Nothofagin is a natural 3′-C-β-D-glucoside of the polyphenol phloretin that is mainly found in Aspalathus linearis, Nothofagus fusca, and Leandra dasytricha. In recent years, nothofagin has been described as a potential therapeutic agent for renal disorders, but the mechanisms that are involved in its renoprotective effects remain unclear. In the present study, perfused rat kidneys were used to test the hypothesis that nothofagin causes the direct relaxation of renal arteries. The molecular mechanisms that underlie these vascular effects were also investigated. The left kidney from Wistar rats was coupled in a perfusion system and continuously perfused with physiological saline solution (PSS). Initially, preparations with and without the endothelium were contracted with phenylephrine and received injections of 1–300 nmol nothofagin. The preparations were then perfused with PSS that contained phenylephrine plus KCl, indomethacin, l-NAME, tetraethylammonium, glibenclamide, 4-aminopyridine, iberiotoxin, charybdotoxin, and apamin. After 15 min under perfusion, nothofagin was injected again. In preparations with an intact endothelium, nothofagin dose-dependently reduced perfusion pressure. Endothelium removal or the inhibition of nitric oxide synthase by l-NAME prevented the vasodilatory effect of nothofagin at all doses tested. Perfusion with PSS that contained KCl or tetraethylammonium chloride also abolished the vasodilatory effect of nothofagin. Treatment with glibenclamide, 4-aminopyridine, and apamin did not affect the vasodilatory effect of nothofagin. Iberiotoxin (selective Ca²⁺-activated high-conductance K⁺ channel [KCa1.1] blocker) and charybdotoxin (selective KCa1.1 and Ca²⁺-activated intermediate-conductance K⁺ channel [KCa3.1] blocker) application blocked the vasodilatory effect of nothofagin at all doses tested, pointing to a predominant role for KCa1.1 in the action of nothofagin. However, these data cannot exclude a potential contribution of endothelial KCa3.1 channel in the nothofagin-induced vasodilation. Overall, our findings indicate that nothofagin induces vasodilation in renal arteries, an effect that is mediated by Ca²⁺ -activated high-conductance K⁺ channels opening and endothelial nitric oxide production.

Nothofagin是多酚Phoreretin的天然3'- C -β-D-葡萄糖苷，主要存在于线性天冬氨酸（Aspalathus linearis），Nothofagus fusca和Leandra dasytricha中。近年来，nothofagin被描述为一种潜在的肾脏疾病治疗剂，但其肾脏保护作用涉及的机制仍不清楚。在本研究中，使用灌注的大鼠肾脏来检验Nothofagin引起肾动脉直接松弛的假说。还研究了这些血管作用基础的分子机制。Wistar大鼠的左肾在灌注系统中耦合，并连续注入生理盐水溶液（PSS）。最初，将有和没有内皮的制剂与去氧肾上腺素收缩，并注射1-300 nmol nothofagin。该制剂然后用PSS灌注含有苯加氯化钾，吲哚美辛，升-NAME，四乙铵，格列本脲，4-氨基吡啶，埃博毒素，炭疽毒素和Apapamin。在灌注下15分钟后，再次注射诺夫肝素。在具有完整内皮的制剂中，Nothofagin剂量依赖性降低灌注压力。1- NAME对内皮的去除或一氧化氮合酶的抑制在所有测试剂量下均阻止了诺法沙星的血管舒张作用。PSS包含KCl或四乙基氯化铵的灌注也消除了nothofagin的血管舒张作用。用格列本脲，4-氨基吡啶和阿帕明治疗不影响Nothofagin的血管舒张作用。伊贝毒素（选择性Ca ²⁺激活的高电导K ⁺通道[KCa1.1]阻滞剂）和炭疽毒素（选择性KCa1.1和Ca²⁺激活的中间电导K ⁺通道[KCa3.1]阻滞剂）在所有测试剂量下均阻断了nothofagin的血管舒张作用，表明KCa1.1在nothofagin作用中起主要作用。然而，这些数据不能排除内皮霍卡因诱导的血管舒张中内皮KCa3.1通道的潜在作用。总体而言，我们的发现表明，三叶红素可诱导肾动脉血管舒张，其作用是由Ca ²⁺激活的高电导K ⁺通道开放和内皮一氧化氮产生的。