Additive effects of cilnidipine and angiotensin II receptor blocker in preventing the progression of diabetic nephropathy in diabetic spontaneously hypertensive rats.

Abstract

BACKGROUND:

Cilnidipine (Cil) is an L/N-type calcium channel blocker (CCB) that is known to provide renal protection by decreasing the activity of the sympathetic nervous system and the renin-angiotensin system (RAS). However, very few studies have evaluated the renoprotective effects of Cil in hypertension complicated by diabetes mellitus. In this study, we compared the effects of cilnidipine and the L-type CCB, amlodipine (Aml), in combination with an angiotensin II receptor blocker (ARB) on diabetic nephropathy that developed as a result of inducing diabetes in hypertensive rats.

METHODS:

Diabetes was induced in 9-week-old male spontaneously hypertensive rats by intraperitoneally injecting them with streptozotocin (40 mg/kg twice) and the rats (8 per group) were randomly assigned to receive valsartan (Val), Cil + Val, Aml + Val, or vehicle for 8 weeks through a gastric tube.

RESULTS:

There were no significant differences in systolic blood pressure or plasma parameters between the two combination therapy groups. Blood pressure lowering by neither combination therapy significantly affected the glycemic variables. However, the increased glycogen levels in the kidney as a result of hyperglycemia were significantly suppressed in the groups that received combination therapy, and the increased proteinurea and glomerulosclerosis due to progression of the diabetic nephropathy were significantly suppressed in the Cil + Val group. In addition, a significant decrease in ED-1-positive cells was observed in the Cil + Val group alone.

CONCLUSION:

The results of this study suggested that the L/N-type CCB, cilnidipine, had additive antihypertensive and proteinuria-lowering effects when administered in combination with an ARB, even in type-1 diabetic rats, and that the L-type CCB, amlodipine, did not. Furthermore, combination therapy with cilnidipine and valsartan significantly reduced glycogen accumulation and ED-1-positive cell infiltration, suggesting that cilnidipine suppressed the excessive increase in the activity of the sympathetic nervous system and RAS through N-type calcium channel blockade.

• Authors: Shizuka Aritomi, Kazumi Niinuma, Tetsuya Ogawa, Tomoyuki Konda, Kosaku Nitta
• Journal: Clinical and experimental nephrology (Clin Exp Nephrol) Vol. 17 Issue 1 Pg. 41-50 (Feb 2013) ISSN: 1437-7799 [Electronic] Japan
• PMID: 23011292 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Angiotensin II Type 1 Receptor Blockers
• Antihypertensive Agents
• Biomarkers
• Blood Glucose
• Calcium Channel Blockers
• Dihydropyridines
• Glucose Transporter Type 1
• Glycated Hemoglobin A
• Slc2a1 protein, rat
• Tetrazoles
• Tgfb1 protein, rat
• Transforming Growth Factor beta1
• hemoglobin A1c protein, human
• Amlodipine
• Valsartan
• Glycogen
• Glucagon
• cilnidipine
• Valine
• Norepinephrine

Topics

• Amlodipine (pharmacology)
• Angiotensin II Type 1 Receptor Blockers (pharmacology)
• Animals
• Antihypertensive Agents (pharmacology)
• Biomarkers (blood)
• Blood Glucose (drug effects, metabolism)
• Blood Pressure (drug effects)
• Calcium Channel Blockers (pharmacology)
• Diabetes Mellitus, Experimental (blood, complications, physiopathology)
• Diabetic Nephropathies (blood, etiology, physiopathology, prevention & control)
• Dihydropyridines (pharmacology)
• Disease Progression
• Drug Therapy, Combination
• Glomerulonephritis (etiology, prevention & control)
• Glucagon (blood)
• Glucose Transporter Type 1 (metabolism)
• Glycated Hemoglobin (metabolism)
• Glycogen (metabolism)
• Hypertension (blood, complications, drug therapy, physiopathology)
• Kidney (drug effects, metabolism)
• Male
• Norepinephrine (blood)
• Proteinuria (etiology, prevention & control)
• Rats
• Rats, Inbred SHR
• Renin-Angiotensin System (drug effects)
• Tetrazoles (pharmacology)
• Transforming Growth Factor beta1 (metabolism)
• Valine (analogs & derivatives, pharmacology)
• Valsartan