**18. Conclusions**

The development of research at the dawn of the millennium, in nanotechnology, genetic engineering and biotechnology for the understanding of the multiple pathogenic mechanisms of cardiovascular diseases and its consequences and hypertension within them, have caused a real boom in the appearance of new therapeutic options for hypertension. About some of them (those that are the most in advanced stages of preclinical and clinical research) we have tried to give a small and modest updating.

Others in earlier stages of experimental research as antagonists of vasopressin receptors (RWJ-676070), NO stimulators and stabilizers: L-arginine, tetrahydrobiopterin (BH4), phosphodiesterase inhibitors PDE-5, N-acetylcysteine, donors of NO (NCX-899,

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However, what has been so far advanced allows us to have useful drugs with proven scientific evidence on cardiovascular risk reduction and augur a promising future in reducing cardiovascular morbility and mortality.

## **19. References**


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**2** 

*Japan* 

Akira Takahara *Toho University,* 

**Dual L/N-Type Ca2+ Channel Blocker: Cilnidipine** 

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

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

Rise in intracellular Ca2+ triggers a variety of physiological processes, and there are many channels and pumps involved in controlling intracellular Ca2+ level. Among them, voltage-

sympathetic N-type Ca2+ channels and renin-angiotensin-aldosterone system.

**2. Ca2+ channels: Physiological role and pharmacological modification** 

**1. Introduction** 

angiotensin II-induced aldosterone synthesis.

**as a New Type of Antihypertensive Drug** 

