Calcium Channel Blocking Properties Research Articles

Review of United States and European clinical trials of zonisamide in the treatment of refractory partial-onset seizures

Zonisamide is an antiepilepsy drug (AED) with both sodium and calcium channel-blocking properties. This dual mechanism may predict efficacy in some refractory patients, and a broad spectrum of action against different seizure types. Zonisamide has been commercially available in Japan since 1989, and became available in the United States for treatment of adults over the age of 12 with partial–onset seizures in March 2000. Several multicenter clinical trials have been conducted in the United States over the past 15 years. These have included three double-blind, placebo-controlled trials as well as long-term open-label studies. Zonisamide was characterized in these studies as a safe and effective adjunctive treatment for partial-onset seizures. Zonisamide has not yet been studied in the United States as an initial monotherapy, but in one long-term study, some patients were able to discontinue other AEDs and successfully transition to monotherapy. The most frequently reported adverse events were somnolence, dizziness, and anorexia. Current United States labeling states that 12 patients with epilepsy receiving zonisamide had symptomatic kidney stones; however, after more than a dozen years of zonisamide use in Japan, the incidence of kidney stones associated with zonisamide remains low.

Nitric oxide synthase expression in the transient ischemic rat retina: neuroprotection of betaxolol

Betaxolol is a β-adrenergic blocker but its neuroprotective action is generally thought to be due to its calcium channel blocking properties. In this study, we investigated neuronal cell damage and changes in the expression of neuronal nitric oxide synthase (nNOS) immunoreactivity in the ischemic retina and its relationship to the neuroprotection of betaxolol treatment after ischemic injury. Using the retina after ischemia, the expression of nNOS was studied by immunocytochemistry. In control retinas, two types of amacrine cells and a class of displaced amacrine cells were nNOS-labeled. After ischemia/reperfusion, the number of nNOS immunoreactive cells increased in both the ganglion cell layer and the inner nuclear layer compared to the control retinas. However, when experiments were carried out on animals that had been treated with betaxolol twice daily after ischemia/reperfusion, the number of nNOS immunoreactive cells decreased compared to the untreated ischemic retinas. These results suggest that an increase in nNOS expression could be associated with the degenerative changes in the ischemic retina, and that betaxolol treatment appears to play a role in protecting retinal tissue from ischemic damage.

Effect of Betaxolol on Aspartate Aminotransferase Activity in Hypoxic Rat Retina In Vitro

We investigated the effect of betaxolol on the decrease of mitochondrial aspartate aminotransferase (mAAT) activity in rat retinas induced by hypoxia in vitro. It is reported that mAAT decreases in ischemic or hypoxic retina and that the decrease is caused by Ca(2+)-dependent proteases such as calpain. Betaxolol is a compound that has beta(1)-adrenergic receptor blocking and voltage-dependent calcium channel blocking properties. The rat eye cups were maintained with Locke's solution saturated with 95% air - 5% CO(2). The eye cups were immersed in glucose-free Locke's solution saturated with 95% N(2) / 5% CO(2) (hypoxic solution). Ninety minutes of hypoxia caused a 20% decrease in mAAT activity. The eye cups incubated with the hypoxic solution containing 1 mM EGTA, 10 micro M MK-801 or 100 micro M betaxolol were protected from the decrease in mAAT activity, so that the residual mAAT activity was 50%, 45% or 40%, respectively, compared to the eye cups incubated in hypoxic solution alone, which had a 100% decrease in mAAT activity. In addition, co-incubation with EGTA and betaxolol had a greater protective effect against the mAAT decrease than a single application. This additive effect of betaxolol was dose-dependent. These results suggested that betaxolol had a protective effect against the decrease of mAAT caused by hypoxia and indicated that betaxolol might inhibit the Ca(2+) release from intracellular Ca(2+) stores.

