Role of the D-1A dopamine receptor in the pathogenesis of genetic hypertension
Role of the D-1A dopamine receptor in the pathogenesis of genetic hypertension
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DOI：
10.1172/jci118670
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发表时间：
1996-05-15
影响因子：
15.9
通讯作者：
Jose, PA
中科院分区：
文献类型：
--
作者：
Albrecht, FE;Drago, J;Jose, PA
由于肾脏产生的多巴胺是钠转运的肾内调节剂，因此多巴胺能系统的异常可能在高血压的发病机制中起重要作用。在自发性高血压大鼠（SHR）中，尽管肾脏分泌多巴胺和受体密度正常，但肾近端小管中D-1受体信号的转导存在缺陷，导致多巴胺对钠转运（Na+/H+交换器[NHE]和Na+/K(+) atp酶活性）的抑制减弱。为了确定近端小管中NHE的D-1受体调节受损是否与高血压有关，研究人员在雌性Wistar Kyoto （WKY）和雄性SHR杂交的F2代中进行了研究，发现D-1激动剂SKF 81297抑制了正常F2s（收缩压< 140 mm Hg, n = 7）的brush border膜中的NHE活性（37.6+/-4.7%），但对高血压F2s （n = 21）没有作用。此外，D-1激动剂SKF 38393输注到肾动脉后，剂量依赖性地增加了正常血压F2s （n = 3）的钠排泄，而不改变肾血流量，但在高血压F2s中无活性（n = 21）。由于在肾近端小管中表达的主要D-1受体基因是D-1A亚型，我们确定了该基因在缺乏功能性D-1A受体的小鼠中控制血压的重要性，纯合子（n = 6）和杂合子（n = 5）小鼠的收缩压高于正常性别匹配的仔鼠对照组（n = 12）；此外，缺乏一个或两个D-1A等位基因的小鼠出现舒张性高血压。在缺乏一个或两个D-1A等位基因的小鼠中，肾钠转运的D-1受体受损与高血压的共分离以及收缩压和舒张压升高的发展表明D-1A受体基因与高血压存在因果关系。
Since dopamine produced by the kidney is an intrarenal regulator of sodium transport, an abnormality of the dopaminergic system may be important in the pathogenesis of hypertension. In the spontaneously hypertensive rat (SHR), in spite of normal renal production of dopamine and receptor density, there is defective transduction of the D-1 receptor signal in renal proximal tubules, resulting in decreased inhibition of sodium transport (Na+/H+ exchanger [NHE] and Na+/K(+)ATPase activity) by dopamine. To determine if impaired D-1 receptor regulation of NHE in proximal tubules is related to hypertension, studies were performed in a F2 generation from female Wistar Kyoto (WKY) and male SHR crosses, A D-1 agonist, SKF 81297, inhibited (37.6+/-4.7%) NHE activity in brush border membranes of normotensive F2s (systolic blood pressure < 140 mm Hg, n = 7) but not in hypertensive F2s (n = 21). Furthermore, a D-1 agonist, SKF 38393, when infused into the renal artery, dose dependently increased sodium excretion in normotensive F2s (n = 3) without altering renal blood flow but was inactive in hypertensive F2s (n = 21). Since the major D-1 receptor gene expressed in renal proximal tubules is the D-1A subtype, we determined the importance of this gene in the control of blood pressure in mice lacking functional D-1A receptors, Systolic blood pressure was greater in homozygous (n = 6) and heterozygous (n = 5) mice compared to normal sex matched litter mate controls (n = 12); moreover, the mice lacking one or both D-1A alleles developed diastolic hypertension. The cosegregation with hypertension of an impaired D-1 receptor regulation of renal sodium transport and the development of elevated systolic and diastolic pressure in mice lacking one or both D-1A alleles suggest a causal relationship of the D-1A receptor gene with hypertension.