**4.2 Suppression of renin-angiotensin-aldosterone system**

It is widely known that renin secretion from the juxtaglomerular apparatus is closely associated with renal sympathetic nerve activity. Thus, cilnidipine may alter reninangiotensin-aldosterone system. In recent studies using spontaneously hypertensive rats, whereas an L-type Ca2+ channel blocker amlodipine increased plasma renin activity and angiotensin II levels at antihypertensive doses, cilnidipine failed to affect plasma renin activity or plasma norepinephrine and angiotensin II levels, which strongly supports that cilnidipine suppresses renin-angiotensin system through sympathetic N-type Ca2+ channel blockade (Konda et al., 2009). In a previous study using the canine cardiac sudden death model, it was found for the first time that cilnidipine decreased the plasma concentration aldosterone level (Takahara et al., 2009). The curious action of cilnidipine was also confirmed in hypertensive rats. A recent study has clearly demonstrated that the endocrine mechanisms of angiotensin II-induced aldosterone production in the adrenocortical cells are closely associated with activities of N-type Ca2+ channels (Aritomi et al., 2011a).

Antihypertensive therapies with angiotensin II receptor blockers sometimes activate reninangiotensin system. As shown in Fig. 3, increases in plasma renin activity and plasma angiotensin II levels can be observed by oral administration of valsartan in spontaneously hypertensive rats, which were effectively suppressed by cilnidipine but not by amlodipine (Aritomi et al., 2011b). Thus, cilnidipine is expected to provide synergistic and effective therapeutic strategies when administered with angiotensin II receptor blockers.

## **4.3 Abbreviation of prolonged QT-interval**

The heart of canine chronic atrioventricular block model (cardiac sudden death model) is known to have a ventricular electrical remodeling, which mimics the pathophysiology of long QT syndrome (Sugiyama, 2008). Using this model, we explored a new pharmacological therapeutic strategy for prevention of cardiac sudden death (Fig. 4; Takahara et al., 2009). Amlodipine, cilnidipine or an angiotensin II receptor blocker candesartan was orally administered to the dogs for 4 weeks. Amlodipine and cilnidipine decreased the blood pressure, while candesartan hardly affected it. The QT interval and monophasic action potential duration were shortened only in the cilnidipine group, but such effects were not observed in the amlodipine or candesartan group. Plasma concentrations of angiotensin II

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

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

It is widely known that renin secretion from the juxtaglomerular apparatus is closely associated with renal sympathetic nerve activity. Thus, cilnidipine may alter reninangiotensin-aldosterone system. In recent studies using spontaneously hypertensive rats, whereas an L-type Ca2+ channel blocker amlodipine increased plasma renin activity and angiotensin II levels at antihypertensive doses, cilnidipine failed to affect plasma renin activity or plasma norepinephrine and angiotensin II levels, which strongly supports that cilnidipine suppresses renin-angiotensin system through sympathetic N-type Ca2+ channel blockade (Konda et al., 2009). In a previous study using the canine cardiac sudden death model, it was found for the first time that cilnidipine decreased the plasma concentration aldosterone level (Takahara et al., 2009). The curious action of cilnidipine was also confirmed in hypertensive rats. A recent study has clearly demonstrated that the endocrine mechanisms of angiotensin II-induced aldosterone production in the adrenocortical cells are

of cilnidipine that reduced infarction volume in the rat focal brain ischemia model.

closely associated with activities of N-type Ca2+ channels (Aritomi et al., 2011a).

therapeutic strategies when administered with angiotensin II receptor blockers.

**4.3 Abbreviation of prolonged QT-interval** 

Antihypertensive therapies with angiotensin II receptor blockers sometimes activate reninangiotensin system. As shown in Fig. 3, increases in plasma renin activity and plasma angiotensin II levels can be observed by oral administration of valsartan in spontaneously hypertensive rats, which were effectively suppressed by cilnidipine but not by amlodipine (Aritomi et al., 2011b). Thus, cilnidipine is expected to provide synergistic and effective

The heart of canine chronic atrioventricular block model (cardiac sudden death model) is known to have a ventricular electrical remodeling, which mimics the pathophysiology of long QT syndrome (Sugiyama, 2008). Using this model, we explored a new pharmacological therapeutic strategy for prevention of cardiac sudden death (Fig. 4; Takahara et al., 2009). Amlodipine, cilnidipine or an angiotensin II receptor blocker candesartan was orally administered to the dogs for 4 weeks. Amlodipine and cilnidipine decreased the blood pressure, while candesartan hardly affected it. The QT interval and monophasic action potential duration were shortened only in the cilnidipine group, but such effects were not observed in the amlodipine or candesartan group. Plasma concentrations of angiotensin II

**4.2 Suppression of renin-angiotensin-aldosterone system** 

antioxidant activity.

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 provide a novel therapeutic strategy.

Dual L/N-Type Ca2+ Channel Blocker: Cilnidipine as a New Type of Antihypertensive Drug 41

hypertension. Indeed, its advantage is demonstrated by the clinical study showing that cilnidipine is superior to amlodipine in preventing the progression of proteinuria in patients with hypertension and chronic renal disease (Fujita et al., 2007). The currently described information suggests that cilnidipine is a new type of antihypertensive drug distinguished from other L-type Ca2+ channel blockers or even other antihypertensives, which will be useful for selection of antihypertensive drugs according to the pathophysiological condition

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of a patient.

