Cilnidipine: An L- and N-Type Blocker of Calcium Channels Ameliorating Renal Damage in Experimental Hypertensive Rats.
Study Goal
The researchers aimed to determine whether cilnidipine, an L/N-type calcium channel blocker, could reduce proteinuria and improve creatinine clearance in hypertensive rats by targeting N-type calcium channels.
Results Summary
Cilnidipine significantly improved creatinine clearance, reduced proteinuria, and lowered angiotensin II levels in hypertensive rats, suggesting renal protective effects. The study did not address long-term human safety or efficacy.
Population
Male Albino Wistar rats (six groups, six rats each) with induced hypertension via L-NAME and high-salt diet.
Effective Dosage
2 mg/kg/day cilnidipine (oral gavage).
Duration
Not explicitly stated (implied chronic intervention based on methodology).
Interactions
None mentioned.
| Intervention | Direction | Endpoint | Population | Dosage | Impact | Claim # |
|---|---|---|---|---|---|---|
L-NAME and 4% sodium chloride (4% NaCl) | increase | blood pressure | rats | synergistic effect | leads to a synergistic effect on | #1 |
L-NAME and 4% sodium chloride (4% NaCl) | increase | ACE and Ang II levels | L-NAME and salt-induced hypertensive rats | elevated | found elevated | #2 |
L-NAME and 4% sodium chloride (4% NaCl) | increase | proteinuria | hypertensive rats | 4.65±0.29 compared to control (1.56±0.044) | observed a significant increase in | #3 |
L-NAME and 4% sodium chloride (4% NaCl) | decrease | creatinine clearance | hypertensive rats | 0.06±0.0019 compared to control (0.078±0.0044) | observed a decrease in | #4 |
cilnidipine | increase | creatinine clearance | groups 4 and 6 rats | 0.077±0.0027 (p < 0.05) | observed that in treatment with there were significant improvements in | #5 |
cilnidipine | decrease | proteinuria | groups 4 and 6 rats | 3.38±0.24 (p < 0.05) | observed a significant decrease in | #6 |
cilnidipine | decrease | Ang II in the urine and serum | rats treated with cilnidipine | p < 0.05 | observed significantly decreased levels of | #7 |
cilnidipine | decrease | ACE in the renal tissue and serum | rats treated with cilnidipine | p < 0.05 | observed a significantly decreased expression of | #8 |
cilnidipine | decrease | proteinuria and urinary creatinine and Ang II levels | hypertensive experimental rats | - | decreases | #9 |
BACKGROUND: Cilnidipine is both an L-type and N-type calcium channel blocker (CCB). Cilnidipine suppresses hyperactivity in the renin-angiotensin system and sympathetic nervous system by blocking N-type calcium channels. We hypothesized that through its N-type calcium channel blockade, cilnidipine may reduce proteinuria and improve creatinine clearance in hypertensive rats. Aim of the study: The current study was done to show the renal protective effect of cilnidipine on chronic hypertensive rats. Our primary objective is to develop a hypertensive rat model by giving L-NAME (NG-nitro-L-Arginine Methyl Ester Hydrochloride) and 4% sodium chloride (4% NaCl). High salt was given along with L-NAME because the combination of L-NAME and high salt intake leads to a synergistic effect on blood pressure. L-NAME impairs NO production, and high salt intake exacerbates this effect by promoting vasoconstriction and fluid retention. Our secondary objective is to evaluate the kidney damage measures, including recording of proteinuria, creatinine clearance, and urinary angiotensin II (Ang II) levels in hypertensive rats with or without cilnidipine treatment. METHODS: Six groups of male Albino Wister rats (with six rats in each group) were created by a simple randomization technique. Rats were obtained from the animal house of our institution. Group 1 (control) received vehicle treatment; cilnidipine (2mg/kg/day by oral gavage) was given to Group 2; L-NAME (40mg/kg/day by oral gavage) was given to Group 3; Group 4 received L-NAME plus cilnidipine; Group 5 received L-NAME plus 4% NaCl (mixed with diet) treatment; Group 6 received L-NAME, 4% NaCl and cilnidipine. Creatinine excretion and urinary protein were assessed in a 24-hour urine sample. Serum urea and creatinine levels were also measured. Relative expression of serum and renal tissue ACE (angiotensin-converting enzyme) protein was done by Western blotting. Quantitative estimation of urinary and serum Ang II levels was done by enzyme-linked immunosorbent assay (ELISA). Kidney histopathological analysis was carried out. RESULTS: In the renal tissue homogenate and serum of L-NAME and salt-induced hypertensive rats, we found elevated ACE and Ang II levels. We also observed a significant increase in proteinuria (4.65±0.29) compared to control (1.56±0.044) and a decrease in creatinine clearance (0.06±0.0019) compared to control (0.078±0.0044) in hypertensive rats. We observed that in treatment with cilnidipine (groups 4 and 6 rats), there were significant improvements in creatinine clearance (0.077±0.0027) (p < 0.05) and a significant decrease in proteinuria (3.38±0.24) (p < 0.05). In rats treated with cilnidipine, we also observed significantly decreased levels of Ang II in the urine and serum (p < 0.05) and a significantly decreased expression of ACE in the renal tissue and serum. CONCLUSION: These results showed that in hypertensive experimental rats, cilnidipine, apart from its hypotensive actions, decreases proteinuria and urinary creatinine and Ang II levels. These actions of cilnidipine may be because of blocking N-type calcium channels. Therefore, cilnidipine dual L/N type CCB may act as a renoprotective drug and decrease glomerular damage. Further mechanistic studies using selective N-type channel blockers or knockout mice are needed to prove the findings.