Ethnopharmacological evaluation of the anticonvulsant, sedative and antispasmodic activities of Lavandula stoechas L

Lavandula stoechas L. (Lamiaceae) has been used for a long time in traditional medicine as an anticonvulsant and antispasmodic. The aqueous-methanolic extract of L. stoechas flowers (LS) was studied for its possible anticonvulsant and antispasmodic activities. When tested in mice, LS (600 mg/kg) significantly reduced the severity and increased the latency of convulsions induced by pentylene tetrazole (PTZ). LS likewise reduced PTZ's lethality. LS up to a dose of 600 mg/kg was found devoid of any hypnotic effect in mice, however, animals were found to be dull, calm and relaxed. The sedative effect of the plant extract was confirmed, as it prolonged the pentobarbital sleeping time in mice similar to that of diazepam. In isolated rabbit jejunum preparations, LS caused a dose-dependent (0.1–1.0 mg/ml) relaxation of spontaneous contractions. LS also inhibited K +-induced contractions in a similar dose range, thereby suggesting calcium channel blockade. This effect was confirmed when pretreatment of the jejunum preparation with LS produced a dose-dependent shift of the Ca 2+ dose-response curve to the right, similar to the effect of verapamil, a standard calcium channel blocker. These data indicate that the plant extract exhibits anticonvulsant and antispasmodic activities. Its calcium channel blocking property may be mechanistically related to these activities. Its usefulness in folk medicine appears thus to be based on a sound mechanistic background.

Modulation by dihydropyridine-type calcium channel antagonists of cytokine-inducible gene expression in vascular smooth muscle cells.

1. The 1,4-dihydropyridine nifedipine is frequently used in the therapy of hypertension and heart failure. In addition, nifedipine has been shown to exert distinct anti-arteriosclerotic effects both in experimental animal models and in patients. In the present study we have investigated the hypothesis that the latter effect of this class of drugs is mediated by an interference with the expression of pro-arteriosclerotic gene products in the vessel wall. Moreover, to elucidate as to whether nifedipine acts via L-type calcium channel blockade, its effects were compared to those of another dihydropyridine, Bay w 9798, which has no calcium-antagonistic properties in concentrations up to 10 microM as verified by superfusion bioassay. 2. Both, nifedipine and Bay w 9798, in concentrations ranging from 0.01 to 1 microM, augmented the interleukin-1beta/tumour necrosis factor-alpha (IL-1beta/TNF-alpha)-induced expression of the inducible isoform of nitric oxide synthase (iNOS) in rat aortic cultured smooth muscle cells (raSMC) 2 - 3 fold, as judged by RT - PCR and Western blot analyses. 3. In contrast, cytokine-induced mRNA expression of monocyte chemoattractant protein 1 (MCP-1) in these cells was down-regulated by more than 60% in the presence of both dihydropyridines, as judged by RT - PCR and Northern blot analyses. 4. Nuclear run-on assays and incubation with the transcription-terminating drug actinomycin D revealed that both drugs acted at the level of mRNA synthesis rather than stability. 5. These findings suggest that 1,4-dihydropyridines such as nifedipine affect the expression of both potentially pro-arteriosclerotic (MCP-1) and anti-arteriosclerotic (iNOS) gene products in the vessel wall at the level of transcription, and that these effects are unrelated to their calcium channel-blocking properties.

Evidence for a sympatholytic effect of mibefradil in the pithed rat preparation.

The T-type prevalent calcium channel blocker mibefradil (MIB) was shown to possess N-type calcium channel blocking properties. As this particular type of calcium channel is known to be crucially involved in the neuronal release of noradrenaline, we have investigated whether MIB could be a sympatholytic drug. To evaluate the sympathoinhibitory action, the effects of 3 and 10 micromol/kg MIB on the tachycardic effect of electrical stimulation of the preganglionic cardioaccelerator nerves in the pithed rat were investigated. The effect of MIB on the dose-response curve of externally applied noradrenaline was also studied. To compare the results with a classic L-type calcium channel blocker, the experiments were repeated with 3 and 10 micromol/kg verapamil (VER). The maximal increase in heart rate in response to electrical nerve stimulation was 96 +/- 7 bpm (control, n = 6), 70 +/- 6 bpm (3 micromol/kg MIB, n = 8), 57 +/- 6 bpm (10 micromol/kg MIB, n = 5), 93 +/- 5 bpm (3 micromol/kg VER, n = 6) and 46 +/- 7 bpm (10 micromol/kg VER, n = 5). The tachycardic response to electrical stimulation at 1, 5 and 10 Hz was completely blocked by 5 mg/kg intravenous guanethidine. The maximal increase in heart rate in response to noradrenaline was 96 +/- 4 bpm (control, n = 6), 103 +/- 6 (3 micromol/kg MIB, n = 6), 42 +/- 9 bpm (10 micromol/kg MIB, n = 5), 73 +/- 5 bpm (3 micromol/kg VER, n = 5) and 40 +/- 7 bpm (10 micromol/kg VER, n = 6). Under control conditions and in the presence of 3 micromol/kg MIB and VER the maximal effect of noradrenaline was reached at 0.1 micromol/kg whereas in the presence of 10 micromol/kg MIB and VER it was reached at a dose of 1 micromol/kg. MIB at a dose of 3 micromol/kg was significantly more effective in reducing the chronotropic response to electrical stimulation compared with externally applied noradrenaline. For VER the opposite holds true. These differences were not observed with doses of 10 micromol/kg MIB and VER. Mibefradil, besides its direct effect on cardiac T- and L-type calcium channels, reduces the release of noradrenaline from sympathetic nerve endings, most probably by inhibition of presynaptic N-type calcium channels. In the model used this effect is only observable at relatively low concentrations, most probably because of the direct cardiodepressant action of MIB provoked by L-type channel blockade.

