**3. New generation Ca2+ channel blocker: Cilnidipine**

Cilnidipine is a unique dihydropyridine derivative L-type Ca2+ channel blocker with an inhibitory action on the sympathetic N-type Ca2+ channels. As shown in Fig. 1, Ca2+ channels are ordinarily activated by membrane depolarization in the vascular cells or sympathetic neurons, leading to vascular contraction or neurotransmitter releases. During antihypertensive therapies with pure L-type Ca2+ channel blockers like nifedipine, the sympathetic reflex is sometimes occurred due to hypotension, leading to activation of sympathetic N-type Ca2+ channels, which induces several cardiovascular responses including vascular contraction, tachycardia and renin secretion (Takahara 2009). Cilnidipine can directly inhibit the sympathetic neurotransmitter release by its N-type Ca2+ channelblocking property, which may reduce risk of cardiovascular diseases closely associated with sympathetic nerve activation. The wide variety of pharmacological actions of cilnidipine has been investigated, which is summarized in Table 1.

Dual L/N-Type Ca2+ Channel Blocker: Cilnidipine as a New Type of Antihypertensive Drug 33

Mode of action Inhibition of L-type Ca2+ channels (vascular smooth muscle,

 1) Cardiovascular action Vascular relaxation (in vitro); hypotensive action (in vivo) 2) Anti-sympathetic action Decrease of catecholamine release, tissue (kidney)

level of ß-thromboglobulin (clinical)

injury (in vivo); anti-nociception (in vivo)

2-kidney 1-clip hypertensive dogs (in vivo)

stroke-prone spontaneously hypertensive rat, renal hypertensive rats, DOCA-salt hypertensive rats, Otsuka Long-Evans Tokushima Fatty rat, Dahl salt sensitive rat and

with chronic kidney disease, cerebrovascular disease or

arterioles; natriuresis; inhibition of renal nerve stimulationinduced antinatriuresis; suppression of albuminuria; glomerular hypertrophy and interstitial fibrosis; decrease in renal angiotensin II content (in vivo); decrease in albuminuria

suppression of vasopressin-induced ST depression; reduction of the myocardial infarct size and incidence of ventricular premature beats after ischemia-reperfusion; abbreviation of abnormally prolonged ventricular repolarization (in vivo);

cerebral blood flow; reduction of the cerebral infarction size

decrease in BNP, LV mass index, heart rate and

(in vivo); increase in cerebral blood flow (clinical)

4) Anti-oxidation Inhibition of NADPH oxidase-derived superoxide production

5) Others Improvement of insulin resistance (in vivo); increases of nitric

1) Animal model Antihypertensive action in spontaneously hypertensive rats,

2) Human Essential hypertension; severe hypertension; hypertension

1) Kidney Increase in renal blood flow; dilation of afferent and efferent

and urinary protein (clinical)

cardiothoracic ratio (clinical)

3) Brain Downward shift of the lower limit of autoregulation for

Table 1. Summary of pharmacological effects of cilnidipine

diabetes (clinical)

2) Heart Increase in coronary blood flow (in vitro, in vivo);

(kidney, in vivo)

neuron, in vitro)

Pharmacology

3) Suppression of reninangiotensin-aldosterone system

Antihypertensive action

Actions in key organs

in vitro); inhibition of N-type Ca2+ channels (sympathetic

norepinephrine level, (in vitro, in vivo); inhibition of sympathetic tachycardia and cold stress-induced vasoconstriction (in vivo); decrease in plasma/urinary norepinephrine, muscle sympathetic nerve activity, low frequency/high frequency ratio (LF/HF ratio), and plasma

Decrease in plasma level of angiotensin II and aldosterone (in vivo, clinical); inhibition of aldosterone production (adrenocortical cells, in vitro); inhibition of reflex aldosterone production, and angiotensin II-renin feedback (in vivo)

oxide production (in vitro); protection from retinal neuronal

Fig. 1. Diagrammatic representation of L/N-type dual action of cilnidipine. Cilnidipine directly inhibits the sympathetic neurotransmitter (norepinephrine; NE) release by N-type Ca2+ channel-blocking property in addition to vascular L-type Ca2+ channel inhibition, leading to suppression of renin-angiotensin-aldosterone system (RAAS). Thus, the drug can be expected to provide an effective strategy for the treatment of cardiovascular diseases (CVD).

