Different Effects of L/N-Type and L-Type Calcium Channel Blockers on the Renin-Angiotensin-Aldosterone System in SHR/Izm

Konda, Tomoyuki; Enomoto, Azusa; Aritomi, Shizuka; Niinuma, Kazumi; Koganei, Hajime; Ogawa, Tetsuya; Nitta, Kosaku

doi:10.1159/000210396

Cited by 42 publications

(44 citation statements)

References 40 publications

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“…Cilnidipine caused a significant decrease in renal cortical norepinephrine levels in SHR/Izumo, although treatment with amlodipine did not decrease the tissue level of norepinephrine. 42 These results suggest that the N-type calcium channel-blocking action of cilnidipine suppresses reflex sympathetic hyperactivity.…”

Section: Discussionmentioning

confidence: 88%

“…The sympathetic nervous system is closely related to the renin-angiotensin-aldosterone system. In a recent report, Konda et al 42 investigated the different effects of cilnidipine and amlodipine on plasma aldosterone levels in SHR/Izumo, and they showed that the cilnidipine-treated group had significantly lower plasma aldosterone levels. Furthermore, it has been reported that cilnidipine treatment tended to decrease renal tissue angiotensin II levels in Dahl-salt-sensitive rats.…”

Section: Discussionmentioning

confidence: 99%

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L/N-type calcium channel blocker cilnidipine ameliorates proteinuria and inhibits the renal renin–angiotensin–aldosterone system in deoxycorticosterone acetate-salt hypertensive rats

et al. 2011

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Cilnidipine, an N/L-type calcium channel blocker, has been reported to inhibit sympathetic nerve activity and has a greater renoprotective effect than L-type calcium channel blockers. To investigate the hypothesis that cilnidipine might ameliorate advanced hypertensive nephropathy and inhibit the renal renin-angiotensin-aldosterone system, cilnidipine (1 mg per kg per day) or amlodipine (1 mg per kg per day) was administered to uninephrectomized deoxycorticosterone (DOCA)-salt hypertensive rats (DOCA-salt) for 4 weeks by gavage. Although the blood pressure in the DOCA-salt group was higher than that of control, neither cilnidipine nor amlodipine had any effect on the increase in blood pressure in the DOCA-salt group. The DOCA (40 mg per kg per week, subcutaneously (s.c.)) and salt (1% NaCl in drinking water) treatment significantly aggravated the levels of urinary protein excretion and creatinine clearance and increased glomerulosclerosis and collagen deposition in the tubulointerstitial area of the kidney. These effects were attenuated by cilnidipine treatment. Reverse transcription-polymerase chain reaction analysis revealed that the renal expression of mRNA for collagen I/IV and transforming growth factor-b was enhanced in the DOCA-salt group and that the overexpression of these molecules was suppressed by cilnidipine. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived superoxide production in the kidney and urinary norepinephrine excretion, which were enhanced in the DOCA-salt group, were suppressed by cilnidipine. Cilnidipine also decreased the activity and expression of angiotensin-converting enzyme (ACE) and the aldosterone concentration in the renal homogenate. Although neither cilnidipine nor amlodipine had any effect on the increased blood pressure in the DOCA-salt group, these renal changes were not induced by treatment with amlodipine. In conclusion, cilnidipine inhibited renal dysfunction, sympathetic nerve activity and renal renin-angiotensin-aldosterone system in the DOCA-salt group.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

L/N-type calcium channel blocker cilnidipine ameliorates proteinuria and inhibits the renal renin–angiotensin–aldosterone system in deoxycorticosterone acetate-salt hypertensive rats

et al. 2011

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“…14 N-type calcium channels have been identified in several types of cells, [15][16][17] and these channels have been reported to mediate rapid calcium influx into the synaptic terminal, which triggers synaptic vesicle exocytosis, neurotransmitter release, synaptogenesis, and gene expression. [18][19][20] We have reported that cilnidipine reduced the plasma aldosterone level in spontaneously hypertensive rats 21 and in a canine model of chronic atrioventricular block that is known to show ventricular electrical remodeling; 22 however, the L-type CCB, amlodipine, did not show any suppressive effect on plasma aldosterone levels. These results suggest that N-type calcium channels are important regulators of the plasma aldosterone level.…”

