Background/Aims: The L/N-type calcium channel blocker (CCB) cilnidipine has been demonstrated to suppress progressive renal disease in a variety of experimental models, but the characteristic effects of N-type calcium channel blocking action on renal injury have not been examined in detail. Therefore, we investigated the beneficial effects of cilnidipine on renal injury in Dahl salt-sensitive (Dahl S) rats fed a high-sucrose diet (HSD), which mimics metabolic syndrome, and compared them with the effects of an L-type CCB, amlodipine. Methods: Male Dahl S rats were divided into groups with similar blood pressure at 8 weeks of age and fed an HSD. They received vehicle, cilnidipine or amlodipine for 27 weeks. At 35 weeks of age, urine and blood samples were collected for physiological analysis, and the kidneys were removed for histopathological evaluation. Results: Cilnidipine reduced albuminuria, glomerular hypertrophy, glomerular expression of ICAM-1, ED-1-positive cell infiltration and interstitial fibrosis compared with vehicle-treated rats. In contrast, amlodipine had no effect on these parameters. Urinary norepinephrine excretion, renal expression of renin mRNA and renal tissue levels of angiotensin II were increased only in the amlodipine-treated group. Conclusion: Cilnidipine provided superior protection against renal damage compared with amlodipine in Dahl S rats given an HSD. The different effects between these two drugs may be partly explained by their different actions on the renal sympathetic nerve activity and the renin-angiotensin system through the N-type calcium channel blocking action.

Background: The L/N-type calcium channel blocker (CCB) cilnidipine has been demonstrated to suppress sympathetic nerve activity. In the present study, we investigated the effects of cilnidipine on the renin-angiotensin-aldosterone system (RAAS) in SHR/Izm rats to confirm differences from the effects of L-type CCB. Methods: Male SHR/Izm rats received vehicle, cilnidipine (0.3, 3 mg/kg) or amlodipine (0.3, 3 mg/kg) by gavage for systolic blood pressure (SBP) measurement. For biochemical analyses, the experiments were performed under anesthesia. Results: Low doses of cilnidipine or amlodipine had no effect on SBP or RAAS parameters. A high dose of either drug produced similar effects on SBP levels. Although cilnidipine had no effect on plasma renin activity or the plasma angiotensin II level, amlodipine significantly increased these parameters as compared to levels in the vehicle group. The cilnidipine group had a significantly lower plasma aldosterone level and renal cortical tissue norepinephrine level than the vehicle group. Conclusions: Cilnidipine had effects different from those of L-type CCB on the RAAS in SHR/Izm rats. Our results indicate that suppression of RAAS hyperactivity by cilnidipine can be partly explained by its sympatholytic action.

No abstract

Renal sympathetic nerve activity plays an important role on renal function through the vasoactive system 1,2) and the renin-angiotensin system.3) In the clinical study, it has been suggested that sympathetic overactivity plays a pivotal role for progression of renal disease in patients with chronic renal failure or end-stage renal disease. 4,5) Recent studies suggesting that renal sympathetic denervation prevent glomerular hyperfiltration and glomerulosclerosis in some experimental models.6,7) From these indications, it is expected that treatments aimed at modulating sympathetic nerve activity will suppresses progressive renal injury.N-Type (neuronal) calcium channels, predominantly distributed on the sympathetic nerves have been widely recognized to control the neurotransmitter releases. 8,9) Cilnidipine is a dihydropyridine (DHP) calcium channel blocker (CCB), and it has been demonstrated to inhibit both N-type and Ltype (long acting) calcium channels in various types of neurons.10,11) Cilnidipine also has been confirmed to suppress the norepinephrine (NE) releases from the isolated rat vascular preparation. 12) In the experiments of anesthetized dogs, sympathetic nerve stimulation-induced increase in plasma NE level was suppressed by cilnidipine.2,13) Thus cilnidipine suppressed sympathetic hyperactivity in a variety of experimental models through the blocking action of N-type calcium channels.The Dahl salt-sensitive (Dahl S) rats that develop hypertension and renal injuries with a high-salt diet have been widely recognized to be a model of chronic renal failure. [14][15][16] It has been suggested that sympathetic nerve activity is increased or easy to increase by physical stress in Dahl S rats on a high-salt diet.17,18) Wu et al. 19) reported that high-salt induced changes in intrarenal vessel structure and renal haemodynamic function in Dahl S rats are dependent on the activity of the sympathetic nervous system. These reports suggest that increase in sympathetic nerve activity is considered to be a one of precipitating cause of renal failure in Dahl S rats.Many reports have been suggested that L-type calcium channel antagonist has renal protective effects in a renal injury model with hypertension.14,15) But there are not enough data to elucidate the effects of N-type calcium channel antagonist against progressive renal injury. Although L/N-type calcium channel antagonist, cilnidipine is expected to suppress the renal injury by both blocking action of L-type calcium channel that lead to hypotensive effect and N-type calcium channel that lead to suppression of sympathetic nerve activity, renal protective profile of cilnidipine has not ever been assessed in animal model of renal injury with hypertension. In the present study, we investigated to clarify the renal protective effects of L/N-type calcium channel antagonist, cilnidipine in Dahl S rats as a model of chronic renal failure. MATERIALS AND METHODS Animal PreparationAll experiments were conducted according to animal ethics committee of Ajinomoto Co., Inc...

No abstract