EA3452 CITHEFOR Drug Targets, Formulation and Preclinical Assessment, Faculté de Pharmacie, Université de Lorraine, Nancy, France.
PLoS One. 2012;7(9):e42469. doi: 10.1371/journal.pone.0042469. Epub 2012 Sep 5.
Chronic treatment with angiotensin receptor blockers is largely accepted for protecting cerebral circulation during hypertension, but beneficial effects of short-term treatments are questionable, as highlighted by the recent SCAST trial. We compared the impact of 10 days treatment with candesartan (as SCAST) versus telmisartan (previously described to reverse arteriolar remodeling, chronic treatment) on pial arterioles of spontaneously hypertensive rats (SHR). We explored whether PPAR-gamma agonist activity or AT(1) receptor blockade are involved in their differential effects. In the first study, 4-month-old male SHR were treated with telmisartan (TELMI, 2 mg/kg per day) or candesartan cilexetil (CANDE, 10 mg/kg per day) and compared to vehicle treated SHR and normotensive WKY. In a second study, SHR were treated with CANDE, pioglitazone (a PPAR-gamma agonist, PIO 2.5 mg/kg per day) or CANDE+PIO, compared to TELMI. Internal diameter of pial arterioles (ID, cranial window) was measured at baseline, during hemorrhage-induced hypotension, or following suffusion of Ang II (10(-6) mol/L) or EDTA inactivation of smooth muscle cells (passive ID). PPAR-gamma and eNOS (target gene of PPAR-gamma) mRNA were evaluated in brain microvessels. For similar antihypertensive effects, TELMI (+44% versus SHR), but not CANDE, increased baseline ID. During hemorrhage, ID in TELMI group was similar to WKY, while ID in SHR and CANDE remained lower. In the second study, TELMI (+36%, versus SHR) and CANDE+PIO (+43%) increased baseline ID, but not CANDE or PIO alone. TELMI (-66%) and CANDE+PIO (-69%), but neither CANDE nor PIO alone, decreased Ang II-induced vasoconstriction. CANDE+PIO, but not CANDE, increased passive ID. In both studies, PPAR-gamma and eNOS expressions were higher in TELMI than CANDE. Short-term treatment with TELMI, but not with CANDE, reverses narrowing of pial arteriolar ID in SHR. This may involve PPAR-gamma related mechanisms, since CANDE+PIO treatment induced similar effects, and a better blockade of AT(1) receptors.
血管紧张素受体阻滞剂的慢性治疗被广泛用于保护高血压期间的脑循环，但短期治疗的有益效果是值得怀疑的，正如最近的 SCAST 试验所强调的那样。我们比较了坎地沙坦（如 SCAST）与替米沙坦（先前被描述为逆转小动脉重塑，慢性治疗）对自发性高血压大鼠（SHR）软脑膜小动脉的 10 天治疗的影响。我们探讨了过氧化物酶体增殖物激活受体-γ激动剂活性或 AT1 受体阻断是否参与了它们的差异作用。在第一项研究中，4 月龄雄性 SHR 用替米沙坦（TELMI，每天 2mg/kg）或坎地沙坦西酯（CANDE，每天 10mg/kg）治疗，并与用载体处理的 SHR 和正常血压 WKY 进行比较。在第二项研究中，SHR 用 CANDE、吡格列酮（一种过氧化物酶体增殖物激活受体-γ激动剂，每天 2.5mg/kg）或 CANDE+PIO 治疗，并与 TELMI 进行比较。软脑膜小动脉（颅内窗）的内径（ID）在基线时、出血性低血压期间或 Ang II（10-6mol/L）灌流或 EDTA 失活平滑肌细胞（被动 ID）后进行测量。评估脑微血管中的过氧化物酶体增殖物激活受体-γ和内皮型一氧化氮合酶（过氧化物酶体增殖物激活受体-γ的靶基因）mRNA。对于类似的降压效果，TELMI（+44%与 SHR），而不是 CANDE，增加了基线 ID。在出血期间，TELMI 组的 ID 与 WKY 相似，而 SHR 和 CANDE 的 ID 仍然较低。在第二项研究中，TELMI（+36%与 SHR）和 CANDE+PIO（+43%）增加了基线 ID，但不是 CANDE 或 PIO 单独。TELMI（-66%）和 CANDE+PIO（-69%），但不是 CANDE 或 PIO 单独，减少了 Ang II 诱导的血管收缩。CANDE+PIO，但不是 CANDE，增加了被动 ID。在两项研究中，TELMI 的过氧化物酶体增殖物激活受体-γ和内皮型一氧化氮合酶表达均高于 CANDE。替米沙坦（TELMI）的短期治疗，而不是坎地沙坦（CANDE）的治疗，可逆转 SHR 软脑膜小动脉 ID 的变窄。这可能涉及过氧化物酶体增殖物激活受体-γ相关机制，因为 CANDE+PIO 治疗诱导了类似的作用，并且对 AT1 受体的阻断更好。
