Jiang J, Sun C W, Alonso-Galicia M, Roman R J
Department of Physiology, Medical College of Wisconsin, Milwaukee 53226, USA.
Am J Hypertens. 1998 Oct;11(10):1222-31. doi: 10.1016/s0895-7061(98)00143-5.
We have reported that lovastatin attenuates the development of hypertension in spontaneously hypertensive rats (SHR). The fall in arterial pressure is associated with an elevation in renal medullary blood flow, normalization of the pressure-natriuresis relationship, and diminished hypertrophy of renal arterioles. However, the mechanism by which lovastatin alters renal vascular tone is unknown. The present study examined the effects of lovastatin on renal vascular tone and the expression of G proteins. Four-week-old SHR were chronically treated with lovastatin (20 mg/kg/day) or vehicle by gavage for 4 weeks. At the end of the study, mean arterial pressure averaged 131 +/- 4 (n = 5) and 160 +/- 4 mm Hg (n = 6) in lovastatin- and vehicle-treated SHR, respectively. Renal arterioles isolated from lovastatin-treated SHR were significantly less responsive to norepinephrine and vasopressin than those obtained from vehicle-treated rats (ED50: 5.0 v 1.8 x 10(-7) mol/L for norepinephrine, and 8.0 v 5.2 x 10(-10) mol/L for vasopressin). The fall in renal vascular reactivity in lovastatin-treated SHR was associated with reduced levels of ras and rho proteins in renal arterioles, whereas the expressions of heterotrimeric G proteins (Gs Gq, Gi) were similar in renal arterioles from vehicle- and lovastatin-treated SHR. Overnight culture of renal arterioles with media containing lovastatin also diminished the expression of ras and rho proteins and the response to vasoconstrictors. These findings indicate that lovastatin diminishes the response to vasoconstrictors and the expression of small G proteins in the renal vasculature of SHR and suggest that a fall in the levels of ras and rho proteins in these vessels may contribute to the antihypertensive effects of lovastatin.
我们已报道洛伐他汀可减轻自发性高血压大鼠（SHR）的高血压发展。动脉血压下降与肾髓质血流量增加、压力-利钠关系正常化以及肾小动脉肥大减轻有关。然而，洛伐他汀改变肾血管张力的机制尚不清楚。本研究检测了洛伐他汀对肾血管张力和G蛋白表达的影响。4周龄的SHR通过灌胃长期接受洛伐他汀（20mg/kg/天）或溶剂处理4周。在研究结束时，洛伐他汀处理组和溶剂处理组SHR的平均动脉压分别平均为131±4（n = 5）和160±4mmHg（n = 6）。与溶剂处理大鼠分离的肾小动脉相比，洛伐他汀处理的SHR分离的肾小动脉对去甲肾上腺素和血管加压素的反应明显降低（去甲肾上腺素的ED50：5.0对1.8×10⁻⁷mol/L，血管加压素的ED50：8.0对5.2×10⁻¹⁰mol/L）。洛伐他汀处理的SHR肾血管反应性下降与肾小动脉中ras和rho蛋白水平降低有关，而在溶剂处理和洛伐他汀处理的SHR的肾小动脉中，异源三聚体G蛋白（Gs、Gq、Gi）的表达相似。用含洛伐他汀的培养基对肾小动脉进行过夜培养也降低了ras和rho蛋白的表达以及对血管收缩剂的反应。这些发现表明，洛伐他汀可降低SHR肾血管系统对血管收缩剂的反应以及小G蛋白的表达，并提示这些血管中ras和rho蛋白水平的下降可能有助于洛伐他汀的降压作用。