Hormone replacement therapy reduces mean 24-hour blood pressure and its variability in postmenopausal women with treated hypertension.

The rate and severity of hypertension increase dramatically after menopause. Complications seem to be more frequent and marked in hypertensive patients with greater blood pressure (BP) variability, and antihypertensive treatment does not easily reduce this variability. The effect of hormone replacement therapy (HRT) on BP and its variability is not well understood in moderate to severe hypertension, but estrogen may have calcium channel-blocking properties. Cardiovascular events occur more frequently in the morning, likely in part because of a rise in BP. We prospectively studied 34 postmenopausal women with treated hypertension (mean age = 53 years) and receiving a cyclic combination of estradiol and norgestrel for 19 weeks with 24-h ambulatory BP monitoring. Mean daily BP and its variability decreased significantly with HRT (149.3 +/- 6.1 mm Hg vs. 140.3 +/- 8.5 mm Hg [p < 0.001]; diastolic: 95.4 +/- 4.7 mm Hg vs. 92.4 +/- 7.2 mm Hg [p < 0.05]). There was also a significant decrease in the early morning BP values after HRT (154.0 +/- 6.9 mm Hg vs. 145.6 +/- 11.0 mm Hg [p < 0.001]; diastolic: 98.0 +/- 4.8 mm Hg vs. 95.1 +/- 10.0 mm Hg [p < 0.05]). Subjects who were taking calcium channel blockers (n = 11) had only half the reduction in 24-h systolic BP compared with those who were not taking calcium channel blockers (5.3 mm Hg vs. 10.5 mm Hg), and the reduction in those who were taking calcium channel blockers failed to reach statistical significance. Our results demonstrate that HRT may have a role in decreasing the severity of hypertension, and the mechanism of its action might be through calcium channels.

Effect of propofol on reperfusion injury after regional ischaemia in the isolated rat heart

Free oxygen radicals and intracellular calcium homeostasis play important roles in the development of myocardial reperfusion injury. Propofol is a radical scavenger with calcium channel blocking properties. We have investigated the effects of propofol on myocardial reperfusion injury. We used an isolated rat heart model where heart rate, ventricular volume and perfusion pressure were constant. The left anterior descending coronary artery (LAD) was occluded for 30 min and reperfused for 2 h. We studied an untreated control group, an Intralipid group (1 microliter ml-1) and a propofol group (Intralipid 1 microliter ml-1 and propofol 1 microgram ml-1) (n = 12 each). Drugs were infused for 20 min starting 5 min before reperfusion. We measured left ventricular developed pressure (LVDP), coronary flow and infarct size. LAD occlusion reduced mean LVDP from 129 (SEM 4) to 36 (3) mm Hg and mean coronary flow from 12.2 (0.3) to 5.2 (0.2) ml min-1. During reperfusion, LVDP recovered to 98 (4) mm Hg and coronary flow to 11.9 (0.4) ml min-1. Haemodynamic variables were similar in all groups. Propofol had no effect on infarct size compared with the Intralipid group (25.0 (3.7) vs 26.9 (3.3)% of the area at risk; P = 0.89). Infarct size in the Intralipid group tended to be smaller compared with the control group (34.8 (3.2)%; P = 0.19). We conclude that propofol, at a clinically relevant concentration, provided no protective effect against myocardial reperfusion injury in the rat heart in vitro.

