Sodium Pump Inhibitors In Blood Pressure Regulation

钠泵抑制剂在血压调节中的作用

• 批准号: 6969305
• 负责人: Olga V Fedorova
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6969305
• 关键词: angiotensin /renin /aldosterone hypertension; antihypertensive agents; blood pressure; cardiovascular disorder chemotherapy; dietary sodium; enzyme activity; heart failure; hypertension; laboratory rat; nonhuman therapy evaluation; nutrition related tag; ouabain; phosphatase inhibitor; preeclampsia; protein isoforms; protein kinase C; sodium chloride; sodium potassium exchanging ATPase; ventricular hypertrophy

Our previous studies demonstrated that two endogenous sodium pump ligands (SPL), endogenous ouabain (EO) and marinobufagenin (MBG), coexist in mammalian tissues. MBG acts as a selective inhibitor of ouabain resistant alpha-1 isoform of Na/K-ATPase (NKA), the main sodium pump isoform in the kidney, vascular smooth muscle and adult myocardiocytes. In Dahl salt-sensitive rats (DS), in which the defect of alpha-1 NKA underlies development of NaCl sensitive hypertension, brain EO triggers peripheral MBG, which raises the blood pressure. In vivo administration of MBG antibody to hypertensive DS lowered the blood pressure. During last year our research efforts concentrated on the studies of: (i) relationship between central and peripheral SPL during the establishment of Dahl hypertension, and (ii) pathogenetic role of MBG in preeclampsia, and (iii) changes in SPLs and their receptors, NKA isoforms, during cardiac remodeling in NaCl-sensitive hypertension. (i) Pathogenesis of NaCl sensitive hypertension. In the course of development of NaCl hypertension in DS, an initial transient rise of EO in the hippocampus and amygdala, followed by an increase in EO in the supraoptic nucleus of the hypothalamus and pituitary, stimulates pituitary angiotensin II (ATII), and, via activation of sympathetic nervous system activates renin-angiotensin system in the adrenal cortex. Adrenocortical ATII acting through AT1 receptors stimulates production of MBG. An increase in MBG production induces inhibition of the sodium pump in renal tubules and in cardiovascular tissues. The later contributes to the chronic blood pressure elevation induced by a sustained high NaCl intake. Intrahippocampal administration of low concentrations of ouabain to NaCl naive rats mimics the effects of NaCl loading, i.e. stimulates MBG production, induces natriuretic and pressor responses and sustained inhibition of renal sodium pump. These effects of central ouabain administration are prevented by peripheral administration of anti-MBG antibody. Thus, MBG, an effector of NaCl induced natriuresis and blood pressure elevation, plays a key role in the complex sequence of events, which underlies the onset of NaCl sensitive hypertension. (ii) Preeclampsia. Previously we have shown that dramatic increases in plasma MBG accompany preeclampsia. In two rat models of preeclampsia (NaCl supplementation of pregnant with and without administration of deoxycorticosterone acetate- DOCA) elevations of blood pressure are associated with sustained increases in the levels of MBG, but not that of EO. Administration of specific antibodies to MBG to pregnant hypertensive rats lowers the blood pressure and restores the activity of vascular NKA, a target enzyme for MBG. In patients with preeclampsia activity of the NKA in erythrocytes is inhibited by 40%, which is accompanied by a rise in plasma MBG levels. In vitro treatment of erythrocytes obtained from preeclamptic patients with anti-MBG antibody restored the enzyme activity to the levels observed in normal pregnancy. These findings provide further evidence that MBG is a target for therapy in preeclampsia. (iii) Left ventricular remodeling in NaCl-sensitive hypertension. On an 8% NaCl intake within 4 weeks DS develop compensated left ventricular hypertrophy, which progresses to heart failure at 8-12 weeks. The hypertrophic stage is associated with increased plasma MBG (1.22?0.22 nmol/L vs. 0.31?0.03 nmol/L; P<0.01), increased sensitivity of NKA from left ventricular sarcolemma to MBG, and an increased abundance of alpha-1 NKA. Plasma levels of EO do not change, and the sensitivity of NKA to ouabain decreases. The transition to heart failure is accompanied by a decrease in alpha-1 NKA, a reduction in plasma MBG, decreased sensitivity of NKA to MBG, increased abundance of ouabain-sensitive alpha-3 NKA, 3-fold rise in plasma EO (1.01?0.13 nmol/L vs. 0.27?0.06 nmol/L), and a 7-fold increase in ouabain sensitivity of NKA compared to control. One of the factors, which sensitizes cardiac NKA to MBG, is PKC-dependent NKA phosphorylation. Chronic administration of cicletanine, an antihypertensive compound which inhibits PKC, to NaCl loaded DS, reduces pressor response to heightened NaCl intake, reduces left ventricular weight, prevents up-regulation of alpha-1 NKA and beta 2- and delta-PKC isoforms in myocardiocytes, and desensitizes cardiac NKA to MBG. Endogenous NKA inhibitors function through differential binding to multiple NKA isoforms that are differentially expressed at different stages of hypertensive heart disease. Thus, alterations in the levels and types of NKA isoforms may alter the responsiveness to cardiovascular tissues to SPL, and the interaction of MBG and PKC on the cardiovascular NKA, i.e., PKC induced sensitization of cardiac alpha-1 NKA to MBG via its phosphorylation, is a target for therapy of hypertensive heart disease. Taken together, these findings demonstrate that MBG is an important factor in pathogenesis of hypertension, and open new pharmacological possibilities in the treatment of hypertension, including blockade of circulating MBG with a specific antibody, attenuation of NKA inhibitory effect of MBG on cardiac NKA by inhibition of PKC, and inhibition of adrenocortical MBG production by ATII receptor blockade.

