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.     

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.     

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.     

Protective effect of benidipine against sodium azide-induced cell death in cultured neonatal rat cardiac myocytes

We investigated the effect of benidipine, a calcium antagonist, against sodium azide (NaN(3))-induced cell death in cultured neonatal rat cardiac myocytes with increase of LDH release, depletion of cellular ATP contents, and collapse of mitochondrial membrane potential (DeltaPsi) as indicators. Cells were treated with 1 mmol/L NaN(3) for 18 h. Benidipine concentration-dependently inhibited NaN(3)-induced cell death. The protective effect of benidipine was compared with those of amlodipine, nifedipine, candesartan, and captopril. Calcium antagonists exhibited a protective effect and the IC(50) values of benidipine, amlodipine, and nifedipine were 0.65, 90, and 65 nmol/L, respectively. NaN(3)-induced cell death was inhibited completely with the calpain inhibitor. It was considered that the sustained elevation of [Ca(2+)](i) might be implicated in NaN(3)-induced cell death. Benidipine, moreover, concentration-dependently preserved cellular ATP contents and maintained DeltaPsi the extent of the control level. In conclusion, benidipine exhibited the protective effect at an approximately 100-fold lower concentration than those of amlodipine and nifedipine in the NaN(3)-induced cardiac cell death model. It was considered that both the inhibition of Ca(2+) influx and the preservation of cellular ATP contents might play an important role in the protective effect of benidipine.     

Mechanisms of long-lasting effects of benidipine on Ca current in guinea-pig ventricular cells.

1. Benidipine (KW-3049), a new derivative of 1,4-dihydropyridine (DHP), showed dose-dependent inhibition of Ca current (ICa) which was elicited by depolarization from -40 mV to +10 mV at 0.2 Hz in single cardiac cells isolated from guinea-pig ventricle under whole cell voltage clamp. Half inhibition doses (IC50) of benidipine and nifedipine for the peak ICa at +10 mV were 2.7 nM and 63.1 nM, respectively. 2. A change in holding potential from -40 to -75 mV partially removed the block induced by both 10 nM benidipine and 100 nM nifedipine. The block of ICa by benidipine strongly depended upon holding potentials as did that induced by nifedipine. 3. The effect of 100 nM nifedipine was mostly removed when the cells were kept quiescent at holding potentials negative to -75 mV for 5 min after withdrawal of nifedipine. In contrast, hyperpolarization for several minutes did not significantly accelerate the removal of benidipine-induced block after withdrawal of the drug. Effects of 10 nM benidipine could not be washed out for up to 30 min regardless of the holding potentials. 4. It is suggested that the dissociation of benidipine from the DHP binding site, like that of nifedipine, is greatly accelerated by hyperpolarization. Benidipine but not nifedipine may have an additional interaction with the channel or lipid membrane and cannot be washed away even after the dissociation. Alternatively, the dissociation of benidipine from the DHP binding site may be too slow to occur substantially during the limited period of hyperpolarization in the present study (less than 30 min).(ABSTRACT TRUNCATED AT 250 WORDS)     

Benidipine, an anti-hypertensive drug, inhibits reactive oxygen species production in polymorphonuclear leukocytes and oxidative stress in salt-loaded stroke-prone spontaneously hypertensive rats

Oxidative stress is associated with exacerbation of renal injuries in hypertension. In clinical studies benidipine hydrochloride (benidipine), a dihydropyridine calcium channel blocker with antioxidant activity, reduced oxidative stress. However, the mechanism of suppression of oxidative stress remains to be fully characterized. Reactive oxygen species production by polymorphonuclear leukocyte plays important pathological roles in hypertension. Therefore, we examined the effects of benidipine both on reactive oxygen species production of human polymorphonuclear leukocytes and oxidative stress of an animal model. Human peripheral polymorphonuclear leukocytes or polymorphonuclear leukocyte-like differentiated HL-60 cells were used to examine effects of benidipine (0.1-30 microM) on formyl-Met-Leu-Phe-induced reactive oxygen species production, calcium mobilization, NADPH oxidase activation and phosphorylation of protein kinase C substrates. High-salt (8% NaCl) loaded stroke-prone spontaneously hypertensive rats were treated with or without benidipine (1, 3, 10 mg/kg/day) for 2 weeks, and thiobarbituric acid reactive substances, a plasma oxidative stress marker, and renal expression of oxidative stress-induced genes were measured. Benidipine concentration-dependently suppressed formyl-Met-Leu-Phe-induced reactive oxygen species production in polymorphonuclear leukocytes more potently than other calcium channel blockers such as amlodipine, azelnidipine, nitrendipine and nifedipine. Benidipine partially inhibited all of intracellular Ca(2+) elevation, protein kinase C activation and NADPH oxidase activation. Salt loading in stroke-prone spontaneously hypertensive rats augmented plasma thiobarbituric acid reactive substances levels; renal dysfunction; and renal expression of transforming growth factor-beta, collagen I and collagen III mRNAs; which were attenuated by benidipine treatment. These results indicate that benidipine prevents the polymorphonuclear leukocyte-derived reactive oxygen species production, which is due at least in part to its antioxidant action and inhibition of Ca(2+)/protein kinase C/NADPH oxidase signaling. The attenuation of reactive oxygen species production might contribute to the drug's reduction of oxidative stress and renal injuries in hypertension.     

