Effects of benidipine hydrochloride (Coniel) on blood pressure, heart rate and plasma norepinephrine concentration in spontaneously hypertensive rats]

We investigated the effects of benidipine hydrochloride (benidipine, Coniel) on blood pressure, heart rate and plasma norepinephrine (NE) concentration in spontaneously hypertensive rats and compared them with those of other calcium channel blockers. Benidipine (2 mg/kg, p.o.) was compared with the equihypotensive doses of nifedipine (5 mg/kg), cilnidipine (6 mg/kg) and amlodipine (3 mg/kg). All the 4 calcium channel blockers exhibited significant antihypertensive effects. Nifedipine and cilinidipine significantly increased heart rate, as compared with that in the control group, whereas benidipine or amlodipine did not significantly affect it. The area under the curves for hypotensive effect and tachycardic effect for 10 hr after the drug administration were compared among the 4 compounds. As a result, the tachycardic effect of benidipine was significantly lower than those of nifedipine, cilnidipine and amlodipine, while the hypotensive effects were similar among the 4 compounds. Nifedipine and amlodipine, significantly increased plasma NE concentration, cilnidipine tended to increase it. In contrast, benidipine did not significantly affect plasma NE concentration. These results suggest that the effects of benidipine on plasma NE concentration and heart rate are less prominent than those of the other calcium channel blockers.     

Comparison between the antiproteinuric effects of the calcium channel blockers benidipine and cilnidipine in combination with angiotensin receptor blockers in hypertensive patients with chronic kidney disease

Aims: Benidipine, an L-/T-type calcium channel blocker, dilates renal efferent and afferent arterioles and reduces glomerular pressure; therefore, it may exert renoprotective effects. We conducted an open-labeled randomized trial to compare the effects of benidipine with cilnidipine in hypertensive patients with chronic kidney disease (CKD).

Methods: The patients who were already being treated with angiotensin receptor blockers (ARBs) received one of the following treatment regimens: benidipine at a dose of 2 mg/day that was increased up to a dose of 8 mg/day (benidipine group; n = 118) or cilnidipine at a dose of 5 mg/day that was increased up to a dose of 20 mg/day (cilnidipine group; n = 115).

Results: After 12 months of treatment, we observed a significant and comparable reduction in the systolic and diastolic blood pressure in both groups. The urinary protein:creatinine ratio was significantly decreased in both groups after 3 months of treatment and thereafter; however, the difference between both groups was not significant after 12 months of treatment. Benidipine exerted an antiproteinuric effect to a greater extent than cilnidipine in patients with diabetes.

Conclusion: The addition of benidipine as well as cilnidipine reduces urinary protein excretion in hypertensive patients with CKD who are already being administered ARBs.     

Blockade of T-type voltage-dependent Ca2+ channels by benidipine, a dihydropyridine calcium channel blocker, inhibits aldosterone production in human adrenocortical cell line NCI-H295R

Benidipine, a long-lasting dihydropyridine calcium channel blocker, is used for treatment of hypertension and angina. Benidipine exerts pleiotropic pharmacological features, such as renoprotective and cardioprotective effects. In pathophysiological conditions, the antidiuretic hormone aldosterone causes development of renal and cardiovascular diseases. In adrenal glomerulosa cells, aldosterone is produced in response to extracellular potassium, which is mainly mediated by T-type voltage-dependent Ca2+ channels. More recently, it has been demonstrated that benidipine inhibits T-type Ca2+ channels in addition to L-type Ca2+ channels. Therefore, effect of calcium channel blockers, including benidipine, on aldosterone production and T-type Ca2+ channels using human adrenocortical cell line NCI-H295R was investigated. Benidipine efficiently inhibited KCl-induced aldosterone production at low concentration (3 and 10 nM), with inhibitory activity more potent than other calcium channel blockers. Patch clamp analysis indicated that benidipine concentration-dependently inhibited T-type Ca2+ currents at 10, 100 and 1000 nM. As for examined calcium channel blockers, inhibitory activity for T-type Ca2+ currents was well correlated with aldosterone production. L-type specific calcium channel blockers calciseptine and nifedipine showed no effect in both assays. These results indicate that inhibition of T-type Ca2+ channels is responsible for inhibition of aldosterone production in NCI-H295R cells. Benidipine efficiently inhibited KCl-induced upregulation of 11-beta-hydroxylase mRNA and aldosterone synthase mRNA as well as KCl-induced Ca2+ influx, indicating it as the most likely inhibition mechanism. Benidipine partially inhibited angiotensin II-induced aldosterone production, plus showed additive effects when used in combination with the angiotensin II type I receptor blocker valsartan. Benidipine also partially inhibited angiotensin II-induced upregulation of the above mRNAs and Ca2+ influx inhibitory activities of benidipine for aldosterone production. T-type Ca2+ channels may contribute to additional benefits of this drug for treating renal and cardiovascular diseases, beyond its primary anti-hypertensive effects from blocking L-type Ca2+ channels.     

