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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 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.

SUBMITTER: Foulquier S

PROVIDER: S-EPMC3434186 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Differential effects of short-term treatment with two AT1 receptor blockers on diameter of pial arterioles in SHR.

Foulquier Sébastien S Dupuis François F Perrin-Sarrado Caroline C Gatè Katy Maguin KM Leroy Pierre P Liminana Patrick P Atkinson Jeffrey J Capdeville-Atkinson Christine C Lartaud Isabelle I

PloS one 20120905 9

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 agon ...[more]

PMID: 22957022

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Project description:BackgroundPrior work suggests that some but not all antihypertensive treatments may benefit cognition and risk for Alzheimer's disease, independent of stroke. Angiotensin II receptor blockers (ARBs) have been highlighted as one antihypertensive drug class that may confer greatest benefit.MethodsThe participants comprised 1626 nondemented adults, aged 55-91 years, recruited from Alzheimer's Disease Neuroimaging Initiative sites. Three groups were compared: ARB users (HTN-ARBs), other antihypertensive drug users (HTN-Other), and normotensives. In post hoc analyses, we also examined (1) users of ARBs and angiotensin-converting enzyme inhibitors (ACEIs), (2) users of blood-brain barrier (BBB)-crossing ARBs and users of non-BBB-crossing ARBs, and (3) users of BBB-crossing ARBs and ACEIs (BBB crossers) and users of non-BBB-crossing ARBs and ACEIs (BBB noncrossers). Groups were compared regarding cognition and magnetic resonance imaging measures of brain volume and white matter hyperintensities (WMH), using analysis of covariance and multilevel models.ResultsAt baseline, the HTN-Other group performed worse than normotensives on Rey Auditory Verbal Learning Test (RAVLT) Immediate Recall (p?=?0.002), Delayed Recall (p?<?0.001), Recognition Memory (p?=?0.001), and Trails A (p?<?0.001) and B (p?=?0.01). ARB users performed better than the HTN-Other group on Recognition Memory (p?=?0.04) and worse than normotensives on Trails A (p?=?0.04). The HTN-Other group performed worse than normotensives on Logical Memory Immediate (p?=?0.02) and Delayed Recall over the 3-year follow-up (p?=?0.007). Over the follow-up period, those taking BBB-crossing ARBs performed better than the HTN-Other group on AVLT Delayed Recall (p?=?0.04), Logical Memory Immediate (p?=?0.02), and Delayed Recall (p?=?0.05). They also had fewer WMH than the HTN-Other group (p?=?0.008) and those taking non-BBB-crossing ARBs (p?=?0.05). There were no group differences in brain volume. Users of BBB-crossing medications (ARBs or ACEIs) showed better performance on AVLT Delayed Recall over time than all other groups, including normotensives (all p?<?0.01), and had less WMH volume over time than the BBB noncrossers group (p?=?0.03), although they had more WMH volume than normotensives (p?=?0.01). The BBB noncrossers group performed worse than normotensives on Logical Memory Delayed Recall over time (p?=?0.01), but the BBB crossers group was not significantly different (p?=?0.13).ConclusionsHypertensive participants demonstrated worse baseline memory and executive function, as well as greater memory decline, over the 3-year follow-up than normotensives, unless they were ARB users, who showed preserved memory compared with those taking other antihypertensive drugs. Users of BBB-crossing ARBs showed superior memory performance over time compared with other antihypertensive drug users and had less WMH volume. Users of BBB-crossing medications (ARBs or ACEIs) showed better list-learning memory performance over time than all other groups, including normotensives, and had less WMH volume over time than users of non-BBB-crossing medications. These findings demonstrate that ARBs, especially those of the BBB-crossing variety, are associated with greater memory preservation and less WMH volume than other antihypertensive medications.

Dataset Information

Differential effects of short-term treatment with two AT1 receptor blockers on diameter of pial arterioles in SHR.

Publications

Differential effects of short-term treatment with two AT1 receptor blockers on diameter of pial arterioles in SHR.

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