Comparison of vasculoprotective effects of benidipine and losartan in a rat model of metabolic syndrome

Although antihypertensive drugs confer improvement in endothelial dysfunction and protection from atherogenesis in hypertension, different classes of antihypertensive drugs may elicit different degrees of vasculoprotective effects. We have investigated the effects of a long-acting calcium antagonist, benidipine, and an angiotensin AT(1) receptor antagonist, losartan, on the vascular damage observed in OLETF rats, an animal model of metabolic syndrome. At 34 weeks of age, OLETF rats were treated with either benidipine (3 mg/kg/day, per os) or losartan (25 mg/kg/day, per os) for 8 weeks. The extent of blood pressure reduction, restoration endothelium-dependent aortic relaxation, and elevation of serum nitrite/nitrate concentration did not differ significantly between benidipine- and losartan-treated OLETF rats. Benidipine and losartan also reduced the aortic expression of transforming growth factor-beta1 mRNA and thickening of the vascular wall to a similar extent. Increased cardiac fibrosis was also inhibited by both benidipine and losartan. These data suggest that, when used in an antihypertensive dose, benidipine is as effective as losartan in restoring vascular endothelial function and in suppressing of cardiovascular remodeling in an animal model of metabolic syndrome.     

Inhibition of human cytochrome P450 enzymes by 1,4-dihydropyridine calcium antagonists: prediction of in vivo drug–drug interactions

OBJECTIVE: 1,4-Dihydropyridine calcium antagonists such as nifedipine are potent vasodilators. It is now commonly agreed that the oxidation of 1,4-dihydropyridine into pyridine, which is one of the main metabolic pathways, is catalysed by the cytochrome P450 (CYP) 3A4 isoform. In the present study, the inhibitory effects of 13 kinds of 1,4-dihydropyridine calcium antagonists clinically used in Japan on human CYP-isoform-dependent reactions were investigated to predict the drug interactions using microsomes from human B-lymphoblast cells expressing CYP. RESULTS: The specific activities for human CYP isoforms included 7-ethoxyresorfin O-deethylation (CYP1A1), phenacetin O-deethylation (CYP1A2), coumarin 7-hydroxylation (CYP2A6), 7-benzyloxyresorufin O-dealkylation (CYP2B6), S-warfarin 7-hydroxylation (CYP2C9), S-mephenytoin 4'-hydroxylaion (CYP2C19), bufuralol 1'-hydroxylation (CYP2D6), chlorzoxazone 6-hydroxylation (CYP2E1), and testosterone 6beta-hydroxylation (CYP3A4). Benidipine and amlodipine competitively inhibited the CYP1A1 activity. Nifedipine, nisoldipine and aranidipine competitively inhibited the CYP1A2 activity. No 1,4-dihydropyridie calcium antagonists used in this study inhibited the CYP2A6 activity. Barnidipine and amlodipine inhibited the CYP2B6 activity. Nicardipine, benidipine, manidipine and barnidipine competitively inhibited the CYP2C9 and CYP2D6 activities. Inhibition extent of the CYP2E1 activity by nifedipine and aranidipine were weak. Nicardipine, benidipine and barnidipine inhibited the CYP2C19 and CYP3A4 activities. Among the human CYP isoforms investigated, the inhibitory effects of 1,4-dihydropyridine calcium antagonists were potent on human CYP1A2, CYP2B6, CYP2C9, CYP2C19 and CYP2D6 as well as CYP3A4. Furthermore, the isoform selectivity of inhibition by 1,4-dihydropyridine calcium antagonists was clarified. CONCLUSIONS: In consideration of the Ki values obtained in the in vitro inhibition study and the concentration of 1,4-dihydropyridine calcium antagonists in human liver, the possibility of in vivo drug interactions of nicardipine and other drugs which are mainly metabolised by CYP2C9 and/or CYP3A4 was suggested. The inhibition of human CYP isoforms by 1,4-dihydropyridine calcium antagonists except nicardipine might be clinically insignificant.     

