Zicha Josef, Behuliak Michal, Vavřínová Anna, Dobešová Zdenka, Kuneš Jaroslav, Rauchová Hana, Vaněčková Ivana
Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic.
Hypertens Res. 2021 Sep;44(9):1067-1078. doi: 10.1038/s41440-021-00659-5. Epub 2021 Apr 19.
Salt hypertensive Dahl rats are characterized by sympathoexcitation and relative NO deficiency. We tested the hypothesis that the increased blood pressure (BP) response to fasudil in salt hypertensive Dahl rats is due to augmented calcium sensitization in the salt-sensitive strain and/or due to their decreased baroreflex efficiency. BP reduction after acute administration of nifedipine (an L-type voltage-dependent calcium channel blocker) or fasudil (a Rho kinase inhibitor) was studied in conscious intact rats and in rats subjected to acute NO synthase inhibition or combined blockade of the renin-angiotensin system (captopril), sympathetic nervous system (pentolinium), and NO synthase (L-NAME). Intact salt-sensitive (SS) Dahl rats fed a low-salt diet had greater BP responses to nifedipine (-31 ± 6 mmHg) or fasudil (-34 ± 7 mmHg) than salt-resistant (SR) Dahl rats (-16 ± 4 and -17 ± 2 mmHg, respectively), and a high-salt intake augmented the BP response only in SS rats. These BP responses were doubled after acute NO synthase inhibition, indicating that endogenous NO attenuates both calcium entry and calcium sensitization. Additional pentolinium administration, which minimized sympathetic compensation for the drug-induced BP reduction, magnified the BP responses to nifedipine or fasudil in all groups except for salt hypertensive SS rats due to their lower baroreflex efficiency. The BP response to the calcium channel blocker nifedipine can distinguish SS and SR rats even after calcium sensitization inhibition by fasudil, which was not seen when fasudil was administered to nifedipine-pretreated rats. Thus, enhanced calcium entry (potentiated by sympathoexcitation) in salt hypertensive Dahl rats is the abnormality that is essential for their BP increase, which was further augmented by increased calcium sensitization in salt-sensitive Dahl rats.
盐敏感性高血压 Dahl 大鼠的特征是交感神经兴奋和相对一氧化氮缺乏。我们检验了以下假设：盐敏感性高血压 Dahl 大鼠对法舒地尔的血压（BP）反应增强是由于盐敏感品系中钙敏化增强和/或由于其压力反射效率降低。在清醒的完整大鼠以及接受急性一氧化氮合酶抑制或肾素 - 血管紧张素系统（卡托普利）、交感神经系统（潘托铵）和一氧化氮合酶（L - 精氨酸甲酯）联合阻断的大鼠中，研究了急性给予硝苯地平（一种 L 型电压依赖性钙通道阻滞剂）或法舒地尔（一种 Rho 激酶抑制剂）后的血压降低情况。喂食低钠饮食的完整盐敏感（SS）Dahl 大鼠对硝苯地平（-31±6 mmHg）或法舒地尔（-34±7 mmHg）的血压反应比盐抵抗（SR）Dahl 大鼠（分别为 -16±4 和 -17±2 mmHg）更大，高盐摄入仅增强了 SS 大鼠的血压反应。急性一氧化氮合酶抑制后，这些血压反应增加了一倍，表明内源性一氧化氮可减弱钙内流和钙敏化。额外给予潘托铵可最大程度减少交感神经对药物诱导的血压降低的代偿，在除盐敏感性高血压 SS 大鼠外的所有组中，由于其较低的压力反射效率，放大了对硝苯地平或法舒地尔的血压反应。即使在法舒地尔抑制钙敏化后，对钙通道阻滞剂硝苯地平的血压反应仍可区分 SS 和 SR 大鼠，而当法舒地尔给予预先用硝苯地平处理的大鼠时则未观察到这种情况。因此，盐敏感性高血压 Dahl 大鼠中增强的钙内流（由交感神经兴奋增强）是其血压升高所必需的异常情况，盐敏感性 Dahl 大鼠中钙敏化增加进一步加剧了这种情况。
