Kunimi M, Seki G, Hara C, Taniguchi S, Uwatoko S, Goto A, Kimura S, Fujita T
Department of Nephrology and Endocrinology, and Department of Infectious Diseases, Faculty of Medicine, University of Tokyo, Japan.
Kidney Int. 2000 Feb;57(2):534-43. doi: 10.1046/j.1523-1755.2000.00873.x.
Dopamine (DA) is thought to regulate renal proximal transport through the inhibition of the Na+,K+-ATPase and/or Na+/H+ exchanger. Defects in this dopaminergic system are proposed to be a pathogenic factor of genetic hypertension. However, microperfusion studies have not consistently confirmed direct tubular effects of DA.
Isolated proximal straight tubules were perfused peritubularly with Dulbecco's modified Eagle's tissue culture medium (DMEM) containing norepinephrine (NE) to improve incubation conditions. Intracellular Na+ concentrations ([Na+]i) and cell pH (pHi) were measured with fluorescence probes.
When incubated in DMEM plus NE, DA increased [Na+]i in rabbit tubules. Inhibition of Na+,K+-ATPase could not explain this response, as it was not suppressed by ouabain. An analysis of pHi responses to bath HCO3- reduction revealed that DA, SKF 38393 (a DA1 agonist), and adenosine 3',5'-cyclic monophosphate (cAMP) inhibited the basolateral Na+:HCO3- cotransporter in rabbit and Wistar-Kyoto rat (WKY), if its transport stoichiometry was converted to 3 HCO3-:1 Na+ by DMEM plus NE incubation. The inhibitory effect of DA was abolished by SCH 23390, a DA1 antagonist, but not by (-)-sulpiride, a DA2 antagonist. In spontaneously hypertensive rats (SHRs), however, DA and SKF 38393 failed to inhibit the cotransporter, although the inhibitory effects of cAMP and parathyroid hormone were comparable to those in WKY.
These results indicate that DA inhibits the Na+:HCO3- cotransporter in renal proximal tubules and also suggest that dysregulation of the cotransporter, possibly through the defect in DA1 receptor signaling, could play an important role in development of hypertension in SHRs.
多巴胺（DA）被认为可通过抑制钠钾ATP酶和/或钠氢交换体来调节肾近端转运。该多巴胺能系统的缺陷被认为是遗传性高血压的致病因素。然而，微量灌注研究并未始终如一地证实DA对肾小管的直接作用。
将分离的近端直小管在含有去甲肾上腺素（NE）的杜氏改良 Eagle 组织培养基（DMEM）中进行肾小管周围灌注，以改善孵育条件。用荧光探针测量细胞内钠浓度（[Na⁺]i）和细胞pH值（pHi）。
在DMEM加NE中孵育时，DA可增加兔肾小管中的[Na⁺]i。钠钾ATP酶的抑制并不能解释这种反应，因为它不受哇巴因的抑制。对pHi对浴液中HCO₃⁻减少的反应分析表明，如果通过DMEM加NE孵育将其转运化学计量转换为3 HCO₃⁻:1 Na⁺，则DA、SKF 38393（一种DA1激动剂）和腺苷3',5'-环磷酸（cAMP）可抑制兔和Wistar-Kyoto大鼠（WKY）的基底外侧钠-碳酸氢根共转运体。DA的抑制作用被DA受体拮抗剂SCH 23390消除，但未被DA2拮抗剂（-）-舒必利消除。然而，在自发性高血压大鼠（SHR）中，尽管cAMP和甲状旁腺激素的抑制作用与WKY中的相当，但DA和SKF 38393未能抑制该共转运体。
这些结果表明DA可抑制肾近端小管中的钠-碳酸氢根共转运体，也提示该共转运体的失调，可能是通过DA1受体信号缺陷，在SHR高血压的发生中起重要作用。
