抗高血压新药--西尼地平的药理作用和临床评价

目的:介绍西尼地平的药理作用及临床评价.方法:检索Medline,查找原文.结果:西尼地平对血管平滑肌的L-型和交感神经元的N-型钙通道都有阻滞作用,对原发性高血压病人能有效降压并且不引起心率加快.本品还能拮抗急性冷应激诱导的血压上升,这一作用不为其他钙拮抗剂所具有.结论:西尼地平有可能成为抗高血压治疗的理想药物之一.     

西尼地平与非洛地平治疗高血压病疗效及对自主神经功能的影响

目的 比较原发性高血压患者使用西尼地平与非洛地平的降压效果及对自主神经功能的影响。方法 轻中度原发性高血压患者随机分为西尼地平组(n=38，西尼地平10mg，每日1次)与非洛地平组(n=36，非洛地平5mg，每日1次)，治疗3个月后，比较两组血压与心率的改变，用动态心电图进行能量光谱分析。结果 西尼地平与非洛地平均有良好降压作用，但西尼地平对心率无明显的影响，而非洛地平增加心率，并使白天与夜晚R-R间期低频／高频(LF/HF)比率明显增加，西尼地平仅在白天有增加。结论 西尼地平对轻中度原发性高血压有良好降压疗效，且不增加交感神经活性，为有利于防止心脏事件发生的新型钙通道阻滞剂。     

新型钙通道阻滞剂—西尼地平

西尼地平是第 3代双通道二氢吡啶类钙通道阻滞剂 ,除具备大多数钙通道阻滞剂的L通道阻滞作用外 ,还作用于周围神经的N通道 ,不会引起降压后反射性心率增快及压力感受器对急性冷刺激的升压反应 ,从而成为具有独特药理作用的新型钙通道阻滞剂。1　概述西尼地平由日本富士株式会社研制开发 ,并于 1995年 12月在日本首次上市。化学名 :消旋 2 ,6—二甲基— 4 ( 3—硝基苯 )— 1,4—二氢吡啶— 3,5—二羧酸 2—甲氧乙基(E)— 3—苯基— 2—丙烯基双酯。　　化学式 :　　　　　　　　　 OOO ph 50～ 1 50℃ ,0 5～ 1 5hinactivesolventNHH3C…     

国产西尼地平治疗原发性高血压的多中心随机双盲双模拟临床研究

目的 对西尼地平治疗原发性高血压患者的疗效与安全性进行临床评价。方法 用多中心双盲双摸拟随机平行对照的试验方法,研究国产西尼地平与对照药苯磺酸氨氯地平对233例轻中度原发性高血压患者的降压疗效及药物不良反应。结果 治疗8周后,西尼地平组平均坐位收缩压(SBP)及舒张压(DBP)下降幅度分别为16.2,1 2.7 mmHg,苯磺酸氨氯地平组分别下降23.1,15.1 mmHg;两药总有效率分别为76.6％和87.7％,与治疗前比较有显著性差异(P<0.01);两药对心率无明显影响;两组药物不良反应的发生率分别为16.7％和12.9％。长期服用西尼地平疗效能持续,并有良好的耐受性。结论 西尼地平治疗轻中度原发性高血压具有明确的降压疗效与良好的安全性。     

西尼地平胶囊治疗原发性高血压双盲双模拟随机对照多中心研究

目的:评价国产西尼地平胶囊治疗轻度至中度高血压的临床疗效及安全性。方法:以国产西尼地平片为对照药,在252例轻度至中度高血压病人中进行多中心、随机、双盲、平行、活性药物对照的临床试验。结果:治疗8wk后,西尼地平胶囊组平均坐位收缩压和舒张压分别下降(18±s 11)mmHg (11．9％)和(12±8)mmHg(12．6％),西尼地平片组平均坐位收缩压和舒张压分别下降(19±13)mmHg (12．5％)和(12±8)mmHg(12．9％),2药的总有效率分别为80．3％和82．9％。西尼地平胶囊和西尼地平片对心率无明显影响,与药物有关的不良反应分别为6例和4例,主要表现为轻到中度的头晕、头痛、面红、心悸等。2药的疗效和不良反应比较无统计学差异(P＞0．05)。结论:国产西尼地平胶囊与国产西尼地平片相似,治疗轻中度原发性高血压具有明确的降压疗效与良好的安全性。     

