title: Powerful vascular protection by combining cilnidipine with valsartan in stroke-prone, spontaneously hypertensive rats.
abstract: Cilnidipine is an L- and N-type calcium channel blocker (CCB), and amlodipine is an L-type CCB. Valsartan (10 mg kg(-1)), valsartan (10 mg kg(-1)) and amlodipine (1 mg kg(-1)), and valsartan (10 mg kg(-1)) and cilnidipine (1 mg kg(-1)) were administered once daily for 2 weeks to stroke-prone, spontaneously hypertensive rats (SHR-SPs). Blood pressure was significantly reduced by valsartan, and it was further reduced by the combination therapies. Vascular endothelial dysfunction was significantly attenuated in all therapeutic groups, and further significant attenuation was observed in the valsartan+cilnidipine-treated group, but not in the valsartan+amlodipine-treated group. Vascular nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit NOX1 gene expression was significantly attenuated in all therapeutic groups, and significantly greater attenuation was observed in the valsartan+cilnidipine-treated group than in the valsartan-treated group. Compared with the valsartan-treated group, the positive areas for 4-hydroxy-2-nonenal were significantly lower only in the valsartan+cilnidipine-treated group. Plasma renin activity was significantly augmented in the valsartan-treated group, and it was significantly attenuated in the valsartan+cilnidipine-treated group. A significant increase in the ratio of plasma angiotensin-(1-7) to angiotensin II was observed only in the valsartan+cilnidipine-treated group. Vascular angiotensin-converting enzyme (ACE) gene expression was significantly attenuated only in the valsartan+cilnidipine-treated group, but ACE2 gene expression was significantly higher in all of the therapeutic groups. Thus, valsartan and cilnidipine combination therapy might have a powerful protective effect in the vascular tissues via increases in the angiotensin-(1-7)/angiotensin II ratio in plasma.
authors.affiliation: Department of Pharmacology, Osaka Medical College, Takatsuki City, Osaka, Japan. pha010@art.osaka-med.ac.jp
authors.forename: Shinji
authors.initials: S
authors.lastname: Takai
authors.forename: Denan
authors.initials: D
authors.lastname: Jin
authors.forename: Shizuka
authors.initials: S
authors.lastname: Aritomi
authors.forename: Kazumi
authors.initials: K
authors.lastname: Niinuma
authors.forename: Mizuo
authors.initials: M
authors.lastname: Miyazaki
mesh_terms: D000447:Aldehydes / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D020746:Calcium Channels, L-Type / Q000187:drug effects; D020864:Calcium Channels, N-Type / Q000187:drug effects; D002339:Carotid Arteries / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004095:Dihydropyridines / Q000627:therapeutic use*; D006321:Heart / Q000187:drug effects; D007150:Immunohistochemistry; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009247:NADH, NADPH Oxidoreductases / Q000096:biosynthesis / Q000235:genetics; D000074624:NADPH Oxidase 1; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis / Q000235:genetics; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D060888:Real-Time Polymerase Chain Reaction; D013777:Tetrazoles / Q000627:therapeutic use*; D014633:Valine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000068756:Valsartan; D014652:Vascular Diseases / Q000209:etiology / Q000235:genetics / Q000517:prevention & control*
chemical_list: D000447:Aldehydes; D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020864:Calcium Channels, N-Type; D015853:Cysteine Proteinase Inhibitors; D004095:Dihydropyridines; D013777:Tetrazoles; D000068756:Valsartan; C065927:cilnidipine; D052250:Nitric Oxide Synthase Type III; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; C000614712:NOX1 protein, rat; D014633:Valine; C027576:4-hydroxy-2-nonenal