我院2009～2011年住院药房口服抗高血压药应用分析

目的了解我院口服抗高血压药物的应用情况,为临床合理用药提供参考。方法采用限定日剂量分析方法,对我院2009～2011年口服抗高血压药物的药品名称、销售金额、用药频度、日均费用等指标进行统计分析。结果近3年我院住院患者使用抗高血压药物销售金额前3位一直是钙离子拮抗剂(CCB)、血管紧张素受体阻滞剂(ARB)、血管紧张素转换酶抑制剂(ACEⅠ);用药频度前3位一直是CCB、利尿剂、ARB;单品种排序中销售金额前2位一直是硝苯地平控释片(拜心同)、氨氯地平片(络活喜),第3位2009年为左旋氨氯地平片,后由培哚普利片(雅施达)替代;用药频度前3位一直是硝苯地平控释片、氨氯地平片和螺内酯片。结论我院口服抗高血压药物使用基本合理。     

Antianginal effects of lercanidipine on the vasopressin or methacholine induced anginal model in rats

The antianginal effects of lercanidipine, a newly synthesized 1,4-dihydropyridine derivative calcium channel antagonist, were evaluated in experimental angina model rats and the effects were compared with those of nifedipine, benidipine and amlodipine. In the vasopressin-induced angina model, intravenous administration of lercanidipine dose-dependently suppressed vasopressin-induced ST-depression. Amlodipine barely suppressed it, while benidipine, at the same dose, completely suppressed it. Nifedipine had a potency between that of amlodipine and benidipine. Oral administration of lercanidipine showed similar effects to the intravenous administration test on ST change. High doses of amlodipine, benidipine and nifedipine suppressed ST-depression by almost 100%. In the methacholine-induced angina model, lercanidipine suppressed the ST elevation dose dependently. Amlodipine barely suppressed it, while benidipine at 30 microg/kg effected almost total suppression. Nifedipine had a potency between that of amlodipine and benidipine. Intraduodenal administration of lercanidipine also suppressed the ST-elevation dose dependently. Nifedipine, benidipine and amlodipine at 10 mg/kg all markedly suppressed the elevation. Lercanidipine was more potent than the other calcium channel antagonists tested. In conclusion, it was explicitly demonstrated that lercanidipine exerts potent protective effects on the ischemic electrocardiography (ECG) changes in a variety of putative angina pectoris models in rats. An antispasmolytic coronary vasodilating action may be involved in the mechanism. It is expected that lercanidipine will be useful as an antianginal agent.     

氟康唑与硝苯地平/贝尼地平联合抗真菌作用研究

目的：通过联合用药的方式,寻找新的对抗真菌耐药方法。方法：通过微量稀释法和时间-杀菌曲线法分别从静态和动态方面评价硝苯地平和贝尼地平与氟康唑联用抗白色念珠菌的作用。结果：硝苯地平和贝尼地平单用本身无抗真菌作用,当分别与氟康唑联用对抗耐药白色念珠菌时,可将氟康唑的单用浓度从512 μg·mL^-1降低到1 μg·mL^-1,FICI分别为0.019和0.035,表现为强协同作用;而两类药物联用对敏感白色念珠菌表现出无关作用,时间杀菌曲线法进一步证实了结果。结论：硝苯地平和贝尼地平都能消除氟康唑的耐药性,增加氟康唑的抗耐药白色念珠菌作用。     

Antihypertensive drugs and the risk of idiopathic aplastic anaemia

AIMS: A recent report has raised concern that nifedipine may be associated with an increased risk of aplastic anaemia. This large population-based study evaluated the risk of idiopathic aplastic anaemia in users of calcium channel blockers compared with that of other antihypertensive drugs. METHODS: The study was based on information derived from the General Practice Research Database. We conducted a follow-up study with a nested case-control analysis of 322 448 subjects who received antihypertensive drugs. Cases were people who had a first-time diagnosis of aplastic anaemia during January 1, 1988 through September 30, 1997. The risk estimate of aplastic anaemia was calculated for all antihypertensive drugs. For the nested case-control analysis, six controls were matched to each case on age, sex and general practice attended. Odds ratios compared the risk of idiopathic aplastic anaemia for all antihypertensive drugs relative to nonusers. RESULTS: There were 13 cases of newly diagnosed idiopathic aplastic anaemia. The estimated risk of aplastic anaemia per 100 000 users was 0.8 (95% CI 0.1, 4.7) for calcium channel blockers, 1.4 (95% CI 0.5, 4.1) for beta-adrenoceptor blockers, 2.3 (95% CI 0.6, 8.6) for angiotension-converting enzyme (ACE) inhibitors and 5.9 (95% CI 1.6, 21.5) for users of other antihypertensive drugs. In the case-control analysis of 13 cases and 77 controls, the odds ratio was 0.3 (95% CI 0.02, 3.3) for calcium channel blockers, 0.5 (95% CI 0.1, 2.5) for beta-adrenoceptor blockers, 0.7 (95% CI 0.1, 5.6) for ACE inhibitors, 1.2 (95% CI 0.1, 11.8) for users of other antihypertensive drugs and 0.7 (95% CI 0.1, 7.2) for users of multiple drugs with a calcium channel blocker compared with nonusers. CONCLUSIONS: The present study suggests that the use of calcium channel blockers is not associated with an increased risk of aplastic anaemia.     

