Disparate effects of angiotensin II antagonists and calcium channel blockers on albuminuria in experimental diabetes and hypertension: potential role of nephrin.
OBJECTIVE
To explore the effects of various antihypertensive regimes which achieve similar blood pressure control using a range of agents including the angiotensin II type 1 receptor antagonist, valsartan, as monotherapy or in combination with two subclasses of calcium channel blockers (CCBs) (the dihydropyridine, amlodipine and the phenylalkylamine, verapamil) on the progression of renal disease and the expression of the podocyte slit pore protein, nephrin in an accelerated model of diabetic nephropathy.


RESULTS
Valsartan treatment reduced systolic blood pressure as assessed by radiotelemetry (135 +/- 3 versus diabetic 153 +/- 6 mmHg) as well as retarding the increase in albumin excretion rate by approximately 50%. Combination therapy of valsartan with either amlodipine or verapamil was equally effective in reducing blood pressure to valsartan monotherapy (valsartan + amlodipine 129 +/- 4 valsartan + verapamil 133 +/- 6 mmHg;) but was not as effective at reducing albuminuria. A reduction in glomerulosclerosis was observed with valsartan monotherapy with less reduction in injury with the valsartan + amlodipine combination, despite a similar reduction in blood pressure. The decrease in nephrin, in diabetic rats was attenuated by valsartan monotherapy, but not by other treatments.


CONCLUSIONS
The results of this study demonstrate that despite a similar reduction in blood pressure, the addition of the CCB amlodipine to the AII antagonist failed to provide similar renoprotection to that observed with an equihypotensive regimen of valsartan as monotherapy. Furthermore, the depletion in glomerular nephrin expression in diabetic animals was only abrogated by valsartan treatment, the therapy which was most effective at retarding the development of albuminuria in this model.
Davis
Belinda J
BJ
Department of Medicine, University of Melbourne, Repatriation Campus, Heidelberg West, Victoria 3081, Australia.
Cao
Zemin
Z
de Gasparo
Marc
M
Kawachi
Hiroshi
H
Cooper
Mark E
ME
Allen
Terri J
TJ
D000419:Albuminuria / Q000188:drug therapy / Q000209:etiology / Q000652:urine*; D017311:Amlodipine / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D003928:Diabetic Nephropathies / Q000150:complications / Q000473:pathology / Q000503:physiopathology / Q000652:urine*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D006973:Hypertension / Q000150:complications / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology / Q000652:urine*; D007678:Kidney Glomerulus / Q000473:pathology; D008297:Male; D008565:Membrane Proteins; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D044140:Receptor, Angiotensin, Type 1; D012598:Sclerosis; D013599:Systole; D013777:Tetrazoles / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan; D014700:Verapamil / Q000494:pharmacology
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D008565:Membrane Proteins; D011506:Proteins; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; C113267:nephrin; D017311:Amlodipine; D000068756:Valsartan; D014700:Verapamil; D014633:Valine