From the Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (D.D.G., J.C.C., Z.Z., A.E.G.P., E.W., J.O.L., M.C.).
Biotechnology Center (D.D.G., J.C.C., A.C.-G., C.M.B., V.A.B.), Federal University of Paraiba, Joao Pessoa, Brazil.
Hypertension. 2019 Apr;73(4):839-848. doi: 10.1161/HYPERTENSIONAHA.118.12425.
Several experimental and clinical studies have shown that dietary nitrate supplementation can increase nitric oxide bioavailability. In the oral cavity, commensal bacteria reduce nitrate to nitrite, which is subsequently absorbed into the circulation where reduction to nitric oxide by enzymatic systems occur. Although it is well-known that boosting the nitrate-nitrite-nitric oxide pathway can improve cardiovascular, renal, and metabolic functions and that sympathoexcitation contributes to the development of the same disorders, the potential effects of dietary nitrate on sympathetic activity remain to be elucidated. In this study, we hypothesized that treatment with inorganic nitrate could prevent the increase in sympathetic nerve activity in an experimental model of Ang II (angiotensin II)-induced hypertension. Multiple in vivo approaches were combined, that is, Wistar rats orally treated with the nitric oxide synthase inhibitor L-NAME (N(G)-nitro-L-arginine methyl ester, 0.5 g/L) and implanted with subcutaneous osmotic minipump for continuous delivery of Ang II (120 ng/kg per minute; 14 days). Simultaneously, rats were supplemented with sodium nitrate (10 mmol/L) or placebo (sodium chloride; 10 mmol/L) in the drinking water. Blood pressure, heart rate, and renal sympathetic nerve activity were recorded. In placebo-treated rats, Ang II+L-NAME treatment-induced arterial hypertension, which was linked with reduced spontaneous baroreflex sensitivity and increased renal sympathetic nerve activity, as well as upregulation of ATRs (Ang II type-1 receptors) in the rostral ventrolateral medulla. Supplementation with nitrate normalized the expression of ATRs in rostral ventrolateral medulla and reduced sympathetic nerve activity, which was associated with attenuated development of hypertension. In conclusion, chronic dietary nitrate supplementation blunted the development of hypertension via mechanisms that involve reduction of sympathetic outflow.
几项实验和临床研究表明，膳食硝酸盐补充可以增加一氧化氮的生物利用度。在口腔中，共生细菌将硝酸盐还原为亚硝酸盐，然后被吸收到循环中，在循环中酶系统将亚硝酸盐还原为一氧化氮。尽管众所周知，增强硝酸盐-亚硝酸盐-一氧化氮途径可以改善心血管、肾脏和代谢功能，交感神经兴奋也会导致这些疾病的发生，但膳食硝酸盐对交感神经活性的潜在影响仍有待阐明。在这项研究中，我们假设无机硝酸盐的治疗可以预防血管紧张素 II（angiotensin II）诱导的高血压实验模型中交感神经活性的增加。我们结合了多种体内方法，即 Wistar 大鼠经口给予一氧化氮合酶抑制剂 L-NAME（N（G）-硝基-L-精氨酸甲酯，0.5 g/L），并植入皮下渗透型迷你泵以持续输送血管紧张素 II（120 ng/kg/分钟；14 天）。同时，大鼠在饮用水中补充硝酸钠（10 mmol/L）或安慰剂（氯化钠；10 mmol/L）。记录血压、心率和肾交感神经活性。在安慰剂处理的大鼠中，Ang II+L-NAME 处理引起的动脉高血压与自发性血压反射敏感性降低和肾交感神经活性增加有关，并且在延髓头端腹外侧区上调了 ATRs（血管紧张素 II 型 1 受体）。硝酸盐补充使延髓头端腹外侧区 ATRs 的表达正常化，并降低了交感神经活性，从而减轻了高血压的发展。总之，慢性膳食硝酸盐补充通过减少交感神经输出的机制减弱了高血压的发展。