西尼地平与尼群地平治疗高血压病的疗效比较

目的:比较西尼地平与尼群地平治疗高血压病的疗效及安全性。方法:86例原发性高血压病患者随机均分为西尼地平组和尼群地平组,西尼地平组给予西尼地平,起始剂量为5mg,qd,根据血压可调整至10mg,qd;尼群地平组给予尼群地平,起始剂量为10mg,qd,根据血压可调整至20mg,bid。比较2组的降压疗效及药品不良反应。结果:西尼地平组与尼群地平组的总有效率分别为90.7%和88.4%,2组比较差异无统计学意义(P>0.05);西尼地平组和尼群地平组收缩压的最大降幅分别为(34.2±3.8)和(29.2±2.2)mmHg,舒张压最大降幅分别为(23.8±2.6)和(19.4±2.3)mmHg,差异有统计学意义(P<0.05)。尼群地平组治疗后心率明显快于治疗前及西尼地平组治疗后(P<0.05),但西尼地平组患者心率治疗前、后无显著变化(P>0.05)。治疗过程中2组均未见明显不良反应发生。结论:西尼地平用于治疗高血压疗效与尼群地平相近,但其对患者的心率影响较小。     

西尼地平的光稳定性试验研究

目的 研究西尼地平的光稳定性。方法以西尼地平原料、西尼地平甲醇溶液、西尼地平片剂溶出液为对象，分别用强光(4500lx)或自然光照射，用HPLC法测定光照射后的降解产物，以卯LC-MS研究光降解产物的结构，并研究自然光对片剂溶出度测定的影响。结果西尼地平原料、西尼地平甲醇溶液对光敏感，在强光(4500lx)照射下分解生成Z-异构体。自然光可影响西尼地平片剂的溶出度测定，在不避光时西尼地平片剂溶出液吸收度下降，溶出度测定结果偏低。结论西尼地平对光敏感，西尼地平及其制剂均应该避光保存，西尼地平制剂的溶出度测定时应注意避光操作。     

自拟“降压2号”治疗肝阳上亢证型原发性高血压患者30例疗效观察

目的观察自拟“降压2号”方对中医辨证分型为肝阳上亢证型的原发性高血压患者血浆睾酮、雌二醇水平及血压的影响。方法选择肝阳上亢原发性高血压患者60例，随机分为治疗组和对照组，每组各30例。对照组给予西尼地平治疗，治疗组在西尼地平基础上加用“降压2号”。两组均连用4周。观察治疗前后血浆睾酮、雌二醇激素水平及血压变化。结果两组治疗后，血压水平均降低（P〈0．05），但组间比较差异无统计学意义（P〉0．05）。治疗组治疗后血浆睾酮、雌二醇水平均升高，且高于对照组（均P〈0．05）。结论自拟“降压2号”方对肝阳上亢原发性高血压患者的睾酮、雌二醇有明显的影响。     

西尼地平治疗轻、中度原发性高血压临床疗效的观察

目的：评价Ⅱ类新药西尼地平治疗轻、中度原发性高血压的疗效和安全性。方法：采用随机、双盲、平行对照法，将43例轻、中度高血压患者分为西尼地平组和氨氯地平组，检测2组治疗前后血压、心率及血液生化值变化。同时，在开放组患者中进行动态血压的监测。结果：西尼地平组血压控制显效率为63．64％，有效率为13．64％，总有效率为77．28％；氨氯地平组血压控制显效率为66．67％，有效率为11．11％，总有效率为77．78％。两组比较无显著性差异。与治疗前基线情况相比，治疗8周末两组受试者的坐、立位血压都有明显下降，两组间比较无显著性差异。用药前后血糖、血脂、血电解质及肾功能无显著变化。开放组显示T／P比值均已达到美国FDA提出的对长效降压药物的要求，即50％以上。结论：国产西尼地平治疗轻、中度高血压降压平稳，对心率影响小，副作用少。     

西尼地平治疗轻、中度原发性高血压临床疗效及安全性观察

目的 :评价西尼地平治疗高血压的有效性和安全性。方法 :16例原发性轻、中度高血压患者入组本研究 ,应用西尼地平治疗 2 4wk。西尼地平起始剂量为 5mg,1日 1次 ,1mo后根据舒张压情况可将西尼地平剂量调整至 10mg,1日 1次。结果 :与治疗前相比 ,收缩压和舒张压的下降均具有显著性差异。 2 4wk时收缩压和舒张压分别下降了 13.38mmHg和 12 75mmHg。心率无改变。不良反应轻微。结论 :西尼地平是新型第三代双通道二氢吡啶类钙通道阻滞剂 ,在治疗轻、中度高血压过程中安全有效 ,不良反应轻微 ,患者能很好耐受。     

Cilnidipine, a slow-acting Ca2+ channel blocker, induces relaxation in porcine coronary artery: role of endothelial nitric oxide and [Ca2+]i