我们的前期研究表明，两种内源性钠泵配体（SPL），内源性哇巴因（EO）和海蟾毒配基（MBG），在哺乳动物组织中共存。MBG作为哇巴因抗性Na/K-ATP酶（NKA）α-1亚型的选择性抑制剂，NKA是肾脏、血管平滑肌和成人心肌细胞中的主要钠泵亚型。在Dahl盐敏感大鼠（DS）中，α-1 NKA的缺陷是NaCl敏感性高血压发展的基础，脑EO触发外周MBG，从而升高血压。体内给药MBG抗体高血压DS降低血压。在过去的一年里，我们的研究工作集中在：（i）中央和外周SPL之间的关系，在建立Dahl高血压，和（ii）MBG在先兆子痫的发病机制的作用，和（iii）的变化，SPL及其受体，NKA亚型，在心脏重构NaCl敏感性高血压。 (i)NaCl敏感性高血压的发病机制 在DS中NaCl高血压的发展过程中，海马和杏仁核中EO的初始瞬时升高，随后下丘脑和垂体的视上核中EO的增加，刺激垂体血管紧张素II（ATII），并通过激活交感神经系统激活肾上腺皮质中的肾素-血管紧张素系统。肾上腺皮质ATII通过AT 1受体作用刺激MBG的产生。MBG产生的增加会诱导肾小管和心血管组织中钠泵的抑制。后者导致持续高氯化钠摄入引起的慢性血压升高。海马内施用低浓度的哇巴因至NaCl未处理大鼠模仿NaCl负荷的作用，即刺激MBG产生，诱导利钠和升压反应以及持续抑制肾钠泵。通过外周给予抗MBG抗体可预防中枢哇巴因给药的这些作用。因此，MBG，NaCl诱导的钠尿排泄和血压升高的效应器，在复杂的事件序列中起着关键作用，这是NaCl敏感性高血压发病的基础。 (ii)先兆子痫。 以前我们已经表明，血浆MBG的显着增加伴随先兆子痫。在两种先兆子痫大鼠模型中（妊娠期补充NaCl，同时给予和不给予醋酸脱氧皮质酮- DOCA），血压升高与MBG水平持续升高相关，但与EO水平无关。对妊娠高血压大鼠给予MBG特异性抗体可降低血压并恢复血管NKA（MBG的靶酶）的活性。在患有先兆子痫的患者中，红细胞中NKA的活性被抑制40%，这伴随着血浆MBG水平的升高。用抗MBG抗体体外处理先兆子痫患者的红细胞，使酶活性恢复到正常妊娠中观察到的水平。这些发现提供了进一步的证据，MBG是先兆子痫治疗的靶点。 (iii)NaCl敏感性高血压患者的左心室重构 在4周内摄入8% NaCl时，DS发生代偿性左心室肥大，在8-12周时进展为心力衰竭。肥厚期与血浆MBG（1.22？0.22 nmol/L vs. 0.31？0.03 nmol/L（P<0.01），心肌肌膜NKA对MBG的敏感性增加，α 1 NKA丰度增加。血浆EO水平没有变化，NKA对哇巴因的敏感性降低。向心力衰竭的转变伴随着α-1 NKA减少，血浆MBG减少，NKA对MBG的敏感性降低，哇巴因敏感的α-3 NKA丰度增加，血浆EO升高3倍（1.01？0.13 nmol/L vs. 0.27？0.06 nmol/L），并且与对照相比，NKA的哇巴因敏感性增加了7倍。心肌NKA对MBG敏感的因素之一是PKC依赖性NKA磷酸化。西来他宁（一种抑制PKC的抗高血压化合物）对NaCl负荷的DS长期给药，降低了对增加的NaCl摄入的升压反应，降低了左心室重量，阻止了心肌细胞中α-1 NKA和β 2-和δ-PKC亚型的上调，并使心脏NKA对MBG脱敏。内源性NKA抑制剂通过与在高血压性心脏病的不同阶段差异表达的多种NKA同种型的差异结合发挥作用。因此，NKA亚型水平和类型的改变可能会改变心血管组织对SPL的反应性，以及MBG和PKC对心血管NKA的相互作用，即，PKC通过其磷酸化诱导心脏α-1 NKA对MBG的增敏作用，是治疗高血压性心脏病的靶点。 总之，这些发现表明MBG是高血压发病机制中的重要因素，并在高血压治疗中开辟了新的药理学可能性，包括用特异性抗体阻断循环MBG，通过抑制PKC减弱MBG对心脏NKA的NKA抑制作用，以及通过ATII受体阻断抑制肾上腺皮质MBG产生。