Mineralocorticoid receptor blockade and calcium channel blockade have different renoprotective effects on glomerular and interstitial injury in rats.
We hypothesized that combination treatment with the mineralocorticoid receptor antagonist eplerenone and the calcium channel blocker amlodipine elicits better renoprotective effects than monotherapy with either drug, via different mechanisms in Dahl salt-sensitive (DS) hypertensive rats. DS rats were fed a high-salt diet (4% NaCl) for 10 wk and were treated with vehicle (n = 12), eplerenone (50 mg x kg(-1) x day(-1), p.o., n = 12), amlodipine (3 mg x kg(-1) x day(-1), p.o., n = 12), or eplerenone plus amlodipine (n = 12) after 2 wk of salt feeding. Vehicle-treated DS rats developed proteinuria, which was attenuated by eplerenone or amlodipine. Interestingly, eplerenone attenuated the glomerulosclerosis and podocyte injury, but amlodipine did not. Conversely, treatment with amlodipine markedly improved interstitial fibrosis, while the effect of eplerenone was minimal. Combination treatment markedly improved proteinuria, glomerulosclerosis, podocyte injury, and interstitial fibrosis in DS rats. Renal hypoxia estimated by pimonidazole, vascular endothelial growth factor expression, and density of peritubular endothelial cells was exacerbated by salt feeding. Amlodipine, either as monotherapy or in combination, ameliorated the renal hypoxia, whereas eplerenone treatment had no effect. In conclusion, both eplerenone and amlodipine attenuated renal injuries in high salt-fed DS rats, but the targets for renoprotection differed between these two drugs, with eplerenone predominantly acting on glomeruli and amlodipine acting on interstitium. The combination of eplerenone and amlodipine improved renal injury more effectively than either monotherapy in high salt-fed DS rats, presumably by achieving their own renoprotective effects.
Du
Jun
J
Department of Pharmacology, Kagawa University Medical School, Kagawa, Japan.
Fan
Yu-Yan
YY
Hitomi
Hirofumi
H
Kiyomoto
Hideyasu
H
Kimura
Shoji
S
Kong
Chui-Ze
CZ
Noma
Takahisa
T
Kohno
Masakazu
M
Nishiyama
Akira
A
Nakano
Daisuke
D
D017311:Amlodipine / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015687:Cell Hypoxia; D003404:Creatinine / Q000097:blood; D004359:Drug Therapy, Combination; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D000077545:Eplerenone; D005355:Fibrosis; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D017874:Immediate-Early Proteins / Q000378:metabolism; D007674:Kidney Diseases / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000473:pathology; D007684:Kidney Tubules / Q000187:drug effects* / Q000473:pathology; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D050199:Podocytes / Q000187:drug effects / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011507:Proteinuria / Q000209:etiology / Q000517:prevention & control; D051381:Rats; D020303:Rats, Inbred Dahl; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D017673:Sodium Chloride, Dietary; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099184:Serum-Glucocorticoid Regulated Kinases
D017311:Amlodipine; D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D003404:Creatinine; D000077545:Eplerenone; D017874:Immediate-Early Proteins; D000451:Mineralocorticoid Receptor Antagonists; D017346:Protein Serine-Threonine Kinases; D018161:Receptors, Mineralocorticoid; D017673:Sodium Chloride, Dietary; D013148:Spironolactone; D042461:Vascular Endothelial Growth Factor A; D000099184:Serum-Glucocorticoid Regulated Kinases; C467498:vascular endothelial growth factor A, rat