Topically Applied Betaxolol Attenuates NMDA-induced Toxicity to Ganglion Cells and the Effects of Ischaemia to the Retina

The present results show that topically applied Betoptic®(0.5% betaxolol) to the rabbit or rat eye reaches the retina and can counteract the detrimental effects caused by ischaemia/reperfusion or N -methyl- d -aspartate (NMDA)-induced insults to the retina. Betaxolol is a β1-adrenergic blocker but its neuroprotective action is generally thought to be due to its calcium channel blocking properties. Support for this view comes from studies on cultures of cortical neurones where it was found that betaxolol attenuated the NMDA-induced influx of45Ca2+while β-adrenoreceptor agonists were ineffective.Topically applied Betoptic®to the rabbit eye was observed to reach the retina in maximal amounts within 60 min. Some of the substance was also found in the contralateral retina of the untreated eye suggesting that the agent reaches the retina by local systemic and retinal circulation. Concurrent treatment with Latanoprost®did not result in a greater amount of betaxolol reaching the retina.An ophthalmodynamometric procedure, which raises the intraocular pressure, was used to apply an ischaemic insult to the rabbit retina. After three days of reperfusion the b-wave of the electroretinogram was reduced by an average of 59% and the choline acetyltransferase immunoreactivity in the retina was almost obliterated. However, when experiments were carried out on animals which had been treated with one drop of Betoptic® twice daily for 4 weeks before ischaemia and also during the reperfusion phase, the reductions in both the b-wave of the electroretinogram and retinal choline acetyltransferase immunoreactivity due to ischaemia/reperfusion were greatly attenuated.Intravitreal injection of NMDA into the rat eye caused a decrease in the immunostaining for Thy-1 antigen which is associated with ganglion cells. The Thy-1 mRNA level was also reduced as was the mRNA for the common subunit of the NMDA receptor, the NR1 subunit. However, in animals subjected to a topical Betoptic®regime, before and after intravitreal injection of NMDA, the decreases in the mRNA levels of Thy-1 and NR1 were significantly attenuated.

Atheroprotection with amlodipine: cells to lesions and the PREVENT trial. Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial.

Oxidized lipid and calcium regulatory abnormalities appear to play important roles in early atherogenesis secondary to cholesterol enrichment of the cell membrane in endothelial and arterial smooth muscle cells (SMCs). However, the link between the two is poorly understood. The findings reviewed here demonstrate that amlodipine has membrane-modifying and antioxidant actions at the cell membrane level in addition to its classical calcium channel blocking properties. These multiple pharmacologic actions may explain the cellular mechanisms of the atheroprotective effects of amlodipine in spontaneous atherogenesis and in accelerated atherosclerotic syndromes. Recent animal model studies have demonstrated that amlodipine inhibits the progression of atherosclerotic lesions and protects against restenosis after angioplasty. Amlodipine inhibits the cholesterol-induced increase in calcium permeability in SMCs, and has been shown to repair abnormalities in SMC membrane structure. Recent data have also demonstrated that amlodipine has a marked antioxidant action in membrane bilayers enriched with polyunsaturated fatty acids. However, these findings have been in animal models only; the efficacy of amlodipine in atheroprotection in humans cannot be predicted. The PREVENT trial has therefore been launched to examine the atheroprotective potential of amlodipine in spontaneous lesion development in humans with ischemic heart disease and in the prevention of restenosis after angioplasty.

Synthesis, electrophysiological properties and analysis of structural requirements of a novel class of antiarrhythmic agents with potassium and calcium channel blocking properties

Class III antiarrhythmic agents have been shown to prevent reentrant arrhythmias but also to be responsible for initiating arrhythmias characterised by afterdepolarizations and triggered activities. By combining potassium and calcium channel antagonistic actions, as with BRL-32872 [1, 2] ( 1), it might be possible to reduce the incidence of proarrhythmias albeit retaining antiarrhythmic efficacy. In the present study we synthesised and tested for their electrophysiological activity in guinea pig papillary muscle a wide panel of analogues of BRL-32872. Some qualitative relationships between compound structure and the inhibitory effect on the rapidly activating component of the delayed rectifier potassium current and/or the l-type calcium current will be presented. New derivatives depicting bell-shaped dose–response curves on action potential duration may therefore represent novel agents for improved antiarrhythmic therapy.

