Caveney S W, Taylor D A, Fleming W W
Department of Pharmacology and Toxicology, West Virginia University Robert C. Byrd Health Sciences Center, Morgantown 26506-9223, USA.
Naunyn Schmiedebergs Arch Pharmacol. 1997 Sep;356(3):374-82. doi: 10.1007/pl00005065.
Previous experiments have suggested that the vascular smooth muscle of Dahl salt-sensitive (DS) rats may possess a difference in the alpha1-adrenoceptor population or its transduction processes compared to Dahl salt-resistant (DR) rats. The purpose of the current research is to study the role of alpha1-adrenoceptors in the specific supersensitivity to norepinephrine (NE) seen prior to and early in the development of hypertension in the DS rat. Experiments in isolated perfused superior mesenteric arterial vasculature from DS rats chronically fed a high (7%) salt diet for 5 days or 3 weeks, in the absence or presence of an elevation in systolic blood pressure, respectively, demonstrated a specific supersensitivity to NE relative to DR rats. The enhanced responsiveness was specific to NE after 5 days of high salt since no differences in sensitivity of these preparations was observed to either KCl or 5-HT. A small but significant elevation in sensitivity to KCl following 3 weeks of treatment suggests that multiple factors may contribute to tissue responsiveness at this time. Radioligand binding experiments were performed using [125I]-HEAT to study the alpha1-adrenoceptor population and its subtypes. Saturation experiments using membranes prepared from the superior mesenteric arterial vasculature or mesenteric arterial branches showed no significant differences in overall alpha1-adrenoceptor population between DS and DR rats fed a high-salt diet for 5 days or 3 weeks. Competition experiments using membranes prepared from the superior mesenteric arterial branches in the presence of the alpha1A-subtype selective antagonist 5-methylurapidil showed two binding sites (high and low affinity) in these resistance vessels but no significant differences in nature or ratio of these sites between the DS and DR groups. These results suggest that changes in the alpha1-adrenoceptor population are not responsible for the specific supersensitivity to NE, which may be an early event in the induction and development of hypertension.
先前的实验表明，与 Dahl 盐抵抗（DR）大鼠相比，Dahl 盐敏感（DS）大鼠的血管平滑肌在α1 - 肾上腺素能受体数量或其转导过程中可能存在差异。当前研究的目的是探讨α1 - 肾上腺素能受体在 DS 大鼠高血压发生前及早期对去甲肾上腺素（NE）的特异性超敏反应中的作用。分别对长期喂食高（7%）盐饮食 5 天或 3 周的 DS 大鼠进行实验，在收缩压未升高或升高的情况下，分离灌注其肠系膜上动脉血管系统，结果表明相对于 DR 大鼠，DS 大鼠对 NE 具有特异性超敏反应。高盐饮食 5 天后，这种增强的反应性对 NE 具有特异性，因为观察到这些制剂对氯化钾（KCl）或 5 - 羟色胺（5 - HT）的敏感性没有差异。治疗 3 周后对 KCl 的敏感性有小幅但显著的升高，这表明此时多种因素可能导致组织反应性。使用[125I] - HEAT 进行放射性配体结合实验，以研究α1 - 肾上腺素能受体数量及其亚型。使用从肠系膜上动脉血管系统或肠系膜动脉分支制备的膜进行饱和实验，结果显示，喂食高盐饮食 5 天或 3 周的 DS 大鼠和 DR 大鼠之间，总体α1 - 肾上腺素能受体数量没有显著差异。在存在α1A 亚型选择性拮抗剂 5 - 甲基尿嘧啶的情况下，使用从肠系膜动脉分支制备的膜进行竞争实验，结果表明在这些阻力血管中有两个结合位点（高亲和力和低亲和力），但 DS 组和 DR 组之间这些位点的性质或比例没有显著差异。这些结果表明，α1 - 肾上腺素能受体数量的变化不是对 NE 特异性超敏反应的原因，而这可能是高血压诱导和发展过程中的早期事件。
