Combination therapy with irbesartan and efonidipine for attenuation of proteinuria in Dahl salt-sensitive rats.
Angiotensin receptor blockers (ARBs) or T- and L-type calcium channel blockers (CCBs) are useful for glomerular protection; however, the protective effects of combination therapy remain unclear. In this study, Dahl salt-sensitive rats were fed a high-salt diet and were treated daily with placebo, irbesartan (60 mg kg(-1)), efonidipine (30 mg kg(-1)), irbesartan (60 mg kg(-1))+efonidipine (30 mg kg(-1)), amlodipine (3 mg kg(-1)), or irbesartan (60 mg kg(-1))+amlodipine (3 mg kg(-1)) for 4 weeks. Significant reductions in systolic blood pressure were seen in the irbesartan-, efonidipine- and amlodipine-treated groups compared with the placebo-treated group; a further significant reduction was seen in the irbesartan+efonidipine-treated group compared with the irbesartan-treated group. Compared with the placebo-treated group, proteinuria was significantly lower in the irbesartan- and efonidipine-treated groups, but not in the amlodipine-treated group. Furthermore, a significant attenuation of proteinuria in the irbesartan+efonidipine-treated group compared with the irbesartan-treated group was observed; this effect was not observed in the irbesartan+amlodipine-treated group. The glomerulosclerosis index was significantly attenuated by all active treatments except amlodipine. The glomerulosclerosis index in the irbesartan+efonidipine-treated group, but not in the irbesartan+amlodipine-treated group, was significantly lower than that in the irbesartan-treated group. Significant attenuations of gene expressions of p22(phox), transforming growth factor-beta, monocyte chemoattractant protein-1 and collegen I were observed in the irbesartan- and efonidipine-treated groups, but not in the amlodipine-treated group. Values for these parameters were reduced to control levels in the irbesartan+efonidipine-treated group. Combination therapy with ARB and T- and L-type CCB might produce a powerful renal protective effect.
Department of Pharmacology, Osaka Medical College, Takatsuki City, Osaka, Japan. pha010@art.osaka-med.ac.jp
Shinji
S
Takai
Denan
D
Jin
Hiroshi
H
Sakonjo
Mizuo
M
Miyazaki
D017311:Amlodipine / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D001713:Biphenyl Compounds / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D018932:Chemokine CCL2 / Q000032:analysis; D024042:Collagen Type I / Q000032:analysis; D004095:Dihydropyridines / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D015870:Gene Expression / Q000187:drug effects; D005923:Glomerulosclerosis, Focal Segmental / Q000188:drug therapy / Q000473:pathology; D006973:Hypertension / Q000188:drug therapy; D000077405:Irbesartan; D007678:Kidney Glomerulus / Q000187:drug effects; D008297:Male; D019255:NADPH Oxidases / Q000032:analysis; D009596:Nitrophenols / Q000627:therapeutic use*; D009943:Organophosphorus Compounds / Q000627:therapeutic use; D011507:Proteinuria / Q000188:drug therapy*; D051381:Rats; D020303:Rats, Inbred Dahl; D013777:Tetrazoles / Q000627:therapeutic use*; D016212:Transforming Growth Factor beta / Q000032:analysis
D047228:Angiotensin II Type 1 Receptor Blockers; D001713:Biphenyl Compounds; D002121:Calcium Channel Blockers; D018932:Chemokine CCL2; D024042:Collagen Type I; D004095:Dihydropyridines; D009596:Nitrophenols; D009943:Organophosphorus Compounds; D013777:Tetrazoles; D016212:Transforming Growth Factor beta; D017311:Amlodipine; C066425:efonidipine; D019255:NADPH Oxidases; C515768:Cyba protein, rat; D000077405:Irbesartan