Section: Introductionmentioning

confidence: 92%

Expression of N-type calcium channels in human adrenocortical cells and their contribution to corticosteroid synthesis

et al. 2010

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The inhibition of aldosterone activity is a useful approach for preventing the progression of cardiovascular and renal diseases in hypertensive patients. Although the results of our previous in vivo study suggested that N-type calcium channels may have a role in regulating plasma aldosterone levels, the direct relationship between N-type calcium channels and aldosterone production in adrenocortical cells has not been examined. In this study, the analysis of quantitative reverse transcription-PCR, western blotting, and immunocytological staining indicated the possible presence of N-type calcium channels in human adrenocortical cells (H295R cell line). Patch clamp analysis indicated that omega-conotoxin GVIA (CnTX), an N-type calcium channel inhibitor, suppressed voltage-dependent barium currents. During steroidogenesis, CnTX significantly reduced the transient calcium signaling induced by angiotensin II (Ang II) and partially prevented Ang II-induced aldosterone and cortisol formation with no significant influence on CYP11B2 and CYP11B1 mRNA expression. In addition, in a1B calcium channel subunits, knockdown significantly decreased Ang II-induced aldosterone formation with increments in CYP11B2 mRNA expression. We also investigated the inhibitory activities of some types of dihydropyridine calcium channel blockers (CCBs; cilnidipine: L-/N-type CCB, efonidipine: L-/T-type CCB, and nifedipine: L-type CCB), and these agents showed a dose-dependent inhibition effect on Ang II-induced aldosterone and cortisol production. Furthermore, only cilnidipine failed to suppress CYP11B1 expression in H295R cells. These results suggest that N-type calcium channels have a significant role in transducing the Ang II signal for aldosterone (and cortisol) biosynthesis, which may explain the mechanism by which N-type calcium channels regulate plasma aldosterone levels.

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“…Previous in vitro electrophysiological studies have demonstrated that angiotensin II decreases IKr, transient outward K+ currents (Ito) and inward rectifier K+ currents (IK1) of the cardiomyocytes [27][28][29] and that aldosterone decreases Ito. [30] Based on the differences in the effects on the neurohumoral factors between cilnidipine and other drugs, it can be speculate that the inhibitory effect of cilnidipine on the renin-angiotensin-aldosterone system by its N-type calcium channel blocking action [31][32][33][34] may have decreased the suppression of the K+ channels. It is well known that angiotensin II and aldosterone have direct proarrhythmic effects which by several BP-independent mechanisms such as an increase in sympathetic activation, increases in extracellular Ca 2+ entry and Ca 2+ release from intracellular stores and modulation of voltage-dependent potassium channels stated above.…”

Section: Discussionmentioning

confidence: 99%

Comparative assessment of effects of calcium channel antagonists, amlodipine, and cilnidipine, on QT interval in hypertensive patients - An observational study

Sarkar¹,

Srivastava²,

Mohanty³

2017

Natl J Physiol Pharm Pharmacol

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Background:The duration of the QT interval as measured by 12-lead electrocardiography is a measure of myocardial repolarization and is widely used to describe cardiac abnormalities, to determine the presence of cardiac toxicity and to evaluate drug safety. In hypertension, the QT interval is a predictor of the risk of both coronary events and cardiovascular death, after adjusting for the effects of additional risk factors. According to AHA and JNC VIII calcium channel blockers are first-line drug in the treatment of hypertension. The equipotent antihypertensive effect of cilnidipine and amlodipine in their equivalent dose has been demonstrated in number of studies. Aims and Objectives: To compare and evaluate the effects of calcium channel antagonists amlodipine and cilnidipine on QT interval among hypertensive patients. Materials and Methods: A total of 258 patients were screened, examined, and enrolled as study participants during that period. The enrolled patients were then divided as (1) hypertensive patient (n = 159) -selected patients received either amlodipine (2.5-10 mg) or cilnidipine (5-20 mg) with or without angiotensin receptor blocker (ARB) and (2) hypertensive with controlled diabetic patients (n = 99) -selected patients received either amlodipine (2.5-10 mg) or cilnidipine (5-20 mg) with or without ARB along with antidiabetic medication. Calculated by Bazett's formula (most commonly used) = QT Interval/√ (relative risk [RR] interval) where RR interval = 60/heart rate, normal QTc ≤440 ms. The QT interval was measured at the baseline and after 12 months of treatment for hypertensive patients. Results: There was extremely significant QTc reduction was seen with cilnidipine therapy and significant elevation seen by amlodipine treatment but without any clinical relevance. While comparing the effect of amlodipine and cilnidipine, extremely significant as well as clinically relevant difference between the two treatments was noted. Conclusions: From this study, it can be concluded that cilnidipine reduces QTc interval, and hence is a better choice over amlodipine for patients suffering from long QT interval.

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Different Effects of L/N-Type and L-Type Calcium Channel Blockers on the Renin-Angiotensin-Aldosterone System in SHR/Izm

Cited by 42 publications

References 40 publications

L/N-type calcium channel blocker cilnidipine ameliorates proteinuria and inhibits the renal renin–angiotensin–aldosterone system in deoxycorticosterone acetate-salt hypertensive rats

L/N-type calcium channel blocker cilnidipine ameliorates proteinuria and inhibits the renal renin–angiotensin–aldosterone system in deoxycorticosterone acetate-salt hypertensive rats

Expression of N-type calcium channels in human adrenocortical cells and their contribution to corticosteroid synthesis

Comparative assessment of effects of calcium channel antagonists, amlodipine, and cilnidipine, on QT interval in hypertensive patients - An observational study

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