title: Calcium channel blocker enhances beneficial effects of an angiotensin II AT1 receptor blocker against cerebrovascular-renal injury in type 2 diabetic mice.
abstract: Recent clinical trials have demonstrated that combination therapy with renin-angiotensin system inhibitors plus calcium channel blockers (CCBs) elicits beneficial effects on cardiovascular and renal events in hypertensive patients with high cardiovascular risks. In the present study, we hypothesized that CCB enhances the protective effects of an angiotensin II type 1 receptor blocker (ARB) against diabetic cerebrovascular-renal injury. Saline-drinking type 2 diabetic KK-A(y) mice developed hypertension and exhibited impaired cognitive function, blood-brain barrier (BBB) disruption, albuminuria, glomerular sclerosis and podocyte injury. These brain and renal injuries were associated with increased gene expression of NADPH oxidase components, NADPH oxidase activity and oxidative stress in brain and kidney tissues as well as systemic oxidative stress. Treatment with the ARB, olmesartan (10 mg/kg/day) reduced blood pressure in saline-drinking KK-A(y) mice and attenuated cognitive decline, BBB disruption, glomerular injury and albuminuria, which were associated with a reduction of NADPH oxidase activity and oxidative stress in brain and kidney tissues as well as systemic oxidative stress. Furthermore, a suppressive dose of azelnidipine (3 mg/kg/day) exaggerated these beneficial effects of olmesartan. These data support the hypothesis that a CCB enhances ARB-associated cerebrovascular-renal protective effects through suppression of NADPH oxidase-dependent oxidative stress in type 2 diabetes.
authors: Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors: Kazi
authors: K
authors: Rafiq
authors: Shamshad J
authors: SJ
authors: Sherajee
authors: Hirofumi
authors: H
authors: Hitomi
authors: Daisuke
authors: D
authors: Nakano
authors: Hiroyuki
authors: H
authors: Kobori
authors: Koji
authors: K
authors: Ohmori
authors: Hirohito
authors: H
authors: Mori
authors: Hideki
authors: H
authors: Kobara
authors: Tsutomu
authors: T
authors: Masaki
authors: Masakazu
authors: M
authors: Kohno
authors: Akira
authors: A
authors: Nishiyama
mesh_terms: D057911:Angiotensin Receptor Antagonists / Q000819:agonists / Q000494:pharmacology*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000473:pathology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002561:Cerebrovascular Disorders / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004357:Drug Synergism; D015971:Gene Expression Regulation, Enzymologic; D051379:Mice; D019255:NADPH Oxidases / Q000096:biosynthesis / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics
chemical_list: D057911:Angiotensin Receptor Antagonists; D002121:Calcium Channel Blockers; D019255:NADPH Oxidases