title: Comparative effects of valsartan in combination with cilnidipine or amlodipine on cardiac remodeling and diastolic dysfunction in Dahl salt-sensitive rats.
abstract: Angiotensin receptor blockers (ARBs) are often supplemented with calcium channel blockers (CCBs) for treatment of hypertension. We recently showed that the L/N-type CCB cilnidipine has superior cardioprotective effects compared with the L-type CCB amlodipine in Dahl salt-sensitive (DS) rats. We have now compared the effects of the ARB valsartan combined with cilnidipine or amlodipine on cardiac pathophysiology in DS rats. DS rats fed a high-salt diet from 6 weeks of age were treated with vehicle, valsartan alone (10 mg kg(-1) per day), or valsartan combined with either cilnidipine (1 mg kg(-1) per day) or amlodipine (1 mg kg(-1) per day) from 7 to 11 weeks. The salt-induced increase in systolic blood pressure apparent in the vehicle group was attenuated similarly in the three drug treatment groups. Valsartan-cilnidipine attenuated left ventricular (LV) fibrosis and diastolic dysfunction as well as cardiac oxidative stress and inflammation to a greater extent than did valsartan alone or valsartan-amlodipine. In addition, the increases in urinary excretion of dopamine and epinephrine as well as in cardiac renin-angiotensin-aldosterone-system (RAAS) gene expression apparent in vehicle-treated rats were attenuated to a greater extent by valsartan-cilnidipine than by the other two treatments. Valsartan-cilnidipine thus attenuated LV remodeling and diastolic dysfunction more effectively than did valsartan or valsartan-amlodipine in rats with salt-sensitive hypertension, and this superior cardioprotective action of valsartan-cilnidipine compared with valsartan-amlodipine is likely attributable, at least in part, to the greater antioxidant and antiinflammatory effects associated with both greater inhibition of cardiac RAAS gene expression and N-type calcium channel blockade.
authors.affiliation: Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Kai
authors.initials: K
authors.lastname: Nagasawa
authors.affiliation: Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Natsumi
authors.initials: N
authors.lastname: Matsuura
authors.affiliation: Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Miwa
authors.initials: M
authors.lastname: Takatsu
authors.affiliation: Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Hattori
authors.affiliation: Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: Pharmacology Research Laboratory, Research Institute, Ajinomoto Pharmaceuticals Co., Ltd., Kawasaki, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Harada
authors.affiliation: Pharmacology Research Laboratory, Research Institute, Ajinomoto Pharmaceuticals Co., Ltd., Kawasaki, Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Niinuma
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
authors.affiliation: Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Kohzo
authors.initials: K
authors.lastname: Nagata
mesh_terms: D017311:Amlodipine / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004095:Dihydropyridines / Q000494:pharmacology / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D006321:Heart / Q000187:drug effects*; D006973:Hypertension / Q000188:drug therapy*; D017379:Hypertrophy, Left Ventricular / Q000517:prevention & control; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D020303:Rats, Inbred Dahl; D012084:Renin-Angiotensin System; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000068756:Valsartan; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D000959:Antihypertensive Agents; D004095:Dihydropyridines; D013777:Tetrazoles; D017311:Amlodipine; D000068756:Valsartan; C065927:cilnidipine; D014633:Valine