A calcium agonist, Bay k 8644, suppresses the embryotoxic effects induced by dihydropyridines calcium channel blockers in cultured rat embryos.

Day 9 rat embryos were exposed to 1,4-dihydropyridine calcium channel blockers; nifedipine (NIF), nicardipine (NIC) or nitrendipine (NIT), for 48 hr in the whole embryo culture system. There were dose-dependent growth retardation and abnormalities, predominantly in cardiovascular system. The three compounds exhibited very similar pattern of dysmorphogenic effects, but the potency of these compounds were quantitatively different. The incidences of embryos with the abnormalities were 100%, 100% and 85% following either exposure of NIF, NIC or NIT at concentration of 300, 8 and 15 microM, respectively. This study was to investigate whether these blocker-induced embryotoxicity was due to calcium channel blocking properties themselves in the embryos. Day 9 rat embryos were co-exposed to 1,4-dihydropyridine calcium channel agonist, Bay k 8644 (BAY) and each calcium channel blocker under the same culture condition. The retarded embryonic growth induced by 200 or 300 microM of NIF, 8 microM of NIC and 15 microM of NIT nearly of completely ameliorated when embryos were co-exposed with BAY at one-third or half concentration of each calcium channel blocker. Supplementation of BAY reduced the incidence of abnormalities by NIF-, NIC- and NIT-alone. These results suggested that one of mechanisms for embryotoxicity induced by calcium channel blocker was directly related to channel blocking property of the chemicals.

Effects of Oral Propafenone in Patients with Frequent Ventricular Extrasystoles

Propafenone is an antiarrhythmic drug with class IC sodium channel blocking agent with mildly B-blocking and calcium channel blocking properties. Oral therapy effectively suppresses supraventricular and ventricular arrhythmias. However, experience with propafenone in Chinese patients is limited. To assess the efficacy and safety of oral propafenone in Chinese patients with frequent ventricular extrasys-toles(＞ 20/hour in average) and normal treadmill exercise test and echocardiographic results, 23patients (14 males and 9 females, mean age 56.5 years) were studied using 24-hour Holter ECG recording. Oral propafenone at a dose of 300 mg/day (12 patients) and 450 mg/day (11 patients) was then given. The 24-hour Holter ECG recording was repeated 4 weeks later to evaluate the suppressive effect of propafenone. Blood pressure and adverse effects were also recorded at each visit. When all patients taking 300 mg/day were analyzed as a group, no stastistically significant suppression of ventricular extrasystoles was noted, whereas patients taking 450 mg/day had significant suppression of total ventricular ectopies, isolated ventricular ectopies, and average ventricular ectopiees. Therapeutic success (＞85% suppression of ventricular ectop) was achieved in 41.7% (5/12) of in those taking 300 mg/day and in 63.6% (7/11) of those taking 450mg/day. Of the three patients taking 450 mg/day, who did not achieve ＞85% suppression, two patients showed significant suppression of ventricular ectopies without adverse effects when the dose was increased to 600 mg/day. During the treatment period, no patient reported arrhythmia-related ill effects or developed hemodynamic instability, although three patients had transient and asymptomatic bradycardia during the 24-hour Holter ECG recording. Therefore, we conclude that oral propafenone is effective at a dose range of 300 to 600 mg/day is effective and safe in the suppression of frequent ventricular extrasystoles in patients with functionally normal heart.(Tzu Chi Med J 1997;9:259-264)

Novel indole-2-carboxamide and cycloalkeno[1,2-b]indole derivatives. Structure-activity relationships for high inhibition of human LDL peroxidation.

