Büssemaker Eckhart, Popp Rüdiger, Fisslthaler Beate, Larson Christiana M, Fleming Ingrid, Busse Rudi, Brandes Ralf P
Institut für Kardiovaskuläre Physiologie, Klinikum der J.W. Goethe-Universität, Theodor-Stern-Kai 7, D-60596 Frankfurt am Main, Germany.
Hypertension. 2003 Oct;42(4):562-8. doi: 10.1161/01.HYP.0000088852.28814.E2. Epub 2003 Aug 18.
Endothelium-dependent relaxation is frequently attenuated in hypertension. We hypothesized that the contribution of the endothelium-derived hyperpolarizing factor (EDHF) to the acetylcholine (ACh)-induced, endothelium-dependent relaxation is attenuated with aging in the renal artery of spontaneously hypertensive rats (SHR) compared with age-matched Wistar-Kyoto (WKY) rats. ACh-induced, NO-mediated relaxation was identical in young (8-week-old) WKY and SHR, whereas EDHF-mediated relaxations (assessed in the presence of Nomega-nitro-l-arginine and diclofenac) were much more pronounced in SHR than WKY. KCl-induced relaxations were more pronounced in vessels from young WKY rats than from young SHR. The cytochrome P450 inhibitor sulfaphenazole significantly inhibited EDHF-mediated relaxation in vessels from young SHR but not WKY. Vessels from old (22 months) SHR exhibited a slightly reduced NO-mediated relaxation but a complete loss of EDHF-mediated responses. In contrast, aging did not affect EDHF-mediated responses in WKY. Moreover, ACh-induced hyperpolarization and resting membrane potential were decreased in old SHR but not in WKY. KCl-induced relaxation increased with age in WKY, whereas no response to KCl was recorded in arteries from aged SHR. In vessels from old WKY but not old SHR, mRNA expression of the Na-K-ATPase subunit alpha2 was increased by 2-fold compared with young animals. These data indicate that the increase in EDHF responses in renal arteries from aged WKY can be attributed to the release of K+ ions from the endothelium, whereas increased EDHF responses in renal arteries from young SHR can be attributed to a sulfaphenazole-sensitive cytochrome P450-dependent EDHF.
在内皮依赖性舒张在高血压中常常减弱。我们推测，与年龄匹配的Wistar-Kyoto（WKY）大鼠相比，自发性高血压大鼠（SHR）肾动脉中，内皮源性超极化因子（EDHF）对乙酰胆碱（ACh）诱导的内皮依赖性舒张的贡献随衰老而减弱。ACh诱导的、NO介导的舒张在年轻（8周龄）WKY和SHR中是相同的，而EDHF介导的舒张（在Nω-硝基-L-精氨酸和双氯芬酸存在下评估）在SHR中比WKY更明显。KCl诱导的舒张在年轻WKY大鼠的血管中比年轻SHR的血管更明显。细胞色素P450抑制剂磺胺苯吡唑显著抑制年轻SHR血管中EDHF介导的舒张，但不抑制WKY血管中的舒张。老年（22个月）SHR的血管表现出NO介导的舒张略有降低，但EDHF介导的反应完全丧失。相比之下，衰老不影响WKY中EDHF介导的反应。此外，ACh诱导的超极化和静息膜电位在老年SHR中降低，但在WKY中未降低。KCl诱导的舒张在WKY中随年龄增加，而老年SHR的动脉对KCl无反应。在老年WKY而非老年SHR的血管中，Na-K-ATP酶α2亚基的mRNA表达与年轻动物相比增加了2倍。这些数据表明，老年WKY肾动脉中EDHF反应的增加可归因于内皮释放K+离子，而年轻SHR肾动脉中EDHF反应的增加可归因于磺胺苯吡唑敏感的细胞色素P450依赖性EDHF。
