**1. Introduction**

28 Antihypertensive Drugs

Vlassara, H. & Palace, MR. (2002). Diabetes and advanced glycation endproducts. *J Intern* 

Voskuil, M. et al. (2011). Percutaneous renal denervation for the treatment of resistant

Wang, H, Long, CL. & Zhang, YL. (2004). A new ATP sensitive potassium channel opener

Wang, H, Long, CL. & Zhang, YL. (2005). A new ATP-sensitive potassium channel opener

Wang, H. et al. (2007). A new ATP sensitive potassium channel opener protects endothelial

Weir, MR. et al. (2007). Antihypertensive efficacy, safety and tolerability of the oral direct

Wheal, AJ. et al. (2007). Cardiovascular effects of cannabinoids in conscious spontaneously

Wind, S. et al. (2010). Comparative pharmacology of chemically distinct NADPH oxidase

Witkowski, A. et al.(2011). Effects of Renal Sympathetic Denervation on Blood Pressure,

Wood, JM. et al. (2003). Structure-based design of aliskiren, a novel orally effective renin

Wright, J.W., Harding, J.W., 1992. Regulatory role of brain angiotensins in the control of

Wright, J.W., Harding, J.W. (1994). Brain angiotensin receptor subtypes in the control of

Wright, J.W., Harding, J.W. (1997). Important roles for angiotensin III and IV in the brain

Yu, A & Frishman, WH. (1996). Imidazoline receptor agonist drugs: a new approach to the

Zhu, Y.C., Zhu, Y.Z., & Moore, P.K. (2006). The role of urotensin II in cardiovascular and

*Hypertens*, Vol.1, No.4, (Jul-Aug 2007), pp.264-77, ISSN: 1933-1711

essential hypertension; the first Dutch experience. *Neth Heart J*, Vol. 19. No. 7-8,

reduces blood pressure and reverses cardiovascular remodeling in experimental hypertension.*The Journal of Pharmacology and Experimental Therapeutics*,Vol. 312, No.

reduces blood pressure and reverses cardiovascular remodeling in experimental hypertension. *J Pharmacol Exp Ther*, Vol. 312, No. 3, (Mar 2005), pp.1326-33, ISSN:

function in cultured aortic endothelial cells. *Cardiovasc Res*, Vol.73, No.3, (Feb 2007),

renin inhibitor aliskiren in patients with hypertension: a pooled analysis. *J Am Soc* 

hypertensive rats. *Br J Pharmacol*, Vol.152, No.5, (Nov 2007), pp.717-724, ISSN: 1476-

inhibitors. *British Journal of Pharmacology*, Vol.161, No. 4, (Oct 2010), pp.885–898,

Sleep Apnea Course, and Glycemic Control in Patients With Resistant Hypertension and Sleep Apnea. *Hypertension*,Vol. 58, No. 4, (Oct 2011), pp. 559-65,

inhibitor. *Biochem Biophys Res Commun,* Vol.308, No.4, (Sept 2003), pp.698-705, ISSN:

physiological and behavioral responses. *Brain Res. Rev*, Vol.17, No.3, (Sep-Dec

physiological and behavioral responses. *Neurosci. Biobehav. Rev*, Vol.18, No.1,

renin angiotensin system. *Brain Res. Rev*, Vol. 25, No.1, (Sept 1997), pp.96–124,

treatment of systemic hypertension. *J Clin Pharmacol*, Vol. 36, No.2, (Feb 1997), pp.

renal physiology and diseases. *Br.J.Pharmacol*, Vol.148, No.7, (Aug 2006).pp. 884-

*Med,* Vol.251, No.2, (Feb 2002), pp.87–101, ISSN: 1365-2796

(Aug 2011), pp. 319–23, ISSN: 1876-6250

3,(Nov 2004),pp.1326-1333, ISSN: 1521-0103

0022-3565

5381

ISSN: 1476-5381

ISSN: 1524-4563

ISSN: 0165-0173

98-111, ISSN: 1552-4604

901, ISSN: 1476-5381

1992), pp.227–262, ISSN: 0165-0173

(Spring 1994), pp.21–53, ISSN: 0149-7634

0006-291X

pp.497–503, ISSN: 1755-3245

Cilnidipine is a unique dihydropyridine derivative Ca2+ channel blocker with an inhibitory action on the sympathetic N-type Ca2+ channels (Uneyama et al., 1999a). It has been clarified that cilnidipine exerts antisympathetic actions in various examinations from cell to human levels. Furthermore, its renoprotective, neuroprotective and cardioprotective effects have been demonstrated in clinical practice or animal examinations. After the introduction of nifedipine, many Ca2+ channel blockers with long-lasting action have been synthesized to decline sympathetic reflex during antihypertensive therapy. Based on each pharmacokinetic profile, Ca2+ channel blockers have been divided into three groups; namely, 1st, 2nd, and 3rd generation. Since cilnidipine directly inhibits the sympathetic neurotransmitter release by N-type Ca2+ channel-blocking property, the drug can be expected as 4th generation, providing an effective strategy for the treatment of cardiovascular diseases (Takahara, 2009).

Recently, cilnidipine has been demonstrated to suppress renin-angiotensin-aldosterone system at anti-hypertensive doses in animal examinations, whereas other Ca2+ channel blockers usually activates such vasopressor system after acute or repeated administrations. Interestingly, antihypertensive therapies with angiotensin II receptor blockers sometimes activate renin-angiotensin system, which is effectively suppressed by cilnidipine. This may provide synergistic and effective therapeutic strategies during combined administration of cilnidipine and angiotensin II receptor blockers. The possible mechanisms to suppress reninangiotensin-aldosterone system appear to be clarified. In human adrenocortical cells, where N-type Ca2+ channels are recently found to act as a source of intracellular Ca2+ mobilization, cilnidipine as well as a specific N-type Ca2+ channel blocker ω-conotoxin effectively inhibits angiotensin II-induced aldosterone synthesis.

In this chapter, we introduce a pharmacological profile of cilnidipine in combined with its clinical antihypertensive and anti-sympathetic actions. We further review utilities of cilnidipine for management of hypertension and its complications through inhibition of sympathetic N-type Ca2+ channels and renin-angiotensin-aldosterone system.