Different effects of L-type and L+N-type calcium channel blockers on hamster cheek pouch venules

Dihydropyridine calcium channel blockers are not uniform in terms of their action on calcium channel. L-type calcium channel blockers dilate the resistance arterioles. Cilnidipine is a dihydropyridine calcium channel blocker that also acts on N-type calcium channels, and may dilate venules through its effect on the sympathetic receptor. The influence of an L-type calcium channel blocker (nifedipine) or this L+N type blocker at 10(-7) mol to 10(-4) mol on venular diameter was examined by superfusion of male Syrian hamster cheek pouches. Nifedipine dose dependently dilated the arterioles alone, whereas cilnidipine dilated both arterioles and venules. Application of 10(-7) mol omega conotoxin, an inhibitor of N-type channels, after nifedipine led to significant dilation of venules, while it had no influence when administered after cilnidipine. These findings indicate that the effects of calcium channel blockers on the venules differ according to the action on N-type calcium channels, and that cilnidipine (an L+N type calcium channel blocker) dilates venules through its additional action on N-type channels.     

Antihypertensive efficacy and safety of benidipine and its effects on cardiac structure and function in elderly Chinese patients with mild to moderate hypertension: an open-label, long-term study

Benidipine (CAS 91599-74-5) has been reported as an effective antihypertensive treatment and its cardioprotective effects have been shown in several basic and clinical studies. However, the long-term efficacy and safety of benidipine remain unknown in elderly Chinese patient with hypertension. In this prospective, multicenter, open-label clinical trial, 152 eligible patients aged 60 to 75 years with mild to moderate essential hypertension (sitting systolic blood pressure (BP) > or = 140 mmHg and/or sitting diastolic BP > or = 90 mmHg) entered a 52-week study. All patients initially received benidipine 2-4 mg once a day, followed by titration to benidipine 8 mg/day to achieve the target BP (< 140/90 mmHg in non-diabetics and <130/80 mmHg in diabetics). Add-on hydrochlorothiazide (CAS 58-93-5) and/or metoprolol tartaric acid (CAS 3750-58-6) were permitted during the study. Overall, 132 patients completed the 52-week treatment with benidipine as monotherapy or combination therapy. It showed that the regimen based on benidipine provided an obvious mean trough BP reduction of 13.8 +/- 12.4/8.3 +/- 9.2 mmHg (p < 0.001), and 62.5% of patients reached the target BP. In patients with left ventricular hypertrophy, the left ventricular mass index significantly decreased from 147.1 +/- 27.6 g/m2 at baseline to 136.0 +/- 17.5 g/m2 at 52 weeks (p = 0.036). Clinical adverse events (AEs) were found in 15.1% of all patients, and six patients discontinued the treatment due to drug-related AEs during the entire trial. Patients' compliance was an average of 98.7%. Benidipine, with a favorable tolerability profile, provides a long-term antihypertensive effect and potential benefit for the heart in elderly patients with mild to moderate hypertensive, suggesting that it is suitable for elderly patients with hypertension.     

Investigational calcium channel blockers for the treatment of hypertension

Introduction: Voltage-gated Ca²⁺ channels are the primary route of Ca²⁺ entry in vascular smooth muscle cells, playing a key role in the regulation of arterial tone and blood pressure. Since the 60´s, L-type Ca²⁺ channel blockers (CCBs) have been widely used for the treatment of hypertension.

