de P Rodrigues Stephen F, dos Santos Rosangela A, Silva-Antonialli Michelle M, Scavone Cristóforo, Nigro Dorothy, Carvalho Maria Helena C, de Cássia Tostes Rita, Fortes Zuleica B
Laboratory of Hypertension, Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Brazil.
Life Sci. 2006 Apr 4;78(19):2280-5. doi: 10.1016/j.lfs.2005.09.049. Epub 2005 Dec 6.
We demonstrated that the decreased response to acetylcholine observed in aorta of male and female spontaneously hypertensive rats is corrected after sustained (15 days) reduction of blood pressure levels by losartan. In order to verify if the same occurs in resistance vessels, vascular diameter changes induced by topical application of acetylcholine and bradykinin (endothelium-dependent vasodilators) and sodium nitroprusside (endothelium-independent vasodilator) to mesenteric arterioles studied in vivo, in situ were determined in rats treated with losartan for 24 h (acute) or 15 days (chronic). Rats that presented similar reduction (in %) of the blood pressure levels after losartan treatment were chosen. Sodium nitroprusside induced similar responses in losartan-treated and untreated male or female SHR. Whereas in female SHR, losartan corrected the diminished arteriolar response to endothelium-dependent vasodilators after acute and chronic treatment, in male SHR this correction only occurred after chronic treatment. Thus, losartan corrected the endothelial dysfunction more easily in female than in male SHR and independently of the normalization or the magnitude of the reduction of the blood pressure levels. In an attempt to explain the difference, we evaluated the losartan effect on nitric-oxide synthase (NOS) activity and angiotensin II AT1 and AT2 receptor gene expression in these animals. In male and female SHR, NOS activity and AT1 receptor expression were not altered by acute or chronic treatment. On the other hand, AT2 receptor expression was augmented only in female SHR by these treatments. Therefore, augmented AT2 receptor expression, but not alteration of NOS activity or AT1 receptor expression, might explain the difference observed.
我们证明，在雄性和雌性自发性高血压大鼠的主动脉中观察到的对乙酰胆碱反应性降低，在通过氯沙坦持续（15天）降低血压水平后得到纠正。为了验证在阻力血管中是否也会发生同样的情况，在体内原位研究了用氯沙坦治疗24小时（急性）或15天（慢性）的大鼠肠系膜小动脉，通过局部应用乙酰胆碱和缓激肽（内皮依赖性血管舒张剂）以及硝普钠（非内皮依赖性血管舒张剂）来测定血管直径变化。选择氯沙坦治疗后血压水平降低百分比相似的大鼠。硝普钠在氯沙坦治疗和未治疗的雄性或雌性自发性高血压大鼠中诱导相似的反应。在雌性自发性高血压大鼠中，氯沙坦在急性和慢性治疗后纠正了小动脉对内皮依赖性血管舒张剂反应的减弱，而在雄性自发性高血压大鼠中，这种纠正仅在慢性治疗后发生。因此，氯沙坦在雌性自发性高血压大鼠中比在雄性中更容易纠正内皮功能障碍，且与血压水平的正常化或降低幅度无关。为了解释这种差异，我们评估了氯沙坦对这些动物一氧化氮合酶（NOS）活性以及血管紧张素II AT1和AT2受体基因表达的影响。在雄性和雌性自发性高血压大鼠中，急性或慢性治疗均未改变NOS活性和AT1受体表达。另一方面，这些治疗仅在雌性自发性高血压大鼠中增强了AT2受体表达。因此，AT2受体表达的增强而非NOS活性或AT1受体表达的改变，可能解释了观察到的差异。
