Aryal Dinesh, Roy Tithi, Chamcheu Jean Christopher, Jackson Keith E
School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, USA.
Department of Biomedical Affairs, Edward Via College of Osteopathic Medicine, Monroe, LA 71203, USA.
Antioxidants (Basel). 2020 Dec 22;10(1):2. doi: 10.3390/antiox10010002.
Chronic metabolic acidosis (CMA) can be a consequence of persistent hypertension but could potentially play a role in invoking hypertension. Currently, there is a scarcity of studies examining the outcome of induced chronic acidosis on blood pressure regulation. This study investigates CMA as a cause of hypertension. Chronic acidosis was induced in Sprague Dawley rats (100-150 g) by providing a weak acid solution of 0.28 M ammonium chloride (NHCl) in tap water for 8 weeks. To determine whether the rats were acidotic, blood pH was measured, while blood pressure (BP) was monitored by tail-cuff plethysmography weekly. Rats were divided into five groups: control, CMA, CMA ± spironolactone, captopril, and tempol. Serum sodium and potassium; renal interstitial fluid (for Angiotensin II concentration); and kidney proximal tubules (for Na/K ATPase- α1 concentration) were analyzed. Reactive oxygen species (ROS) were detected in renal cortical homogenates using electron paramagnetic resonance (EPR). In the CMA rats, a sustained elevation in mean arterial pressure (MAP) associated with a significant decrease in blood pH was observed compared to that of control over the 8 weeks. A significant decrease in MAP was observed in acidotic rats treated with captopril/tempol, whereas spironolactone treatment caused no decrease in MAP as compared to that of the CMA group. The interstitial angiotensin II was increased in the CMA group but decreased in the CMA with captopril and tempol groups. In addition, the urinary sodium was decreased, and the serum sodium levels increased significantly in the CMA groups as compared to that of control. However, the acidotic groups with captopril and tempol showed reduced levels of serum sodium and an elevation in urinary sodium as compared to that of the CMA group. In addition, there was a significant increase in plasma renin and no change in plasma aldosterone in the CMA group with no significant differences in plasma renin or aldosterone observed during spironolactone, captopril, or tempol treatments. The increased expression of Na/K ATPase-α1 in the CMA group suggests that active transport of Na to the blood could be causative of the observed hypertension. Furthermore, the EPR analysis confirmed an elevation in superoxide (O) radical levels in the CMA group, but the tempol/captopril treated acidotic groups showed less (O) compared to that of either the CMA group or control. Taken together, our data suggest that induction of CMA could potentially be causative of hypertension, while the mechanisms underlying the increased BP could be through the activation of intrarenal Ang II and induction of oxidative stress.
慢性代谢性酸中毒（CMA）可能是持续性高血压的结果，但也可能在引发高血压方面发挥作用。目前，研究诱导性慢性酸中毒对血压调节影响的研究较少。本研究调查CMA是否为高血压的一个病因。通过在自来水中提供0.28M氯化铵（NH₄Cl）的弱酸溶液8周，诱导Sprague Dawley大鼠（100 - 150克）发生慢性酸中毒。为了确定大鼠是否发生酸中毒，测量血液pH值，同时每周通过尾袖体积描记法监测血压（BP）。大鼠分为五组：对照组、CMA组、CMA ± 螺内酯组、卡托普利组和Tempol组。分析血清钠和钾；肾间质液（用于检测血管紧张素II浓度）；以及肾近端小管（用于检测Na/K ATP酶-α1浓度）。使用电子顺磁共振（EPR）在肾皮质匀浆中检测活性氧（ROS）。与对照组相比，在8周内，CMA大鼠平均动脉压（MAP）持续升高，同时血液pH值显著降低。用卡托普利/Tempol治疗的酸中毒大鼠MAP显著降低，而与CMA组相比，螺内酯治疗未使MAP降低。CMA组肾间质血管紧张素II增加，但卡托普利和Tempol治疗的CMA组则降低。此外，与对照组相比，CMA组尿钠减少，血清钠水平显著升高。然而，与CMA组相比，卡托普利和Tempol治疗的酸中毒组血清钠水平降低，尿钠升高。此外，CMA组血浆肾素显著增加，血浆醛固酮无变化，在螺内酯、卡托普利或Tempol治疗期间，血浆肾素或醛固酮无显著差异。CMA组中Na/K ATP酶-α1表达增加表明，钠向血液的主动转运可能是观察到的高血压的原因。此外，EPR分析证实CMA组超氧阴离子（O₂⁻）自由基水平升高，但与CMA组或对照组相比，Tempol/卡托普利治疗的酸中毒组超氧阴离子（O₂⁻）较少。综上所述，我们的数据表明，诱导CMA可能是高血压的潜在病因，而血压升高的潜在机制可能是通过激活肾内血管紧张素II和诱导氧化应激。
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