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.     

Changing characteristics of patients with vasospastic angina in the era of new calcium channel blockers

In the 1980s, clinical characteristics and long-term prognosis of patients with vasospastic angina (VSA) were investigated; however, they remain to be updated after the introduction of new calcium channel blockers, benidipine and amlodipine, in 1990s. Our patient cohort registered 726 patients with VSA from January 1980 to December 2002. Before and after 1990, 138 and 527 patients were respectively entered in this study with a follow-up rate of 92%. Most of the patients were treated with calcium channel blockers, while benidipine and amlodipine were used in 28% and 21% of them only after 1990. Survival without cardiovascular events (96% versus 96%) at 5 years remained good before and after 1990. The presence of significant coronary stenosis had a negative prognostic impact both before and after 1990, whereas after 1990, diabetes mellitus, smoking, and a history of myocardial infarction became more influential. Among the calcium channel blockers, benidipine showed a better prognosis. These results suggest that in the era of new calcium channel blockers, the prognosis of patients with VSA remains good with more prognostic impact of diabetes mellitus, smoking, and a history of myocardial infarction and that benidipine might have some better prognostic effects.     

Benidipine, a dihydropyridine-calcium channel blocker, inhibits lysophosphatidylcholine-induced endothelial injury via stimulation of nitric oxide release.

Benidipine hydrochloride (benidipine), which is a long-lasting dihydropyridine calcium channel blocker, exerts antihypertensive action via inhibition of Ca(2+) influx through L-type voltage-dependent calcium channels. In addition, benidipine is shown to restore endothelial function. However, the mechanisms whereby benidipine has protective effects on endothelium are poorly defined. Nitric oxide (NO), which is produced by endothelial NO synthase (eNOS), plays important roles in endothelial function. In this study, we examined effects of benidipine on NO production from human umbilical vein endothelial cells. Benidipine (0.3-10 microM) augmented eNOS expression and total eNOS enzymatic activities. Benidipine also promoted the production of NO and the accumulation of cGMP, a second messenger of NO. Lysophosphatidylcholine (lysoPC), a component of oxidized low-density lipoproteins, induced caspase-3 activation followed by apoptosis of endothelial cells. Benidipine (0.3-10 microM) prevented lysoPC-induced caspase-3 activation, which was canceled by Nomega-nitro-L-arginine-methyl ester (L-NAME) (250-2500 microM), an inhibitor of NOS. Moreover, diethylenetetraamine NONOate (30-100 microM), a NO donor, inhibited the caspase-3 activation. These results suggested that the increase in NO production by benidipine might be involved in the inhibition of caspase induction. The direct enhancement of endothelial NO release by benidipine may be in part responsible for amelioration of endothelial dysfunction.     

Effects of benidipine in a rat model for experimental angina

To compare the antianginal effects of 1,4-dihydropyridine-type calcium-channel blockers, we evaluated the effects of benidipine, amlodipine, nifedipine, and efonidipine on vasopressin-induced myocardial ischemia in rats, an experimental model of angina. Intravenous administration of benidipine (3 microg/kg), amlodipine (1000 microg/kg), and nifedipine (100 microg/kg) suppressed the vasopressin-induced S-wave depression, an index of myocardial ischemia. Efonidipine (100 microg/kg, i.v.) tended to inhibit the S-wave depression. At the antianginal dose of each drug, amlodipine, nifedipine, and efonidipine decreased blood pressure significantly, whereas benidipine had little effect on blood pressure at a dose of 3 microg/kg. These results indicate that benidipine, unlike the other 1,4-dihydropyridine-type calcium-channel blockers examined in this study, inhibits vasopressin-induced coronary vasospasm with fewer undesirable effects such as hypotension in rats, suggesting that benidipine may be useful in the treatment of angina pectoris.     

