Abstract
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 AT1 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 AT1 receptors.
Highlights
Clinical studies show that chronic treatment with angiotensin II (Ang II) receptor blockers (ARBs) affords protection against cerebrovascular complications [1,2]
A chronic treatment with ARBs is largely accepted for protecting cerebral circulation during hypertension and preventing stroke, beneficial effects of short-term treatments remain questionable as highlighted by the conclusion of the recent SCAST trial [6]
A second explanation could be related to a difference in AT1 receptor blockade. As this may participate to the different effects of treatments, we studied vasoreactivity of pial arterioles to Ang II
Summary
Clinical studies show that chronic treatment with angiotensin II (Ang II) receptor blockers (ARBs) affords protection against cerebrovascular complications [1,2]. Protective actions of chronic treatment with ARBs on cerebral circulation have been extensively studied in preclinical models. A chronic treatment with ARBs is largely accepted for protecting cerebral circulation during hypertension and preventing stroke, beneficial effects of short-term treatments remain questionable as highlighted by the conclusion of the recent SCAST trial [6]. In this trial, 7 days with candesartan cilexetil (CANDE) did not improve post-stroke outcome of hypertensive patients. Short-term treatment with CANDE during the brief post-stroke period does not appear to be beneficial [6] This highlights a discrepancy between the lack of effect of ARBs after short-term treatment and the beneficial chronic effects. The present study was conducted to clarify the short-term impact of ARBs
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