Series of indole-2-carboxamide and cycloalkeno[1,2-b]indole derivatives were synthesized and evaluated in order to determine the necessary structural requirements for a high inhibition of human LDL copper-induced peroxidation. Various modulations were systematically performed on the indole and cycloalkeno[1,2-b]indole nuclei as well as on the carboxamide moiety. The best compounds (3c, 3e, 7c, 7f, 7h, 7g, and 7o) are between 5 and 30 times more active than probucol itself. Two of these compounds (3c and 7o) were selected for complementary in vitro and in vivo investigations, which have shown additional properties of interest for the treatment and the prevention of atherosclerosis injuries. Compound 3c was found to have some antiinflammatory properties while compound 7o was proved to protect endothelial cells from the direct cytotoxicity of oxidized LDL with some additional calcium channel blocking properties.

Use-dependent effects of the class III antiarrhythmic agent NE-10064 (azimilide) on cardiac repolarization: block of delayed rectifier potassium and L-type calcium currents.

We studied the effects of NE-10064 (azimilide), a new antiarrhythmic agent reported to be a selective blocker of the slowly activating component of the delayed rectifier, IKs. In ferret papillary muscles, NE-10064 increased effective refractory period (ERP) and decreased isometric twitch tension in a concentration-dependent manner (0.3-30 microM). Increases in ERP showed reverse use-dependence, and were greater at 1 than at 3 Hz. In contrast, changes in tension were use dependent, with larger decreases observed at 3 than at 1 Hz. In guinea pig ventricular myocytes, NE-10064 (0.3-3 microM) significantly prolonged action potential duration (APD) at 1 Hz. At 3 Hz, NE-10064 (0.3-1 microM) increased APD only slightly, and at 10 microM decreased APD and the plateau potential. NE-10064 potently blocked the rapidly activating component of the delayed rectifier, IKr (IC50 0.4 microM), and inhibited IKs (IC50 3 microM) with nearly 10-fold less potency. NE-10064 (10 microM) did not block the inward rectifier potassium current (IKl). NE-10064 (10 microM) blocked the L-type calcium current (ICa) in a use-dependent manner; block was greater at 3 than at 1 Hz. We conclude that (a) NE-10064's block of potassium currents is relatively selective for IKr over IKs, (b) NE-10064 inhibits ICa in a use-dependent fashion, and (c) NE-10064's effects on ERP and tension in papillary muscle as well as APD and action potential plateau level in myocytes may be explained by its potassium and calcium channel blocking properties.

Synergism between diltiazem and MK-801 but not APV in protecting hippocampal slices against hypoxic damage

In the present study, we investigated the possibility that MK-801 (dizocilpine), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, owes its potent neuroprotective properties to calcium channel blocking ability rather than to its NMDA receptor antagonism. Rat hippocampal slices were exposed to a long hypoxic period (20 min) from which only 13.8% recovered their neuronal function after 30 min of reoxygenation. The recovery rate of neuronal function from 20-min hypoxia was increased to 100% when slices were pretreated with 5 μM MK-801.DL-2-amino-5-phosphonovalerate (APV), a competitive NMDA receptor antagonist, even at relatively high concentration (100 μM), provided only marginal protection against a such severe hypoxic insult. The L-type calcium channel blocker diltiazem (DILT) was more effective than APV in protecting hypoxic slices against neuronal damage. Combining suboptimal concentrations of DILT and MK-801 produced a neuroprotective effect which significantly exceeded the calculated additive effect of the two drugs. Such synergism could not be demonstrated between DILT and APV, a combination that produced only the expected additive neuroprotective effect. The observed synergy between the calcium channel blocker (DILT) and MK-801, along with other studies that demonstrated interaction between these two drugs, led us to postulate that MK-801 possesses calcium channel blocking properties through which its neuroprotective effect is exerted. These calcium channels could either be of the L-type or otherwise, channels which are being activated only under stressful conditions, such as hypoxia or ischemia.

Effects of halothane on the immature lamb heart

The choice of anesthesia during pregnancy and fetal operations is controversial. Halothane frequently is used, but its direct effects on fetal cardiac performance are unknown. The effects of halothane on fetal cardiac mechanics were studied in 8 fetal lamb hearts (135 days' gestation) using a modified Langendorff model connected to a membrane oxygenator. The perfusate consisted of oxygenated maternal blood at a constant flow temperature, hematocrit value, and glucose level. Coronary blood flow, left ventricular systolic pressure, left ventricular end-diastolic pressure, and the developed left ventricular pressure at a fixed volume were evaluated at baseline and after the addition of incremental concentrations of halothane to the perfusate through the oxygenator. Perfusate halothane levels were maintained in a clinical range. Systolic and diastolic cardiac function were adversely affected by the administration of even low doses of halothane, despite a concomitant increase in coronary blood flow. Because of the immaturity of their calcium transport system, fetal hearts may be particularly sensitive to the known calcium channel-blocking properties of halothane.