Cilnidipine is a dual blocker of L-type voltage-gated Ca(2+) channels in vascular smooth muscle and N-type Ca(2+) channels in sympathetic nerve terminals that supply blood vessels. However, the clinical benefits of cilnidipine and underlying mechanisms are incompletely understood. This study was designed to compare the time course of relaxant responses to cilnidipine and nifedipine, and to examine the role of endothelial NO and [Ca(2+)](i) in the vasorelaxation. Porcine left circumflex coronary arteries were isolated and isometric tension was measured with Grass force transducers. Endothelial [Ca(2+)](i) in intact arteries was determined by a calcium fluorescence imaging technique. The free radical scavenging capacity was also assayed. Cilnidipine and nifedipine induced concentration-dependent relaxations in high KCl-precontracted artery rings, while the former-induced relaxation was slower as compared to the latter. Treatment with L-NAME or ODQ reduced relaxations to cilnidipine or nifedipine to the same extent as in rings without endothelium. Indomethacin or omega-conotoxin had no effects. L-Arginine antagonized the effect of L-NAME on cilnidipine-induced relaxations. Cilnidipine did not affect sodium nitroprusside-induced relaxation in rings with and without endothelium. Cilnidipine and nifedipine caused extracellular Ca(2+)-dependent increases in endothelial [Ca(2+)](i) in intact arteries and cilnidipine's action had a slower onset, similar to that of cilnidipine-induced relaxation. Neither cilnidipine nor nifedipine exhibited a free radical scavenging property. The present results demonstrate that cilnidipine can produce endothelium-dependent relaxation in porcine coronary arteries in vitro in addition to blocking Ca(2+) channels. Like short-acting nifedipine, cilnidipine-dependent relaxation, albeit to a slower onset, is partly mediated by endothelial NO but not by prostacyclin. The increased release or bioavailability of NO may causally result from elevated endothelial [Ca(2+)](i) in arteries. The Ca(2+) channel-independent effect suggests the usefulness of cilnidipine in the treatment of cardiovascular diseases associated with diminished NO release, such as atherosclerosis.     

A role for Q type Ca2+ channels in neurotransmission in the rat urinary bladder.

1. In isolated bladder strips of the rat, a substantial component (46%) of the Ca(2+)-dependent contractile response to electrical field stimulation (5 Hz) was resistant to combined block of both N and P type Ca2+ channels by omega-conotoxin-GVIA (300 nM) and omega-agatoxin-IVA (100 nM) respectively. 2. The resistant portion (non-N, non-P) was sensitive to omega-conotoxin-MVIIC (3 microM), which in addition to N and P also blocks Q type channels at this concentration. omega-Conotoxin-MVIIC administered alone, inhibited the neurogenic response to the same degree as that observed in the combined presence of omega-agatoxin-IVA, omega-conotoxin-GVIA and omega-conotoxin-MVIIC. 3. omega-Agatoxin-IVA (100 nM), a concentration that fully inhibits P type channels, had a negligible effect on the neurogenic response. Following blockade of N type Ca2+ channels with omega-conotoxin-GVIA (300 nM), omega-agatoxin-IVA (3 microM) (a concentration well above that used to block P channels, inhibits Q type channels, but spares N type channels), inhibited the residual response to the same degree as omega-conotoxin-MVIIC alone. 4. Results suggest that neurotransmission in rat urinary bladder is supported by both N and Q type Ca2+ channels.     

Potentiation of stretch-induced tone in the rabbit facial vein by an isoquinoline derivative, LOE 908

The rabbit facial vein exhibits extracellular Ca2+- and temperature-dependent spontaneous myogenic tone in response to stretch. The present study aimed to elucidate pharmacological characteristics of Ca2+ entry mechanisms responsible for the stretch-induced tension development of the rabbit facial vein. Ca2+- and temperature-sensitive vascular tone in response to stretch was refractory to L-type Ca2+ channel blockers such as nifedipine and diltiazem but was abolished by papaverine or SK&F 96365 which blocks both receptor- and store-operated Ca2+ channels. Interestingly, LOE 908, another type of voltage-independent Ca2+-permeable channel blocker, showed augmentation of the stretch-induced vascular tone instead of inhibition. Potentiation by LOE 908 of stretch-induced vascular tone was also extracellular Ca2+-dependent and counteracted by SK&F 96365. Membrane stretch-activated Ca2+ channels in the rabbit facial vein smooth muscle cells may have a unique characteristic that their opening is stimulated by LOE 908 and thus is distinguishable from other voltage-independent Ca2+-permeable 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.     

