title: 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.
authors.affiliation: EA3452 CITHEFOR Drug Targets, Formulation and Preclinical Assessment, Faculté de Pharmacie, Université de Lorraine, Nancy, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Foulquier
authors.forename: François
authors.initials: F
authors.lastname: Dupuis
authors.forename: Caroline
authors.initials: C
authors.lastname: Perrin-Sarrado
authors.forename: Katy Maguin
authors.initials: KM
authors.lastname: Gatè
authors.forename: Pierre
authors.initials: P
authors.lastname: Leroy
authors.forename: Patrick
authors.initials: P
authors.lastname: Liminana
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Atkinson
authors.forename: Christine
authors.initials: C
authors.lastname: Capdeville-Atkinson
authors.forename: Isabelle
authors.initials: I
authors.lastname: Lartaud
mesh_terms: D057911:Angiotensin Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D001160:Arterioles / Q000187:drug effects*; D001562:Benzimidazoles / Q000627:therapeutic use; D001565:Benzoates / Q000627:therapeutic use; D001713:Biphenyl Compounds; D001921:Brain / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D006973:Hypertension / Q000188:drug therapy*; D008297:Male; D008833:Microcirculation; D009130:Muscle, Smooth / Q000187:drug effects; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D010841:Pia Mater / Q000098:blood supply*; D000077205:Pioglitazone; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D044140:Receptor, Angiotensin, Type 1 / Q000737:chemistry*; D000077333:Telmisartan; D013777:Tetrazoles / Q000627:therapeutic use; D045162:Thiazolidinediones / Q000627:therapeutic use
chemical_list: D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001565:Benzoates; D001713:Biphenyl Compounds; D047495:PPAR gamma; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D045162:Thiazolidinediones; D052250:Nitric Oxide Synthase Type III; C081643:candesartan; D000077333:Telmisartan; D000077205:Pioglitazone