Areas covered: T-type Ca²⁺ channels regulate vascular tone in small-resistance vessels and aldosterone secretion, and N-type channels expressed in sympathetic nerve terminals regulate the release of neurotransmitters. We performed a literature search in MEDLINE, PubMed and ClinicalTrials.gov to identify eligible studies published between January 2001 and March 2016 and reviewed the antihypertensive and renoprotective effects of four CCBs with different pharmacological profiles: azelnidipine (L-type), cilnidipine (L-/N-type) and benidipine and efonidipine (L-/T-type CCBs). Despite similar blood pressure lowering effects, L/N- and L/T-type CCBs, compared with L-type CCBs, decreased intraglomerular pressure, improved renal hemodynamics and provided a greater decrease in proteinuria even in patients already treated with renin-angiotensin-aldosterone inhibitors.

Expert opinion: Dual L/N- and L/T-type CCBs may exhibit therapeutic advantages over L-type blockers in hypertensive patients with chronic kidney disease. Because clinical trials supporting these advantages present important biases, further large-scale, long-term comparative trials are needed to confirm that these differences translate into improved clinical outcomes.     

Effect of cilnidipine on L- and T-type calcium currents in guinea pig ventricle and action potential in rabbit sinoatrial node

Cilnidipine, a dihydropyridine Ca(2+) channel antagonist, is known to have inhibitory effects on both L- and N-type Ca(2+) currents. In the present study, we examined the effect of cilnidipine on myocardial L- and T-type Ca(2+) currents and sinoatrial node action potential configuration. In voltage clamped guinea pig ventricular myocytes, cilnidipine concentration-dependently decreased L- and T-type Ca(2+) currents. In rabbit sinoatrial node tissue, cilnidipine increased cycle length through reduction of phase 4 depolarization slope. In conclusion, cilnidipine has inhibitory effects on T-type Ca(2+) current, which may contribute to its negative chronotropic potency.     

Clinical efficacy of benidipine for vasospastic angina pectoris

BACKGROUND: Most patients with vasospastic angina who have no significant organic coronary arterial stenosis are well controlled by medical therapy and the prognosis is almost satisfactory. Calcium channel (Ca) blockers are used as the first choice and effective agents for vasospastic angina pectoris. However, they do not always work well. Some uncontrolled coronary vasospasms would happen to cause prolonged occlusion of coronary artery resulting in myocardial infarction, life-threatening arrhythmias and sudden death. Therefore, it is very important to pay attention to such a refractory coronary spasm and choose the most effective agent out of Ca blockers for the treatment of each patient with vasospastic angina attacks. This study was designed to evaluate the anti-vasospastic efficacy of benidipine, a long acting dihydropyridine (DHP) Ca blocker, in patients with other Ca blockers-resistant angina. METHODS: Patients treated with diltiazem but not enough to control angina attacks were enrolled in the present study. Treatment with diltiazem (CAS 33286-22-5, 42399-41-7) was changed to treatment with benidipine (CAS 91599-74-5) and the parameters such as angina frequency, duration, blood pressure, heart rate, electrocardiogram and hematological parameters (serum NO(x), plasma cGMP) were measured and compared. RESULTS: Fifteen patients with vasospastic angina were enrolled. After switching from diltiazem to benidipine, angina attacks were completely disappeared in six patients. Although the frequency was not decreased, the average duration of attacks was shorter than before in three patients. Four patients did not improve and two patients obviously worsened. In the improved nine patients, serum nitrite/nitrate (NO(x)) levels showed a significant increase from 37.6 +/- 15.3 to 54.5 +/- 26.7 pmol/L (p < 0.05) and cGMP levels subsequently elevated from 2.2 +/- 0.8 to 2.5 +/- 0.6 micromol/L (p = 0.05) after benidipine therapy started. Adverse effects such as hypotension and bradycardia were not observed. CONCLUSION: This study suggests that benidipine may be helpful in Japanese patients with vasospastic or variant angina pectoris, if diltiazem was not successful.     

