Blockade of N‐type Ca<sup>2+</sup> current by cilnidipine (FRC‐8653) in acutely dissociated rat sympathetic neurones

Uneyama, Hisayuki; Takahara, Akira; Dohmoto, Hideki; Yoshimoto, Ryota; Inoue, Kazuhide; Akaike, Norio

doi:10.1038/sj.bjp.0701342

Cited by 97 publications

(52 citation statements)

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“…Cilnidipine directly blocked the isolated N-type channel current (IC 50 value, Ϸ1 mol/L) but had no effect on the R-type channel current in the differentiated rat PC12 cells (Figs 5 and 6). This observation agreed with previous findings using rat superior ganglion neurons 5 and dorsal horn ganglion neurons. 4 Blockade of N-type Ca 2ϩ channels by cilnidipine results in reduced Ca 2ϩ influx through these channels and thereby reduces CA secretions closely linked with [Ca 2ϩ ] i elevation, which is evoked by various depolarizing stimulations.…”

Section: Discussionsupporting

confidence: 83%

“…1,2 Recent electrophysiological data indicate that cilnidipine might be a dual-channel antagonist for peripheral neuronal N-type and vascular L-type Ca 2ϩ channels. [3][4][5] In humans and rodents, cilnidipine depressed the pressor response to acute cold stress but failed to induce tachycardia evoked by hypotensive baroreflexes. 6,7 In spontaneously hypertensive rats, vasoconstriction induced by electrical sympathetic nerve stimulation was also blocked by cilnidipine.…”

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confidence: 99%

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Effects of a Novel Antihypertensive Drug, Cilnidipine, on Catecholamine Secretion From Differentiated PC12 Cells

et al. 1998

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Abstract-Effects of a novel dihydropyridine type of antihypertensive drug, cilnidipine, on the regulation of the catecholamine secretion closely linked to the intracellular Ca 2ϩ were examined using nerve growth factor (NGF)-differentiated rat pheochromocytoma PC12 cells. By measuring catecholamine secretion with high-performance liquid chromatography coupled with an electrochemical detector, we showed that high K ϩ stimulation evoked dopamine release from PC12 cells both before and after NGF treatments. Cilnidipine depressed dopamine release both from NGF-treated and untreated PC12 cells in a concentration-dependent manner. In contrast, inhibition by nifedipine was markedly decreased in the differentiated PC12 Key Words: cilnidipine Ⅲ calcium channels Ⅲ calcium, cytoplasmic Ⅲ dopamine C ilnidipine (FRC-8653) is a newly synthesized DHP type of organic Ca 2ϩ channel blocker that has been developed as a slow-onset and long-lasting antihypertensive drug in Japan. 1,2 Recent electrophysiological data indicate that cilnidipine might be a dual-channel antagonist for peripheral neuronal N-type and vascular L-type Ca 2ϩ channels. [3][4][5] In humans and rodents, cilnidipine depressed the pressor response to acute cold stress but failed to induce tachycardia evoked by hypotensive baroreflexes. 6,7 In spontaneously hypertensive rats, vasoconstriction induced by electrical sympathetic nerve stimulation was also blocked by cilnidipine. 8 In in vitro experiments, cilnidipine also inhibited [ 3 H]norepinephrine release evoked by electrical stimulation in the rabbit mesenteric artery. 9 PC12 cells are derived from a rat pheochromocytoma cell line that is very popular for investigating neuronal differentiation. In response to externally applied NGF, PC12 cells acquire sympathetic neuronal characteristics such as neurite extension, increased CA synthesis, and expression of neuronal types of voltage-dependent N-type Ca 2ϩ channels. 10 -12 Therefore, the differentiated PC12 cells are widely used as model cells for studying the intracellular mechanisms of the stimulus-secretion coupling, including the activation of the N-type Ca 2ϩ channel. 13,14 With this model cell, it has been revealed that endogenous substances such as neuropeptide Y and proadrenomedullin N-terminal 20 peptide inhibit CA release by inhibiting Ca 2ϩ influx through N-type Ca 2ϩ channels. 15,16 In the present study, we examined the effects of cilnidipine on the cellular functions of the NGF-treated PC12 cells, including CA secretion and intracellular Ca 2ϩ mobilization triggered by membrane depolarizations. Consequently, in addition to its well-known L-type Ca 2ϩ channel blockade, 3 it was clarified that cilnidipine had a potent inhibitory effect for CA secretion from differentiated PC12 cells via the blockade of extracellular Ca 2ϩ influx through the N-type Ca 2ϩ channel. Methods Cell CulturePC12 cells were prepared as described previously. 17 In brief, cells were cultured in Dulbecco's modified Eagle's medium containing 7% fetal bovine serum (Gibco), 7% heat-ina...

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Section: Discussionsupporting

confidence: 83%

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confidence: 99%

Effects of a Novel Antihypertensive Drug, Cilnidipine, on Catecholamine Secretion From Differentiated PC12 Cells

et al. 1998

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“…[10][11][12]18) The N-type calcium channel is involved in sympathetic neurotransmission, [14][15][16] and it was shown that cilnidipine suppresses the release of norepinephrine from sympathetic nerve terminals in perfused SHR mesentery specimens. It was shown that cilnidipine suppresses sympathetic nerve activity of SHRs as well as normotensive rats.…”

Section: Discussionmentioning

confidence: 99%

“…[10][11][12] The L-type calcium channel is the usual target of DHP calcium blockers, thus it is DHP-sensitive, 13) and the Ntype calcium channel is DHP-insensitive. Several studies have shown that when norepinephrine (NE) is released from sympathetic nerve terminals there is an influx of extracellular calcium through calcium channels.…”

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confidence: 99%

Vasodilatory Effect of Cilnidipine, an L-type and N-type Calcium Channel Blocker, on Rat Kidney Glomerular Arterioles

Konno

Kimura

2008

Int. Heart J.

