Differential Effects of Short-Term Treatment with Two AT1 Receptor Blockers on Diameter of Pial Arterioles in SHR

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.

Impact of Short-Term Treatment with Telmisartan on Cerebral Arterial Remodeling in SHR

“…Narrowing of ID of MCA and pial arterioles in SHR is mainly due to structural remodeling (decrease in passive ID) [13] , with no changes in vasomotion nor myogenic tone (present results) [2] , [3] , [10] . This contributes to the increase in cerebrovascular resistance and to the rightward shift of the limits of cerebral blood flow autoregulation, protecting the brain against higher blood pressure during hypertension.…”

“…The present study and the corresponding treatments of the animals have been performed before February 8, 2013, starting date for the application of the european directive 2010/63/EU in France. The procedures were similar to those described in our previous study [10] , in our personal agreements and in a project approved by the regional ethic committee (CELMEA, agreement number CELMEA-2013-0008). The personal permit numbers for animal experimentation (I. Lartaud permit number n° 54-5, F. Dupuis n° 54-105) have been approved by the French Ministry of Agriculture, Paris, France.…”

“…The rats used in the present study had the same age, and TELMI was given orally at the same dose (2 mg/kg/day) and duration (10 days) than in our previous study on small pial arterioles [10] . In total 58 rats were used in this study.…”

“…The experiments were conducted on 4 to 5-month-old male SHR and normotensive Wistar-Kyoto rats (Janvier, Le Genest-Saint-Isles, France). SHR were treated for 10 days by TELMI (2 mg/kg per day, group SHR + TELMI, n = 17 in total) dissolved in drinking water containing mannitol 8.10 −4 mol/L + NaOH 6.10 −5 mol/L [2] , [3] , [10] . Control SHR (group SHR, n = 21 in total) and WKY (group WKY, n = 20 in total) received drinking water with solvents for TELMI.…”

“…As we previously showed that 10 days treatment with telmisartan (TELMI) - but not candesartan - reverses the narrowing of pial arteriolar ID in spontaneously hypertensive rats (SHR), via reversal of structural remodeling and inhibition of the angiotensin II (AngII) vasoconstrictor response [10] , we therefore further investigated the early therapeutic impact of TELMI on cerebral circulation.…”