Sachidanandam Kamakshi, Harris Alex, Hutchinson Jimmie, Ergul Adviye
Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta 30912, USA.
Exp Biol Med (Maywood). 2006 Jun;231(6):1016-21.
Vascular dysfunction characterized by a hyperreactivity to vasoconstrictors and/or impaired vascular relaxation contributes to increased incidence of cardiovascular disease in diabetes. Endothelin (ET)-1, a potent vasoconstrictor, is chronically elevated in diabetes. However, the role of ET-1 in resistance versus larger vessel function in mild diabetes remains unknown. Accordingly, this study investigated vascular function of third-order mesenteric arteries and basilar arteries in control Wistar and Goto-Kakizaki (GK) rats, a model of mild Type 2 diabetes. Six weeks after the onset of diabetes, contractile responses to 0.1-100 nM ET-1 and relaxation responses to 1 nM-10 microM acetylcholine (ACh) in vessels preconstricted (baseline + 60%) with serotonin (5-HT) were assessed by myograph studies in the presence or absence of a nitric oxide synthase (NOS) inhibitor, N-nitro-L-arginine (L-NNA). Maximum contractile response to ET-1 was augmented in mesenteric vessels (155 +/- 18% in GK vs. 81 +/- 6% in control; n = 5-7) but not in the basilar artery (134 +/- 29% in GK vs. 107 +/- 17% in control; n = 4 per group). However, vascular relaxation was impaired in the basilar arteries (22 +/- 4% in GK vs. 53 +/- 7% in control; n = 4 per group) but not in mesenteric arteries of GK rats. Inhibition of NOS decreased the relaxation response of basilar arteries to 15 +/- 8% and 42 +/- 5% in GK and control rats, respectively; whereas, in resistance vessels, corresponding values were 56 +/- 7% and 89 +/- 3% (vs. 109 +/- 2% and 112 +/- 3% without NOS blockade), indicating the involvement of different vasorelaxation-promoting pathways in these vascular beds. These findings provide evidence that the ET system is activated even under mild hyperglycemia and that it contributes to the hyperreactivity of resistance vessels, therefore, the ET system may play an important role in elevated blood pressure in Type 2 diabetes.
血管功能障碍表现为对血管收缩剂反应过度和/或血管舒张受损，这会导致糖尿病患者心血管疾病发病率增加。内皮素（ET）-1是一种强效血管收缩剂，在糖尿病患者体内长期升高。然而，ET-1在轻度糖尿病患者的阻力血管与较大血管功能中的作用尚不清楚。因此，本研究调查了对照Wistar大鼠和轻度2型糖尿病模型Goto-Kakizaki（GK）大鼠的三级肠系膜动脉和基底动脉的血管功能。糖尿病发病六周后，通过肌张力描记法研究评估在有或没有一氧化氮合酶（NOS）抑制剂N-硝基-L-精氨酸（L-NNA）的情况下，血管对0.1 - 100 nM ET-1的收缩反应以及对1 nM - 10 μM乙酰胆碱（ACh）在经5-羟色胺（5-HT）预收缩（基线+60%）的血管中的舒张反应。ET-1在肠系膜血管中的最大收缩反应增强（GK组为155±18%，对照组为81±6%；n = 5 - 7），但在基底动脉中未增强（GK组为134±29%，对照组为107±17%；每组n = 4）。然而，GK大鼠基底动脉的血管舒张受损（GK组为22±4%，对照组为53±7%；每组n = 4），但肠系膜动脉未受损。抑制NOS分别使GK大鼠和对照大鼠基底动脉的舒张反应降至15±8%和42±5%；而在阻力血管中，相应值为56±7%和89±3%（与未进行NOS阻断时的109±2%和112±3%相比），表明这些血管床中存在不同的促进血管舒张的途径。这些发现提供了证据，表明即使在轻度高血糖情况下ET系统也被激活，并且它导致阻力血管反应过度，因此，ET系统可能在2型糖尿病患者血压升高中起重要作用。