Effects of benidipine and some other calcium channel blockers on the prognosis of patients with vasospastic angina. Cohort study with evaluation of the ergonovine coronary spasm induction test

BACKGROUND: It has been reported that the morbidity rate of vasospastic angina is higher in Japan compared to western countries, and its prognosis has already been reported. However, the prognosis of vasospastic angina in relation to coronary angiographic findings, prognostic risk factors and treatment has not yet been fully investigated. METHODS AND RESULTS: From January 2000 to October 2005, 1047 patients with vasospastic angina diagnosed by coronary angiography at Gifu University Hospital and related hospitals were registered in a cohort study (follow-up rate: 91.4%, median follow-up duration: 3.8 years). The presence of coronary artery stenosis, diabetes mellitus, total spasm, and age of more than 65 years had a negative prognostic impact on cardiovascular events. Patients were treated with calcium channel blockers such as diltiazem (CAS 33286-22-5, CAS 42399-41-7), amlodipine (CAS 111470-99-6), nifedipine (CAS 21829-25-4), and benidipine (CAS 91599-74-5). Among these calcium channel blockers, when patient background was matched by the propensity score in patients treated with calcium channel blockers only, the cardiovascular event rate was significantly lower in the benidipine group than in the diltiazem group. CONCLUSION: The study demonstrated for the first time that total spasm is a risk factor, independent of other factors, for cardiovascular events in patients with vasospastic angina. Treatment with benidipine showed a better prognosis than that with diltiazem.     

Effects of benidipine, a long-lasting dihydropyridine-Ca2+ channel blocker, on cerebral blood flow autoregulation in spontaneously hypertensive rats

Chronic hypertension shifts cerebral blood flow (CBF) autoregulation towards higher blood pressure. We examined whether or not benidipine, a long-lasting dihydropyridine calcium channel blocker (CCB), improves the CBF autoregulation in spontaneously hypertensive rats (SHRs). CBF was analyzed by laser-Doppler flowmetry during stepwise hypotension by controlled bleeding. The lower limit of CBF autoregulation was calculated as the mean arterial blood pressure at which CBF decreased by 10% of the baseline. Mean arterial blood pressure and cerebral vascular resistance in SHRs were higher than those in normotensive Wistar rats. Oral administration of benidipine (3 mg/kg) for 8 d lowered the mean arterial blood pressure and cerebral vascular resistance, which were equivalent to the effects of amlodipine (3 mg/kg), another CCB, or candesartan (1 mg/kg), an Angiotensin II type-1 receptor blocker. The lower limit of CBF autoregulation in SHRs (142+/-4 mmHg) was significantly shifted to a higher-pressure level compared with Wistar rats (59+/-2 mmHg). The lower limit of CBF autoregulation was significantly lower in the benidipine-treated group (91+/-4 mmHg) than that in the control SHRs, and similar to that of the amlodipine group (97+/-6 mmHg). Benidipine reduced the lower limit of CBF autoregulation more effectively than candesartan (109+/-4 mmHg). In conclusion, benidipine shifted the limit of CBF autoregulation towards lower blood pressure in SHRs under hypotensive conditions by hemorrhage. These results suggest that benidipine may be useful for the treatment of hypertensive patients with the elderly or cerebrovascular disorders, in whom autoregulation of CBF is impaired.     

Pharmacological, pharmacokinetic, and clinical properties of benidipine hydrochloride, a novel, long-acting calcium channel blocker

Benidipine is a dihydropyridine-derived calcium channel blocker developed in Japan, with several unique mechanisms of action, that is, triple calcium channels (L, N, and T) blocking action with a membrane approach. Benidipine has relatively high vascular selectivity and is expected to show protective effects on vascular endothelial cells. Renal protective effects of benidipine also have been shown in several basic and clinical studies. Moreover, anti-oxidative action and enhancing nitric oxide production have been noted with this drug, following its cardio-protective effects in patients with ischemic heart diseases. In fact, benidipine exerted a better prognostic effect than other calcium channel blockers in the therapy for patients with vasospastic angina. In addition, benidipine showed reliable antihypertensive, renoprotective effects if used in combination with angiotensin II type 1 receptor blockers (ARBs) when adequate anti-hypertensive effects are not achieved by ARBs alone, indicating that benidipine is an useful calcium channel blocker in combination therapy for hypertension. Benidipine was launched on the Japanese market 14 years ago, but few severe side effects have been reported, suggesting that this is a drug with established safety and long-acting pharmacological effects.     