Cardiac effects of L/N-type Ca2+ channel blocker cilnidipine in anesthetized dogs

Cardiac effects of L/N-type Ca2+ channel blocker cilnidipine were assessed using the halothane-anesthetized canine model. Cilnidipine (1 and 3 microg/kg, i.v.) lowered the mean blood pressure by -5 and -14 mm Hg, respectively, without affecting the heart rate or maximum upstroke velocity of left ventricular pressure. Isoproterenol or acetylcholine was intravenously injected to directly or indirectly induce the positive chronotropic responses, respectively. Cilnidipine hardly affected the isoproterenol-induced cardiac responses, but it attenuated the acetylcholine-induced reflex tachycardia to 63-78% of the pre-drug control level. These results suggest that clinically relevant doses of cilnidipine can directly attenuate the sympathetic tone.     

Comparison of the cardioprotective and renoprotective effects of the L/N‐type calcium channel blocker,cilnidipine, in adriamycin‐treated spontaneously‐hypertensive rats

Cilnidipine is an L/N‐type calcium channel blocker (CCB). The effects of cilnidipine on N‐type channels give it unique organ‐protective properties via the suppression of hyperactivity in the sympathetic nervous system (SNS) and renin‐angiotensin‐aldosterone system (RAAS). In the present study, we compared the effects of cilnidipine and amlodipine (an L‐type CCB) on cardiac and renal functions in spontaneously‐hypertensive rats injected with adriamycin (ADR). After the weekly administration of ADR for 3 weeks, spontaneously‐hypertensive rats were orally administered cilnidipine (20 mg/kg per day), amlodipine (3 mg/kg per day), or vehicle once daily for 4 weeks. A control group received saline rather than ADR, followed by vehicle for 4 weeks. Cilnidipine and amlodipine produced similar reductions in blood pressure after 4 weeks. Cilnidipine ameliorated ADR‐induced heart and kidney damage, whereas amlodipine slightly improved cardiac echocardiographic parameters, but did not protect against ADR‐induced renal damage. Cilnidipine (but not amlodipine) suppressed the reflex SNS and RAAS hyperactivity caused by their antihypertensive effects. Furthermore, cilnidipine and amlodipine treatment decreased the urinary levels of adrenocortical hormones. The protective effects of cilnidipine against ADR‐induced renal and cardiac dysfunction might be associated with its blockade of N‐type calcium channels, in addition to its pleiotropic actions, which include the inhibition of the RAAS.     

Receptor-mediated modulation of voltage-dependent Ca2+ channels via heterotrimeric G-proteins in neurons

The activity of voltage-dependent Ca2+ channels is highly regulated by neurotransmitter receptors coupled to heterotrimeric G-proteins. In the expression studies using cloned Ca2+ channel subunits, it has been clarified that the main mechanism of the inhibition of N-type channel current is mediated directly by G-protein betagamma subunits in a membrane-delimited and voltage-sensitive manner. In addition, recent studies have also clarified that N-type channels are modulated by several G-protein alpha subunits in different ways. Among them, G(alpha o) mediates a voltage-resistant inhibition of N-type current by neurotransmitters. This type of inhibition is more apparent in the case of P/Q-type channels in both native cells and expression systems. Moreover, other G-protein subunits, such as G(alpha q) and G(alpha s), also seem to regulate N-type channels in a membrane-delimited manner. The fine tunings of Ca2+ channel activity by intracellular proteins have physiological and pathological meanings in the regulation of Ca2+ influx into excitable cells by neurotransmitters and pharmacological implications as novel drug targets for controlling Ca2+ influx.     

Roles of CRAC and Cav-like channels in T cells: more than one gatekeeper?

Ca2+ channels in the plasma membrane of T cells vitally influence Ca2+-dependent signals that lead ultimately to cytokine secretion, cellular proliferation and apoptosis. Conventional models depict the Ca2+ inrush across the T-cell membrane following T-cell receptor engagement as being due to Ca2+-release-activated Ca2+ (CRAC) channels. A poorly understood mechanism detects the lowered Ca2+ concentrations within intracellular stores that open CRAC channels. Mammalian homologs of the Drosophila transient receptor potential Ca2+ channels possibly help to gate the store-operated, Ca2+-borne CRAC current. In this article, we review evidence of a supplementary involvement of other Ca2+ channels, the opening of which does not necessarily reflect intracellular Ca2+-store depletion. We highlight a role for variants of L-type voltage-dependent Ca2+ channels in increasing intracellular Ca2+ concentrations during activation. For more-accurate modeling of lymphocyte activation and possible pharmacological interventions, future research should aim to identify physiologically relevant situations in which such channels help to shape the Ca2+ signal.     

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.