**4. Pleiotropic effects of cilnidipine**

Renoprotective, neuroprotective and cardioprotective effects of cilnidipine have been demonstrated in clinical practice or animal examinations. It is noticed that cilnidipine may have pleiotropic effects besides N-type Ca2+ channel-blocking action.

### **4.1 Anti-oxidation**

Dihydropiridine derivatives including nifedipine have been reported to act as lipophilic chain-breaking antioxidants; however, there are larger differences in their lipophilicity among dihydropyridines. Lipophilicity of cilnidipine is greater than that of amlodipine, which implies that cilnidipine itself can reduce oxidative stress independently in addition to its N-type Ca2+ channel blockade action.

Excess reactive oxygen species play an essential role in the development of a variety of renal diseases such as glomerulonephritis and tubulointerstitial nephritis. Indeed, in the kidney, cilnidipine significantly inhibited the increase in NADPH oxidase-derived superoxide

Dual L/N-Type Ca2+ Channel Blocker: Cilnidipine as a New Type of Antihypertensive Drug 39

Fig. 3. Effects of combined administration of valsartan and amlodipine or cilnidipine on plasma renin activity (A) and plasma angiotensin II (Ang II) level (B) in spontaneously hypertensive rats. The oral doses of valsartan, amlodipine and cilnidipine were 10, 1 and 1 mg/kg, respectively. Values are expressed as means±SE. ##P < 0.01, vehicle vs. valsartan alone, \*P < 0.05, Ca2+ channel blockers plus valsartan vs. valsartan alone. Data are quoted

and aldosterone decreased in the cilnidipine group. On the other hand, elevation of plasma concentrations of angiotensin II and aldosterone was detected in the amlodipine group. Cilnidipine is expected to restore similar electrical remodeling process to pathophysiology of chronic atrioventricular block. Indeed, a recent electrophysiological study has demonstrated that some cardiac K+ channels (*I*Ks and *I*to) are downregulated in the diabetic canine heart, leading to QT interval prolongation. Long QT interval has also been reported in patients with various cardiovascular diseases including hypertension with hypertrophy, hypertrophic cardiomyopathy and end-stage renal failure (Takahara et al., 2009). Therefore, long-term blockade of L/N-type Ca2+ channels may ameliorate the ventricular electrical remodeling in the hypertrophied heart leading to QT-interval prolongation, which will

and modified from Aritomi et al., 2011b.

provide a novel therapeutic strategy.

production, whereas amlodipine had no effect on the activation of NADPH oxidase in the deoxycorticosterone acetate-salt rat (Toba et al., 2011). Also, cilnidipine elicits podocyteprotection and anti-proteinuric effect in SHR/ND mcr-cp rat model of spontaneous hypertension through the reduction of renal AngII level and a subsequent reduction in oxidative stress (Fan et al., 2010). N-type Ca2+ channels localized in podocyte have been shown to play an important role in angiotensin II-induced superoxide production, which may partly explain the renoprotective mechanisms of cilnidipine. Antiproteinuric effect of cilnidipine in the CARTER study (Fujita et al., 2007) is in part explained by its superior antioxidant activity.

In addition, cilnidipine shows neuroprotection in the model of oxidative stress-induced neurotoxicity using PC12 cells (Lee et al., 2009), which may partly explain the mechanisms of cilnidipine that reduced infarction volume in the rat focal brain ischemia model.
