Maeso R, Rodrigo E, Muñoz-García R, Navarro-Cid J, Ruilope L M, Cachofeiro V, Lahera V
Department of Physiology, School of Medicine, Complutense University, Madrid, Spain.
Kidney Int Suppl. 1998 Dec;68:S30-5. doi: 10.1038/sj.ki.4490561.
In the present study we investigated the effects of losartan (10 mg/kg/day; 12 weeks) on acetylcholine (Ach) induced relaxations in isolated mesenteric vascular beds (MVB) from adult and elderly spontaneous hypertensive rats (SHR). Experiments were done in absence or presence of either the NO synthesis inhibitor, L-NAME (10(-5) mol/liter), L-NAME + indomethacin (10(-5) mol/liter) or L-NAME + indomethacin + KCl (10(-5) mol/liter), to evaluate the participation of the factors (NO, PGs and EDHF, respectively) mediating Ach-relaxations. Systolic blood pressure levels were comparable in both groups. However, urinary nitrites excretion and Ach-response was lower in elderly than in adult SHR. The presence of L-NAME and L-NAME + indomethacin only reduced Ach-relaxations in untreated elderly SHR. Further addition of KCl to the perfusion media totally blunted Ach-relaxation in both groups. The calculated participation of endothelium-derived hyperpolarizing factor (EDHF) in Ach-relaxations was higher than that of nitric oxide (NO) and prostaglandins in both groups, although the EDHF component was lower in elderly when compared to adult SHR. Losartan treatment reduced blood pressure levels and enhanced dose-related Ach-relaxations and urinary nitrites in both groups. Presence of L-NAME and L-NAME + indomethacin blunted the enhancements induced by losartan on Ach-relaxations in both adult and elderly SHR. Further addition of KCl to the perfusion media totally blunted Ach-relaxation in both groups. The calculated participation of NO in Ach-relaxations was increased by losartan in both groups. Neither EDHF or prostanoids (PGs) components were clearly affected by losartan. In conclusion, (1) diminished EDHF availability accounts for the reduced Ach-relaxations produced by aging in MVB from SHR; (2) the enhancement of Ach-relaxations produced by losartan seems to be dependent on an increased NO availability; and (3) angiotensin II via angiotensin I type 1 receptor (AT1) plays an important role in the deleterious consequences of aging on endothelial function in SHR.
在本研究中，我们调查了氯沙坦（10毫克/千克/天；12周）对成年和老年自发性高血压大鼠（SHR）离体肠系膜血管床（MVB）中乙酰胆碱（Ach）诱导的舒张作用。实验在不存在或存在一氧化氮合成抑制剂L - 精氨酸甲酯（L - NAME，10⁻⁵摩尔/升）、L - NAME + 吲哚美辛（10⁻⁵摩尔/升）或L - NAME + 吲哚美辛 + 氯化钾（10⁻⁵摩尔/升）的情况下进行，以评估介导Ach舒张作用的因素（分别为一氧化氮、前列腺素和内皮源性超极化因子（EDHF））的参与情况。两组的收缩压水平相当。然而，老年SHR的尿亚硝酸盐排泄和Ach反应低于成年SHR。L - NAME和L - NAME + 吲哚美辛的存在仅降低了未治疗老年SHR中的Ach舒张作用。向灌注介质中进一步添加氯化钾使两组中的Ach舒张作用完全消失。计算得出，两组中内皮源性超极化因子（EDHF）在Ach舒张作用中的参与度高于一氧化氮（NO）和前列腺素，尽管与成年SHR相比，老年组中EDHF成分较低。氯沙坦治疗降低了两组的血压水平，并增强了与剂量相关的Ach舒张作用和尿亚硝酸盐。L - NAME和L - NAME + 吲哚美辛的存在使氯沙坦对成年和老年SHR中Ach舒张作用的增强作用减弱。向灌注介质中进一步添加氯化钾使两组中的Ach舒张作用完全消失。氯沙坦使两组中计算得出的NO在Ach舒张作用中的参与度增加。氯沙坦对EDHF或前列腺素（PGs）成分均无明显影响。总之，（1）EDHF可用性降低是老年SHR的MVB中衰老导致Ach舒张作用降低的原因；（2）氯沙坦产生的Ach舒张作用增强似乎依赖于NO可用性增加；（3）血管紧张素II通过1型血管紧张素I受体（AT1）在衰老对SHR内皮功能的有害影响中起重要作用。