Role of calcium channel blocking agents in the prevention of atherosclerosis

Summary. Calcium channel blocking agents, although effective and widely used in the symptomatic therapy of hypertension and ischemic heart disease, have an uncertain effect on the development of coronary atherosclerosis, plaque rupture, and postrupture thrombosis. Both nifedipine and nicardipine have been shown to prevent the development of new coronary lesions but not the progression of existing lesions in prospective randomized angiographic studies. Verapamil, in contrast, failed to prevent the development of new coronary lesions and had no significant effect on the progression of existing lesions. Diltiazem, although not studied in patients with coronary atheroscleroses, has been shown to prevent the development of post-transplant coronary vascular disease. Despite the beneficial effects of nifedipine and nicardipine on new coronary lesion development, they have not been shown to reduce the incidence of recurrent ischemic events or mortality in the prospective randomized studies that demonstrated their effect on new coronary lesion development. A relatively new dihydropyridine calcium channel blocking agent, amlodipine, is hypothesized to prevent atherosclerosis due to its calcium channel blocking properties as well as by mechanisms independent of its calcium channel blocking properties. This agent has been selected for evaluation in the Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT) to explore whether the use of amlodipine over 3 years will reduce the incidence of early atherosclerotic lesions and, possibly, the progression of existing lesions in both the coronary and carotid arterial beds. Amlodipine could play an important future role in the secondary prevention of ischemic heart disease, but further study and a demonstration of a beneficial effect on recurrent ischemic events is required before any final conclusions concerning its effectiveness are reached. Cardiovasc Drugs Ther 1995;9:21-24

Neuropharmacology of nimodipine: from single channels to behavior.

To supplement the existing pharmacological evidence describing the effects of nimodipine, a 1,4-dihydropyridine with calcium channel blocking properties, our group has used a multidisciplinary approach. This work attempts to characterize the mechanism of action of nimodipine in neurons as well as investigate the effects of nimodipine in models of neurodegeneration and dementia. Patch voltage clamp studies demonstrated high-affinity nimodipine block of voltage-dependent L-type calcium channel activity in central neurons from primary cultures of neonatal rat hippocampus. Nimodipine potently blocks depolarization-induced increases in free calcium throughout the soma of these hippocampal neurons. In addition, somatic free calcium elevations induced by acute beta A4(25-35) exposure are also potently blocked by nimodipine. In behavioral studies, nimodipine produced enhanced retention in aging rabbits on eyeblink conditioning and also was shown to protect against medial septal lesion-induced retention deficits in a spatial learning task. These findings, from channel to behavioral effects, support the therapeutic usefulness of nimodipine in the treatment of aging and dementia and are consistent with the view that calcium regulation is important in disorders of neuronal degeneration.

Diuretic and antihypertensive activity of ZENECA ZM224,832: a novel eukalemic diuretic with calcium channel blocking activity.

ZENECA ZM224,832 is a novel eukalemic diuretic from the aminomethylphenol pyrazine series which demonstrated a profile of calcium channel blockers. It produced diuretic and saluretic effects in animals but had only minimal alterations in kaliuresis after oral administration. In contrast to standard diuretics, the plasma K+ concentration was not altered in conscious dogs treated for 14 days with ZENECA ZM224,832 and the concurrent plasma renin activity was also minimally elevated. The isolated rat aorta evaluation indicated that ZENECA ZM224,832, like tiapamil and nifedipine, inhibited vascular smooth muscle tone by inhibiting voltage-dependent calcium channels. ZENECA ZM224,832 produced a dose-dependent decrease of blood pressure in spontaneously hypertensive rats (SHR) in which the antihypertensive activity was not noted with HCTZ. In addition, ZENECA ZM224,832, similar to diltiazem, produced an acute blood pressure lowering effect in nephrectomized SHR which was independent of its diuretic activity. It is concluded that ZENECA ZM224,832 is a potent eukalemic diuretic with calcium channel blocking properties.