title: L/N-type calcium channel blocker cilnidipine ameliorates proteinuria and inhibits the renal renin-angiotensin-aldosterone system in deoxycorticosterone acetate-salt hypertensive rats.
abstract: Cilnidipine, an N/L-type calcium channel blocker, has been reported to inhibit sympathetic nerve activity and has a greater renoprotective effect than L-type calcium channel blockers. To investigate the hypothesis that cilnidipine might ameliorate advanced hypertensive nephropathy and inhibit the renal renin-angiotensin-aldosterone system, cilnidipine (1 mg per kg per day) or amlodipine (1 mg per kg per day) was administered to uninephrectomized deoxycorticosterone (DOCA)-salt hypertensive rats (DOCA-salt) for 4 weeks by gavage. Although the blood pressure in the DOCA-salt group was higher than that of control, neither cilnidipine nor amlodipine had any effect on the increase in blood pressure in the DOCA-salt group. The DOCA (40 mg per kg per week, subcutaneously (s.c.)) and salt (1% NaCl in drinking water) treatment significantly aggravated the levels of urinary protein excretion and creatinine clearance and increased glomerulosclerosis and collagen deposition in the tubulointerstitial area of the kidney. These effects were attenuated by cilnidipine treatment. Reverse transcription-polymerase chain reaction analysis revealed that the renal expression of mRNA for collagen I/IV and transforming growth factor-β was enhanced in the DOCA-salt group and that the overexpression of these molecules was suppressed by cilnidipine. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived superoxide production in the kidney and urinary norepinephrine excretion, which were enhanced in the DOCA-salt group, were suppressed by cilnidipine. Cilnidipine also decreased the activity and expression of angiotensin-converting enzyme (ACE) and the aldosterone concentration in the renal homogenate. Although neither cilnidipine nor amlodipine had any effect on the increased blood pressure in the DOCA-salt group, these renal changes were not induced by treatment with amlodipine. In conclusion, cilnidipine inhibited renal dysfunction, sympathetic nerve activity and renal renin-angiotensin-aldosterone system in the DOCA-salt group.
authors.affiliation: Department of Clinical Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto, Japan. toba@mb.kyoto-phu.ac.jp
authors.forename: Hiroe
authors.initials: H
authors.lastname: Toba
authors.forename: Mamiko
authors.initials: M
authors.lastname: Yoshida
authors.forename: Chisato
authors.initials: C
authors.lastname: Tojo
authors.forename: Arisa
authors.initials: A
authors.lastname: Nakano
authors.forename: Yuko
authors.initials: Y
authors.lastname: Oshima
authors.forename: Yushi
authors.initials: Y
authors.lastname: Kojima
authors.forename: Kazuki
authors.initials: K
authors.lastname: Noda
authors.forename: Jiahong
authors.initials: J
authors.lastname: Wang
authors.forename: Miyuki
authors.initials: M
authors.lastname: Kobara
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Nakata
mesh_terms: D017311:Amlodipine / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use*; D020746:Calcium Channels, L-Type / Q000187:drug effects; D020864:Calcium Channels, N-Type / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D003900:Desoxycorticosterone / Q000009:adverse effects; D004095:Dihydropyridines / Q000494:pharmacology* / Q000627:therapeutic use*; D004195:Disease Models, Animal; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D011507:Proteinuria / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000502:physiology; D012965:Sodium Chloride / Q000009:adverse effects; D016212:Transforming Growth Factor beta / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020864:Calcium Channels, N-Type; D004095:Dihydropyridines; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; D016212:Transforming Growth Factor beta; D017311:Amlodipine; D003900:Desoxycorticosterone; D012965:Sodium Chloride; D003094:Collagen; C065927:cilnidipine