 2006 Jun;231(6):925-31.
Vascular tone is regulated through the actions of locally produced agents. Among the vasoconstrictors, the most potent agent is endothelin (ET), which exerts its vasoconstrictor actions principally through ET type A (ET(A)) receptors. Of the vasodilators, nitric oxide (NO) seems to be the most important contributor to the acute regulation of vascular tone. Vasculopathy is an important feature of diabetes mellitus (DM). Endogenous ET-mediated vasoconstrictor tone is augmented in diabetic states, and conflicting results persist concerning the NO system in diabetes. The present study investigated the expressions of inducible NO synthases (iNOS) and endothelial NOS (eNOS) in the heart of diabetic animals and the effects of a selective ET(A) receptor antagonist on these alterations. Type I diabetes was induced by intraperitoneal injection of streptozotocin (65 mg/kg) in Sprague-Dawley rats, while control (Con) rats received only citrate buffer. After 1 week, the streptozotocin-administered rats were randomly divided into two groups: the selective ET(A) receptor antagonist-administered group (DM+TA-0201, 1 mg/kg/day, by osmotic minipump for 2 weeks) and the DM+vehicle group (comprising the diabetic rats that received saline). The random blood glucose level was 405 +/- 103 mg/dl in DM animals, and this level was unchanged by ET antagonism. Body weight was more greatly decreased in DM rats than in Con rats, but the left ventricle to body weight ratio was increased in the DM group and was unaffected by ET antagonism. Protein expressions of eNOS and iNOS were assessed in the left ventricular tissues. eNOS expression was significantly increased in DM heart and was greatly inhibited by the treatment with ET antagonist. The expression of iNOS was also increased in early DM heart but was reversed by the ET antagonist. Thus, endothelin antagonism might be beneficial for DM heart by reversing the upregulated eNOS and iNOS expressions.
血管张力通过局部产生的介质的作用来调节。在血管收缩剂中，最有效的介质是内皮素（ET），它主要通过A型内皮素（ET(A)）受体发挥其血管收缩作用。在血管舒张剂中，一氧化氮（NO）似乎是血管张力急性调节的最重要因素。血管病变是糖尿病（DM）的一个重要特征。在糖尿病状态下，内源性ET介导的血管收缩张力增强，并且关于糖尿病中NO系统的结果仍存在争议。本研究调查了糖尿病动物心脏中诱导型一氧化氮合酶（iNOS）和内皮型一氧化氮合酶（eNOS）的表达，以及选择性ET(A)受体拮抗剂对这些改变的影响。通过向Sprague-Dawley大鼠腹腔注射链脲佐菌素（65 mg/kg）诱导I型糖尿病，而对照（Con）大鼠仅接受柠檬酸盐缓冲液。1周后，给予链脲佐菌素的大鼠被随机分为两组：选择性ET(A)受体拮抗剂给药组（DM+TA-0201，1 mg/kg/天，通过渗透微型泵给药2周）和DM+载体组（包括接受生理盐水的糖尿病大鼠）。DM动物的随机血糖水平为405±103 mg/dl，ET拮抗对此水平无影响。DM大鼠的体重下降幅度比Con大鼠更大，但DM组的左心室与体重比增加，且不受ET拮抗的影响。在左心室组织中评估eNOS和iNOS的蛋白表达。DM心脏中eNOS表达显著增加，而ET拮抗剂治疗可显著抑制其表达。早期DM心脏中iNOS表达也增加，但ET拮抗剂可使其逆转。因此，内皮素拮抗可能通过逆转eNOS和iNOS表达上调而对糖尿病心脏有益。