贝尼地平和培哚普利对老年高血压病伴蛋白尿患者肾功能的影响

目的比较新型钙通道阻滞剂贝尼地平与血管紧张素转换酶抑制剂培哚普利对老年高血压病伴蛋白尿患者肾脏保护作用的差别。方法将60例24h尿蛋白总量<1g的老年高血压病患者,随机分为贝尼地平组(A组)与培哚普利组(B组),分别给予贝尼地平与培哚普利治疗12月,比较A、B两组治疗前后收缩压(SBP),舒张压(DBP),24h尿蛋白(Pro)、血清肌酐(Scr)、肾小球滤过率(GFR)的差别。结果①治疗前A、B两组SBP、DBP、Pro、Scr、GFR无显著性差异(P>0.05);②A、B两组治疗后SBP、DBP、Scr较治疗前有显著下降,GFR均明显升高(P<0.05);③治疗后AB两组间SBP、DBP、Scr、GFR无明显差异(P>0.05)。结论贝尼地平与培哚普利比较,对老年高血压伴蛋白尿的患者,具有相似的肾脏保护作用。     

Evidence for the involvement of distinct voltage-sensitive calcium channels in the release of 3H-dopamine from primary cultures of mesencephalic neurons

In ventral mesencephalic neurons cultured for five days the K+-evoked 3H-dopamine release is mediated through activation of N-type Ca2+ channels, while L- or T-type channels appear to be inactive. In contrast, veratridine-elicited release of 3H-dopamine that was attenuated by tetrodotoxin was not altered by N-, L-, nor T-type Ca2+ channel blockers.     

Effects of benidipine hydrochloride on 24-hour blood pressure and blood pressure response to mental stress in elderly patients with essential hypertension

OBJECTIVE: The effects of a new dihydropyridine calcium antagonist, benidipine hydrochloride, on 24-hour blood pressure and blood pressure response to mental arithmetic test were investigated. SUBJECTS: Ten elderly patients with essential hypertension (mean age: 65+/-4 years; 7 male and 3 female). METHOD: After a control period of 4 weeks, 4 mg benidipine was administered once daily in the morning for 12 weeks. Ambulatory blood pressure was monitored using a non-invasive automatic portable device with the cuff-oscillometric method at the end of both the control and treatment periods. RESULTS: Benidipine administration significantly decreased 24-hour blood pressure, while little change was noted in heart rate. Daytime blood pressure decreased significantly, from 148.2+/-11.5/90.8+/-8.8 to 133.8+/-9.2/82.5+/-10.8 mmHg. However, no significant decrease in nighttime diastolic blood pressure was noted, and the decrease in nighttime systolic blood pressure was small (from 129.8+/-9.9/77.1+/-7.6 to 121.8+/-10.1/74.7+/-9.1 mmHg). No significant changes were observed in diurnal variability of blood pressure and heart rate. The decrease in systolic blood pressure by benidipine administration showed a significant positive correlation with systolic blood pressure before treatment in the 24-hour and daytime periods. Single cosinor analysis showed that benidipine administration significantly decreased MESOR of both systolic and diastolic blood pressure, without an increase in amplitude. Both systolic and diastolic blood pressure during mental arithmetic test were significantly decreased after treatment with benidipine, and the increase in systolic blood pressure induced by mental arithmetic test was also significantly attenuated. CONCLUSIONS: These findings indicate that administration of benidipine once daily in the morning effectively decreases blood pressure and attenuates blood pressure response to mental stress. Neither reflex tachycardia, deterioration of diurnal blood pressure change, nor excessive lowering of nighttime blood pressure was observed after benidipine administration. It is suggested that benidipine is a potent and long-lasting calcium antagonist which may be useful for the treatment of elderly hypertensive patients with cardiovascular disease.     

Antisympathetic and hemodynamic property of a dual L/N-type Ca(2+) channel blocker cilnidipine in rats.