2010～2013年我院门诊口服抗高血压药物使用情况分析

目的：了解我院门诊2010～2013年口服抗高血压药物使用情况,分析其合理性。方法：统计分析我院门诊口服抗高血压药物单品种的用药频度、销售金额、所占比例等指标,并进行排序分析。结果：在2010～2013年,口服降压药年度销售总金额呈逐年递增趋势。每一年销售金额最高的是CCB,销售金额最低的是扩血管药。 CCB、ARB、ACEI类抗高血压药物的销售金额分别居前三位。2010～2011年DDDs排名前两位的是氨氯地平、替米沙坦,2010年和2011年DDDS排名第三的是硝苯地平,2012年和2013年DDDS排名第三位的是缬沙坦。DDDS排名前五位的是CCB、ARB、利尿剂、ACEI、β受体阻滞剂。结论：我院门诊口服抗高血压药物的销售基本稳定,使用合理,符合抗高血压药物的使用原则。     

Comparative Study on the Effect of Calcium Channel Blockers on Basal and Parathyroid Hormone-Induced Bone Resorption in vitro

Abstract: A number of clinical and experimental studies suggest that the effects of calcium channel blockers are not limited to the cardiovascular system but might also involve skeletal calcium metabolism due to the presence of L-type calcium channels in osteoblastic cells. We therefore investigated the influence of calcium channel blockers of the dihydropyridine type (nifedipine, amlodipine) as well as of the phenylalkylamine type (verapamil, gallopamil) on basal and parathyroid hormone-induced bone resorption utilizing organ-cultured neonatal mouse calvaria. Only at 10^-4 M, amlodipine, verapamil and gallopamil reduced basal and parathyroid hormone-induced resorption In contrast, nifedipine, between 10^-6–10^-4 M, exhibited a dose-dependent inhibitory effect on parathyroid hormone-related bone resorption by up to 50%. When calvariae were cultured for 48 hr in the presence of inhibitory concentrations of the calcium channel blockers and then stimulated with parathyroid hormone, only parietal bones pretreated with nifedipine remained completely responsive to the bone resorbing action of the hormone.     

Arteriolar and venular vasodilating properties of benidipine hydrochloride, a 1,4-dihydropyridine Ca2+ antagonist with long-lasting action, assessed in rat mesenteric microcirculation

To obtain direct and visible evidence of the arteriolar vasodilating action in vivo of benidipine hydrochloride, a long-lasting and light-resistant Ca2+ antagonist of the 1,4-dihydropyridine type, we continuously recorded changes in the diameter of mesenteric arterioles (10-40 microm) and venules (20-40 microm) in anesthetized agent-injected Wistar rats by means of digital image processing combined with videomicroscopy. Benidipine injected intravenously brought about a depressor response, and this response persisted much longer than that induced by nifedipine. Benidipine produced a dose-dependent arteriolar vasodilation and a decrease in the blood-flow velocity. It also relaxed the venules during the depressor response, which relaxation was more prominent 1-2 h after the administration. In pithed rats, both pressor response and arteriolar constriction induced by norepinephrine were prevented by benidipine. Benidipine also inhibited adenosine diphosphate (ADP)-induced interruption of arteriolar blood flow. These results suggest that benidipine produced vasodilation in vivo at both the arteriolar and venular levels. The ability of benidipine to prevent microcirculatory disturbance and to produce arteriolar and venular vasodilation seem to account for its long-lasting Ca2+-antagonistic antihypertensive action.     

The Effect of Antihypertensive Agents on New-Onset Diabetes Mellitus

Recent large hypertension trials have shown great differences in incidence of new-onset diabetes mellitus among patients receiving different antihypertensive drug therapies. The incidence of diabetes is unchanged or increased by the use of thiazide diuretics and beta-adrenoceptor antagonists (beta-blockers) and unchanged or decreased by ACE inhibitors, calcium channel blockers (CCBs), and angiotensin II type 1 receptor antagonists (angiotensin receptor blockers). Recent results from ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial) showed superiority of the 'new' combination of CCBs and ACE inhibitors over the 'old' or 'conventional' combination of beta-blockers and diuretics. In this review, the results from some of the large hypertension trials are discussed, and the hypotheses on how different antihypertensive drug regimens can affect glucose homeostasis are considered. The question now is whether the results from these recent trials should affect the choice of antihypertensive treatment, particularly for special groups. However, the key goal is still to reduce BP, and this usually requires combinations of drugs.