Baumann Marcus, Megens Remco, Bartholome Roger, Dolff Sebastian, van Zandvoort Marc A J M, Smits Jos F M, Struijker-Boudier Harry A J, De Mey Jo G R
Department of Pharmacology and Toxicology, Cardiovascular Research Institute Maastricht (CARIM), University Maastricht, Maastricht, The Netherlands.
Hypertens Res. 2007 Sep;30(9):853-61. doi: 10.1291/hypres.30.853.
Arterial function after long-term hypertension is characterized by remodeling, endothelial dysfunction and reduction of previously enhanced contractile responses. We investigated whether transient prehypertensive renin-angiotensin-aldosterone system (RAAS) blockade modifies long-term arterial function. Wistar Kyoto rats (WKY) (i) and spontaneously hypertensive rats (SHR) (ii) were prehypertensively (week 4-8) treated with losartan (iii) or spironolactone (iv) (20 and 0.5 mg/kg/day, respectively) and investigated at 8 and 72 weeks of age. Systolic blood pressure (SBP) was measured intra-arterially. In isolated mesenteric arteries, active wall stress (AWS), relaxation in response to acetylcholine and wall-to-lumen ratio (W/L) were assessed. Western blotting and immunofluorescent staining of whole-mount arterial preparations and two photon laser scanning microscopy (TPLSM) were performed to quantify endothelial nitric oxide synthase (eNOS) and analyze its intracellular distribution. In 8-week-old SHR treatments were found to have reduced SBP. Relaxation, contractile responses and vascular morphology remained unaffected irrespective of treatment. At 72 weeks, SBP was similar in all SHR groups ((i) 129+/-6, (ii) 222 +/- 10, (iii) 210 +/- 16, (iv) 214 +/- 9 mmHg). Relaxation and maximum AWS were enhanced after treatments. W/L demonstrated hypertrophy ((i) 0.10 +/- 0.01, (ii) 0.16 +/- 0.02, (iii) 0.15 +/- 0.01, (iv) 0.17 +/- 0.01). Untreated SHR (p<0.01), SHR treated with losartan and SHR treated with spironolactone (p<0.05) showed less eNOS as compared to WKY. In treated SHR eNOS was concentrated in a perinuclear endothelial cell compartment. In conclusion, these findings demonstrate that transient prehypertensive blockade results in a long-lasting and blood pressure independent improvement of arterial contractility and endothelium-dependent vasodilatation that persists in aging SHR. This might be associated with an intracellular redistribution of eNOS in the endothelial cell layer.
长期高血压后的动脉功能表现为重塑、内皮功能障碍以及先前增强的收缩反应减弱。我们研究了短暂的高血压前期肾素 - 血管紧张素 - 醛固酮系统（RAAS）阻断是否会改变长期动脉功能。将Wistar Kyoto大鼠（WKY）（i）和自发性高血压大鼠（SHR）（ii）在高血压前期（第4 - 8周）分别用氯沙坦（iii）或螺内酯（iv）（分别为20和0.5 mg/kg/天）进行治疗，并在8周龄和72周龄时进行研究。通过动脉内测量收缩压（SBP）。在离体肠系膜动脉中，评估主动壁应力（AWS）、对乙酰胆碱的舒张反应以及壁腔比（W/L）。对整个动脉制剂进行蛋白质印迹和免疫荧光染色，并进行双光子激光扫描显微镜（TPLSM）以定量内皮型一氧化氮合酶（eNOS）并分析其细胞内分布。在8周龄的SHR中，发现治疗可降低SBP。无论治疗如何，舒张反应、收缩反应和血管形态均未受影响。在72周时，所有SHR组的SBP相似（（i）129±6，（ii）222±10，（iii）210±16，（iv）214±9 mmHg）。治疗后舒张反应和最大AWS增强。W/L显示肥大（（i）0.10±0.01，（ii）0.16±0.02，（iii）0.15±0.01，（iv）0.17±0.01）。与WKY相比，未治疗的SHR（p<0.01）、用氯沙坦治疗的SHR和用螺内酯治疗的SHR（p<0.05）显示eNOS较少。在治疗的SHR中，eNOS集中在核周内皮细胞区室。总之，这些发现表明短暂的高血压前期阻断导致动脉收缩性和内皮依赖性血管舒张的长期且与血压无关的改善，这种改善在衰老的SHR中持续存在。这可能与内皮细胞层中eNOS的细胞内重新分布有关。