The in vivo antisympathetic property of a dual L/N-type Ca(2+) channel blocker cilnidipine compared with that of typical N-type Ca(2+) channel blockers has never been clarified. We investigated the effects of the drug on a sympathetic nerve-mediated vascular response and vasodilating action in rats in comparison with those of an N-type Ca(2+) channel blocker omega-conotoxin MVIIA. In pithed rats, omega-conotoxin MVIIA preferentially suppressed the sympathetic nerve stimulation-induced pressor response, whereas cilnidipine suppressed the pressor response induced by sympathetic nerve stimulation and angiotensin II. In anesthetized rats, cilnidipine or omega-conotoxin MVIIA decreased mean blood pressure, while heart rate was decreased by omega-conotoxin MVIIA, but slightly increased by cilnidipine. These results suggest that cilnidipine can affect sympathetic N-type Ca(2+) channels in addition to vascular L-type Ca(2+) channels in antihypertensive doses in the rat in vivo. The antisympathetic activity of cilnidipine is not excessive for an antihypertensive drug in comparison with that of omega-conotoxin MVIIA.     

Prognostic effects of benidipine in patients with vasospastic angina: comparison with diltiazem and amlodipine

We have previously reported the changing clinical characteristics of patients with vasospastic angina (VSA) before and after the introduction of new calcium channel blockers (benidipine and amlodipine) in 1990. In this subanalysis study, we compared the prognostic effects of 3 calcium channel blockers (benidipine, diltiazem, and amlodipine) on the incidence of cardiovascular events in patients with VSA in our cohort study, where 527 patients (318 men and 209 women) enrolled after 1990 (from January 1990 to December 2002) were followed-up for a mean period of 5.2 years. There was no significant difference in the clinical characteristics among the 3 calcium channel blocker groups. Multivariate analysis demonstrated that 4 factors, including smoking, hypertension, diabetes mellitus and reduced left ventricular ejection fraction, were significant risk factors for cardiovascular events. Among the 3 calcium channel blockers examined, benidipine (n = 148) tended to be associated with a lower incidence of total events, cardiovascular events, and cerebral infarction, compared with diltiazem (n = 313) and amlodipine (n = 111). Furthermore, benidipine significantly reduced the incidence of vascular infarction events, a possible indicator of atherosclerosis, as compared with diltiazem. These results suggest that benidipine may be more useful for the treatment of VSA as compared with diltiazem and amlodipine.     

Combined effects of benidipine and diltiazem on cardiohemodynamics in anesthetized dogs

We examined the combined effects of the calcium channel blockers 1,4-dihydropyridine (benidipine) and benzothiazepine (diltiazem) on cardiohemodynamics in anesthetized dogs. Benidipine (3 microg/kg) lowered blood pressure (BP) slightly and continuously increased coronary flow (CF). Diltiazem (300, 1000 microg/kg) decreased BP, heart rate (HR), and the maximum rate of rise of left ventricular pressure (LV dP/dt max) with the increase of doses. Diltiazem increased CF, though it was transient when compared to benidipine. A combination of benidipine (3 microg/kg) and diltiazem (300 microg/kg) showed continuous decreases in BP, HR, and LV dP/dt max, and an increase in CF that was similar to that recorded for the benidipine group. The level of double product (DP: systolic BPxHR, an index of myocardium energy consumption) in the combination group was significantly lower than that of the benidipine group. The plasma concentrations of benidipine and diltiazem in the combination group were similar to those of the groups receiving either drug. These results demonstrate that the combination of benidipine and diltiazem increases CF more continuously than diltiazem alone, and decreases DP more potently than benidipine alone, indicating that the combination therapy possesses favorable properties as a treatment for angina pectoris. Therefore, the combination of benidipine and diltiazem is suggested as a useful treatment for improving the clinical benefits of monotherapy for angina, compared with the use of diltiazem alone at higher doses.     