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Fig. 4. Effects on electrocardiogram (ECG) and monophasic action potential (MAP) signal during idioventricular rhythm in chronic atrioventricular block dogs. A: Typical tracings of effects of cilnidipine on ECG and MAP signal. B: Effects of amlodipine (2.5mg/day), cilnidipine (5mg/day) and candesartan (12mg/day) on QT interval, MAP duration and plasma levels of norepinephrine (NE), angiotensin II (ANG II) and aldosterone (ALDO). These parameters were obtained at pre-drug control (C) and 2 weeks (2W) and 4 weeks (4W) after the start of drug daily administration. Data are presented as the means±SE. Closed symbols represent the significant differences from each pre-drug control (C) value by p<0.05. Data are quoted and modified from Takahara et al., 2009.

#### **5. Conclusion**

Cilnidipine is a promising Ca2+ channel blocker as the 4th generation with a rational pharmacological profile; i.e. dual L/N-type Ca2+ channel-blocking action. The blockade of N-type Ca2+ channels effectively suppresses neurohumoral regulation in the cardiovascular system, including sympathetic nervous system and renin-angiotensin-aldosterone system. Thus, cilnidipine is expected to be favorable for various types of complication of hypertension. Indeed, its advantage is demonstrated by the clinical study showing that cilnidipine is superior to amlodipine in preventing the progression of proteinuria in patients with hypertension and chronic renal disease (Fujita et al., 2007). The currently described information suggests that cilnidipine is a new type of antihypertensive drug distinguished from other L-type Ca2+ channel blockers or even other antihypertensives, which will be useful for selection of antihypertensive drugs according to the pathophysiological condition of a patient.

#### **6. References**

40 Antihypertensive Drugs

Fig. 4. Effects on electrocardiogram (ECG) and monophasic action potential (MAP) signal during idioventricular rhythm in chronic atrioventricular block dogs. A: Typical tracings of effects of cilnidipine on ECG and MAP signal. B: Effects of amlodipine (2.5mg/day), cilnidipine (5mg/day) and candesartan (12mg/day) on QT interval, MAP duration and plasma levels of norepinephrine (NE), angiotensin II (ANG II) and aldosterone (ALDO). These parameters were obtained at pre-drug control (C) and 2 weeks (2W) and 4 weeks (4W) after the start of drug daily administration. Data are presented as the means±SE. Closed symbols represent the significant differences from each pre-drug control (C) value by

Cilnidipine is a promising Ca2+ channel blocker as the 4th generation with a rational pharmacological profile; i.e. dual L/N-type Ca2+ channel-blocking action. The blockade of N-type Ca2+ channels effectively suppresses neurohumoral regulation in the cardiovascular system, including sympathetic nervous system and renin-angiotensin-aldosterone system. Thus, cilnidipine is expected to be favorable for various types of complication of

p<0.05. Data are quoted and modified from Takahara et al., 2009.

**5. Conclusion** 


Dual L/N-Type Ca2+ Channel Blocker: Cilnidipine as a New Type of Antihypertensive Drug 43

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**3** 

*Portugal* 

**Hypertension and Chronic Kidney** 

**Therapeutic Considerations** 

Elsa Morgado and Pedro Leão Neves *Nephrology Department, Hospital of Faro,* 

**Disease: Cause and Consequence –** 

There is a strong relationship between hypertension and Chronic Kidney Disease (CKD). Hypertension is an important cause of End-Stage Renal Disease (ESRD), contributing to the disease itself or, most commonly, contributing to its progression. On the other hand, hypertension is highly prevalent in CKD patients, playing a role in the high cardiovascular morbidity and mortality of this particular population. This chapter will focus on the pathogenesis of hypertension-related CKD and its role on the progression of renal disease itself. The pathogenesis and treatment of hypertension resulting from CKD will also be

The relationship between abnormal blood pressure and kidney dysfunction was first established in the 19th century. The prevalence of both, and of the associated burden of cardiovascular morbidity and mortality, has been dramatically increasing worldwide (Kearney et al., 2005; Kearney et al., 2004; Ong et al., 2007; Schoenborn & Heyman, 2009; USRDS 2010; Meguid El Nahas & Bello, 2005). Data from several renal databases identifies systemic hypertension as the second most common cause of ESRD, with Diabetes mellitus being the first. In the United States (US), hypertension is the leading cause of ESRD in African-American patients (USRDS 2010; Klag et al., 1996; Hsu et al., 2005). Additionally, for any given cause of CKD, the elevation in systemic blood pressure accelerates the rate at which the glomerular filtration rate (GFR) declines (Perry et al., 1995). This is particularly

The exact mechanisms of kidney damage in patients with hypertension still remain elusive. Two complementary pathogenic mechanisms ultimately ending in kidney fibrosis and scarring have been proposed. One starts with the changes in systemic and renal macro and microvasculature leading to the loss of renal auto-regulation with elevation of intraglomerular capillary pressure and the consequent hyperfiltration-mediated injury.

true for patients with proteinuric nephropathies (Jafar et al., 2003).

**2.1 Pathogenesis of hypertensive renal damage** 

**1. Introduction** 

addressed.

**2. Hypertension as a cause of CKD** 

