Adrenergic and endothelin B receptor-dependent hypertension in dopamine receptor type-2 knockout mice
Adrenergic and endothelin B receptor-dependent hypertension in dopamine receptor type-2 knockout mice
复制标题
DOI：
10.1161/01.hyp.38.3.303
复制
发表时间：
2001-09-01
期刊：
影响因子：
8.3
通讯作者：
Jose, PA
中科院分区：
文献类型：
--
作者：
Li, XX;Bek, M;Jose, PA
多巴胺受体2型（D-2）基因多态性与原发性高血压相关。为了评估D-2受体是否参与血压（BP）的调节，我们研究了D-2受体被破坏的小鼠。在麻醉小鼠中，D-2纯合子和杂合子突变小鼠的收缩压和舒张压（毫米汞柱）高于D-2+/+同窝小鼠。D-2-/-小鼠中α-肾上腺素能阻滞后的BP降低程度大于D-2+/+小鼠。D-2-/-小鼠的肾上腺素排泄量大于D-2+/+小鼠，急性肾上腺切除术使D-2-/-和D-2+/+小鼠的血压降低至相似水平。内皮素B（ET[B]）受体阻断剂可降低ET（B1）和ET（B2）受体，而选择性ET（B1）受体阻断剂可升高D-2-/-小鼠的血压，但对D-2+/+小鼠无影响。ET（B）受体在D-2-/-小鼠中的表达高于D-2+/+小鼠。相反，阻断ET（A）和V-1加压素受体对D-2-/-或D-2+/+小鼠的血压没有影响。AT（1）拮抗剂在D-2-/-和D-2+/+小鼠中的抑制作用也相似。D-2+/+小鼠肾皮质和髓质Na+，K+-ATP酶基础活性高于D-2-/-小鼠。在急性盐水负荷前后，D-2-/-小鼠的尿流量和钠排泄量高于D-2+/+小鼠。因此，D-2受体的完全丧失导致高血压，而不是由于钠排泄受损。相反，D-2突变小鼠血管反应性增强可能是由交感神经和ET（B）受体活性增加引起的。
Polymorphism of the dopamine receptor type-2 (D-2) gene is associated with essential hypertension. To assess whether D-2 receptors participate in regulation of blood pressure (BP), we studied mice in which the D-2 receptor was disrupted. In anesthetized mice, systolic and diastolic BPs (in millimeters of mercury) were higher in D-2 homozygous and heterozygous mutant mice than in D-2+/+ littermates. BP after alpha -adrenergic blockade decreased to a greater extent in D-2-/- mice than in D-2+/+ mice. Epinephrine excretion was greater in D-2-/- mice than in D-2+/+ mice, and acute adrenalectomy decreased BP to a similar level in D-2-/- and D-2+/+ mice. An endothelin B (ET[B]) receptor blocker for both ET(B1) and ET(B2) receptors decreased, whereas a selective ET(B1) blocker increased, BP in D-2-/- mice but not D-2+/+ mice. ET(B) receptor expression was greater in D-2-/- mice than in D-2+/+ mice. In contrast, blockade of ET(A) and V-1 vasopressin receptors had no effect on BP in either D-2-/- or D-2+/+ mice. The hypotensive effect of an AT(1) antagonist was also similar in D-2-/- and D-2+/+ mice. Basal Na+,K+-ATPase activities in renal cortex and medulla were higher in D-2+/+ mice than in D-2-/- Mice. Urine flow and sodium excretion were higher in D-2-/- mice than in D-2+/+ mice before and after acute saline loading. Thus, complete loss of the D-2 receptor results in hypertension that is not due to impairment of sodium excretion. Instead, enhanced vascular reactivity in the D-2 mutant mice may be caused by increased sympathetic and ET(B) receptor activities.