Anti-apoptotic effect of benidipine, a long-lasting vasodilating calcium antagonist, in ischaemic/reperfused myocardial cells

1. Ischaemia/reperfusion causes intracellular calcium overloading in cardiac cells. Administration of calcium antagonists reduces myocardial infarct size. Recent in vitro studies have demonstrated that calcium plays a critical role in the signal transduction pathway leading to apoptosis. However, whether or not calcium antagonists may reduce myocardial apoptosis induced by ischaemia-reperfusion, and thus decrease myocardial infarction, has not been directly investigated. 2. The present study investigated the effects of benidipine, an L-type calcium channel blocker, on myocardial infarct size, apoptosis, necrosis and cardiac functional recovery in rabbits subjected to myocardial ischaemia/reperfusion (MI/R, 45 min/240 min). Ten minutes prior to coronary occlusion, rabbits were treated with vehicle or benidipine (10 microg x kg(-1) or 3 microg x kg(-1), i.v.). 3. In the vehicle-treated group, MI/R caused cardiomyocyte apoptosis as evidenced by DNA ladder formation and TUNEL positive nuclear staining (12.2+/-1.1%). Treatment with 10 microg x kg(-1) benidipine lowered blood pressure, decreased myocardial apoptosis (6.2+/-0.8%, P<0.01 vs vehicle) and necrosis, reduced infarct size (20+/-2.3% vs 49+/-2.6%, P<0.01), and improved cardiac functional recovery after reperfusion. Administering benidipine at 3 microg x kg(-1), a dose at which no haemodynamic effect was observed, also exerted significant anti-apoptosis effects, which were not significantly different from those observed with higher dose benidipine treatment. However, treatment with this low dose benidipine failed to reduce myocardial necrosis. 4. These results demonstrate that benidipine, a calcium antagonist, exerts significant anti-apoptosis effects, which are independent of haemodynamic changes. Administration of benidipine at a higher dose produced favourable haemodynamic effects and provided additional protection against myocardial necrotic injury and further improved cardiac functional recovery.     

Effect of morning and bedtime dosing with cilnidipine on blood pressure, heart rate, and sympathetic nervous activity in essential hypertensive patients

Cilnidipine has a blocking action against N-type calcium channels as well as L-type calcium channels. We studied the effect of morning and bedtime dosing on circadian variation of blood pressure (BP), heart rate (HR), and activity of the autonomic nervous system, using an open randomized crossover study in 13 essential hypertensive patients. An automated device allowed 24-hour monitoring of ambulatory BP and HR and the power spectrum of the R-R interval, at the observation period, the morning dosing regimen, and the bedtime dosing regimen. Morning dosing and bedtime dosing with cilnidipine reduced the average systolic BP over 24 hours, during daytime, and during nighttime. The average HR and the average LF/HF ratio over 24 hours, during daytime, and during nighttime, were similar for the three periods. Both morning and bedtime dosing reduced the maximum systolic BP in the early morning and suppressed the morning rise of BP, which were accompanied by partial inhibition of the increase in LF/HF ratio. Our results show that cilnidipine administered once daily is an efficient antihypertensive drug regardless of the time of dosing, without reflex tachycardia and increase in sympathetic nervous activity, and with partial inhibition of the morning activation of the sympathetic nervous system.     

Effect of the calcium antagonist benidipine hydrochloride on 24-h ambulatory blood pressure in patients with mild to moderate hypertension in a double-blind study against placebo

The effects of benidipine hydrochloride (benidipine, CAS 91559-74-5), a dihydropyridine calcium antagonist, on the 24-h ambulatory blood pressure were studied by a double-blind test against placebo in 8 patients with essential hypertension. The mean resting systolic (SBP) and diastolic (DBP) blood pressures were 173 mmHg and 104 mmHg, respectively, at the time of patients enrollment. Blood pressure was measured every 30 min for 24 h after a single oral administration of either benidipine (4 mg/day) or the placebo. The mean through/peak (T/P) ratios were calculated from blood pressure measurements obtained using 2-h moving averages, and the smoothness index (SI) was calculated by subtracting the effect of the placebo from that of benidipine at each interval. The mean SBP and DBP fell to 135 and 88 mmHg, respectively, after dosing, which gave T/P ratios of 82% and 64%, respectively. The SIs for SBP and DBP were 1.82 and 0.76, respectively. These findings indicate that benidipine maintained a satisfactory and durable antihypertensive effect by once-a-day dosing.