## **3.1 Pharmacology**

L-type Ca2+ channel-blocking actions of cilnidipine were widely examined in earlier experimental studies, showing that its potency was greater than that of nifedipine. In 1997, N-type Ca2+ channel-blocking action was found in cilnidipine (Uneyama et al., 1997). Submicromolecular concentrations of cilnidipine effectively suppressed N-type Ca2+ channel currents in isolated sympathetic neurons. The inhibitory effect of various dihydropyridines on cardiac L-type Ca2+ channels was further compared in isolated ventricular myocytes with that on N-type Ca2+ channels in superior cervical ganglion neurons of the rat (Uneyama et al., 1999b). In that study, all dihydropyridines, except cilnidipine, showed a small inhibitory effect at a concentration of 1 μM. The N-type channel-blocking action of cilnidipine has also been confirmed in IMR-32 human neuroblastoma cells and PC12 pheochromocytoma of the rat adrenal medulla cells. Furthermore, it has been demonstrated that the N-type Ca2+ channel-blocking effects of cilnidipine leading to anti-sympathetic action can be observed at its anti-hypertensive doses (Takahara et al., 2002).

Fig. 1. Diagrammatic representation of L/N-type dual action of cilnidipine. Cilnidipine directly inhibits the sympathetic neurotransmitter (norepinephrine; NE) release by N-type Ca2+ channel-blocking property in addition to vascular L-type Ca2+ channel inhibition, leading to suppression of renin-angiotensin-aldosterone system (RAAS). Thus, the drug can be expected to provide an effective strategy for the treatment of cardiovascular diseases

L-type Ca2+ channel-blocking actions of cilnidipine were widely examined in earlier experimental studies, showing that its potency was greater than that of nifedipine. In 1997, N-type Ca2+ channel-blocking action was found in cilnidipine (Uneyama et al., 1997). Submicromolecular concentrations of cilnidipine effectively suppressed N-type Ca2+ channel currents in isolated sympathetic neurons. The inhibitory effect of various dihydropyridines on cardiac L-type Ca2+ channels was further compared in isolated ventricular myocytes with that on N-type Ca2+ channels in superior cervical ganglion neurons of the rat (Uneyama et al., 1999b). In that study, all dihydropyridines, except cilnidipine, showed a small inhibitory effect at a concentration of 1 μM. The N-type channel-blocking action of cilnidipine has also been confirmed in IMR-32 human neuroblastoma cells and PC12 pheochromocytoma of the rat adrenal medulla cells. Furthermore, it has been demonstrated that the N-type Ca2+ channel-blocking effects of cilnidipine leading to anti-sympathetic action can be observed at its anti-hypertensive

(CVD).

**3.1 Pharmacology** 

doses (Takahara et al., 2002).


Dual L/N-Type Ca2+ Channel Blocker: Cilnidipine as a New Type of Antihypertensive Drug 35

and induces renal vasoconstriction, anti-natriuresis and renin secretion via activation of adrenoceptors in the vascular vessels, renal tubular cells and granular cells of the juxtaglomerular apparatus, respectively, which cannot be suppressed by typical L-type Ca2+ channel blockers in several experimental studies (Ogasawara et al., 1993). On the other hand, it has been demonstrated that these responses to renal nerve stimulation are suppressed by natriuretic doses of cilnidipine via its N-type Ca2+ channel blocking property.

Fig. 2. Comparison of effects of Ca2+ channel blockers on hypotension-induced sympathetic

administered to halothane-anesthetized dogs, and changes in mean blood pressure, heart

Glomerular filtration is essentially regulated by afferent and efferent arterial tone. Since sensitivity of Ca2+ channel blockers to afferent and efferent arteries varies, Ca2+ channel blockers should be appropriately selected for hypertensive patients with chronic kidney disease. Since the sympathetic nerves are distributed to the afferent and efferent arteries, N-

activation. Nifedipine, amlodipine, azelnidipine or cilnidipine was intravenously

rate and cardiac contractility were observed. The intravenous doses of nifedipine, amlodipine, azelnidipine and cilnidipine used were 3, 200, 70 and 3 µg/kg, respectively. Values are expressed as means±SE. Data are quoted and modified from Takahara et al., 2007

and Ishizaka et al., 2010.