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SUMMARYCilnidipine is a dihydropyridine calcium channel blocker that acts on both L-type and N-type calcium channels.The effects of cilnidipine given intravenously at doses of 2.5, 5.0, and 10 µg/kg were studied using an ex vivo hydronephrosis model in spontaneously hypertensive rats. The effects of nifedipine at a dose of 10 µg/kg were also studied using the same model as a reference.Cilnidipine caused dose-dependent blood pressure reduction and dilatation of the glomerular afferent arterioles; the arteriolar diameter after cilnidipine infusion at 2.5, 5.0, and 10 µg/kg was 101% ± 3%, 112% ± 4%, and 123% ± 6% relative to baseline, respectively. With cilnidipine, dilatation of the efferent arterioles was also observed; it was maximal after 5 to 10 minutes. Five minutes after administration of 2.5, 5.0, and 10 µg/kg of cilnidipine, the efferent arteriolar diameter was 103% ± 2%, 109% ± 4%, and 119% ± 4% of baseline, respectively. This efferent arteriolar dilating action of cilnidipine was abolished after pretreatment with ω-conotoxin, a selective N-type calcium channel blocker. A dose-dependent increase of glomerular blood flow volume was also observed after cilnidipine infusion. Nifedipine, an L-type calcium channel blocker, at a dose of 10 µg/kg reduced systolic blood pressure to a similar extent as cilnidipine at a dose of 10 µg/kg, but only dilated the afferent arterioles and had no significant effect on efferent arterioles.Cilnidipine dilated both the afferent and efferent glomerular arterioles. The efferent arteriolar dilating effect of cilnidipine may be attributed to its inhibition of the N-type calcium channel. (Int Heart J 2008; 49: 723-732)

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“…[19][20][21][22] The N-type voltage-dependent calcium channel has an important role in sympathetic neurotransmission and regulates the release of NE from sympathetic nerve endings. 23 Cilnidipine inhibits SNA and heart rate and lowers BP in hypertensive patients.…”

Section: Introductionmentioning

confidence: 99%

Efficacy of an L- and N-type calcium channel blocker in hypertensive patients with neurovascular compression of the rostral ventrolateral medulla

et al. 2009

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The rostral ventrolateral medulla is an important regulation center of sympathetic nerve activity. Several clinical studies have indicated a possible association between essential hypertension and neurovascular compression of the rostral ventrolateral medulla. We have found that patients with essential hypertension and neurovascular compression of the rostral ventrolateral medulla by adjacent arteries have increased sympathetic nerve activity and that microvascular decompression of the rostral ventrolateral medulla normalizes blood pressure and sympathetic nerve activity. Although sympatholytic agents are expected to lower blood pressure in these patients, this remains to be clarified. In this study, we evaluated the effect of cilnidipine, a calcium channel blocker that blocks both vascular L-type and sympathetic N-type Ca 2+ channels in hypertensive patients with neurovascular compression. Using high-resolution magnetic resonance imaging, 46 patients with untreated essential hypertension were distributed into those with and without neurovascular compression of the rostral ventrolateral medulla. All patients were prescribed 10 mg of cilnidipine for 16 weeks. Office and home blood pressure, plasma norepinephrine and left ventricular mass index were measured by echocardiography before and after cilnidipine treatment, and changes were compared between the two groups. At baseline, plasma norepinephrine was significantly higher in patients with neurovascular compression. Decreases in office and home blood pressure, plasma norepinephrine and left ventricular mass index were significantly greater in patients with neurovascular compression. These results suggest that cilnidipine lowers blood pressure by inhibiting enhanced sympathetic nerve activity and reduces left ventricular mass in hypertensive patients with neurovascular compression of the rostral ventrolateral medulla.

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Blockade of N‐type Ca²⁺ current by cilnidipine (FRC‐8653) in acutely dissociated rat sympathetic neurones

Cited by 97 publications

References 30 publications

Effects of a Novel Antihypertensive Drug, Cilnidipine, on Catecholamine Secretion From Differentiated PC12 Cells

Effects of a Novel Antihypertensive Drug, Cilnidipine, on Catecholamine Secretion From Differentiated PC12 Cells

Vasodilatory Effect of Cilnidipine, an L-type and N-type Calcium Channel Blocker, on Rat Kidney Glomerular Arterioles

Efficacy of an L- and N-type calcium channel blocker in hypertensive patients with neurovascular compression of the rostral ventrolateral medulla

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Blockade of N‐type Ca2+ current by cilnidipine (FRC‐8653) in acutely dissociated rat sympathetic neurones

Cited by 97 publications

References 30 publications

Effects of a Novel Antihypertensive Drug, Cilnidipine, on Catecholamine Secretion From Differentiated PC12 Cells

Effects of a Novel Antihypertensive Drug, Cilnidipine, on Catecholamine Secretion From Differentiated PC12 Cells

Vasodilatory Effect of Cilnidipine, an L-type and N-type Calcium Channel Blocker, on Rat Kidney Glomerular Arterioles

Efficacy of an L- and N-type calcium channel blocker in hypertensive patients with neurovascular compression of the rostral ventrolateral medulla

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Blockade of N‐type Ca²⁺ current by cilnidipine (FRC‐8653) in acutely dissociated rat sympathetic neurones