Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224-6825, USA.
J Hypertens. 2012 Sep;30(9):1817-26. doi: 10.1097/HJH.0b013e328356399b.
Marinobufagenin (MBG) promotes natriuresis via inhibition of renotubular Na/K-ATPase (NKA) and causes vasoconstriction via inhibition of vascular NKA. Atrial natriuretic peptide (ANP), via cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG)-dependent mechanism, sensitizes renal NKA to MBG but reduces MBG-induced inhibition of vascular NKA. As aging is associated with a downregulation of cGMP/PKG signaling, we hypothesized that in older rats, ANP would not potentiate renal effects of MBG and would not oppose vascular effects of MBG.
In younger (3-month-old) and older (12-month-old) Sprague-Dawley rats, we compared SBP, natriuresis, activity of NKA in aorta and renal medulla, and levels of MBG and α-ANP at baseline and following acute NaCl loading (20%, 2.5 ml/kg, intraperitoneally), and studied modulation of MBG-induced NKA inhibition by α-ANP in vitro.
As compared with younger rats, NaCl-loaded older rats exhibited a greater MBG response, greater SBP elevation (25 vs. 10 mmHg, P < 0.01) and greater inhibition of NKA in aorta (39 vs. 7%, P < 0.01), 30% less natriuresis, and less inhibition of renal NKA (25 vs. 42%, P < 0.05) in the presence of comparable responses of α-ANP and cGMP. In aorta and kidney of older rats, the levels of PKG were reduced, the levels of phosphodiesterase-5 were increased compared with that in young rats, and α-ANP failed to modulate MBG-induced NKA inhibition.
Age-associated downregulation of cGMP/PKG-dependent signaling impairs the ability of ANP to modulate the effects of MBG on the sodium pump, which contributes to salt sensitivity.
马脲酸加压素（MBG）通过抑制肾小管钠钾-ATP 酶（NKA）促进排钠，通过抑制血管 NKA 引起血管收缩。心房利钠肽（ANP）通过环鸟苷酸单磷酸（cGMP）/蛋白激酶 G（PKG）依赖性机制使肾脏 NKA 对 MBG 敏感，但降低了 MBG 对血管 NKA 的抑制作用。由于衰老与 cGMP/PKG 信号转导下调有关，我们假设在老年大鼠中，ANP 不会增强 MBG 对肾脏的作用，也不会对抗 MBG 对血管的作用。
在年轻（3 个月大）和老年（12 个月大）的 Sprague-Dawley 大鼠中，我们比较了 SBP、排钠、主动脉和肾髓质 NKA 的活性，以及基线和急性 NaCl 负荷（20%，2.5 ml/kg，腹腔内）后 MBG 和α-ANP 的水平，并研究了α-ANP 在体外对 MBG 诱导的 NKA 抑制的调节作用。
与年轻大鼠相比，经 NaCl 负荷的老年大鼠表现出更大的 MBG 反应，更高的 SBP 升高（25 对 10 mmHg，P<0.01）和更大的主动脉 NKA 抑制（39 对 7%，P<0.01），排钠量减少 30%，肾 NKA 抑制减少（25 对 42%，P<0.05），同时α-ANP 和 cGMP 的反应相似。与年轻大鼠相比，老年大鼠的主动脉和肾脏中的 PKG 水平降低，磷酸二酯酶-5 水平升高，α-ANP 未能调节 MBG 诱导的 NKA 抑制。
年龄相关的 cGMP/PKG 依赖性信号转导下调削弱了 ANP 调节 MBG 对钠泵作用的能力，导致盐敏感性增加。
