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PubMed1989

Antihypertensive therapy in the geriatric patient. I: A review of the role of calcium channel blockers.

Animal and clinical studies have demonstrated the efficacy of calcium channel blockers in reducing blood pressure, especially in older patients whose hypertension is characterized by increased peripheral vascular resistance. Their chemical heterogeneity, which permits targeted therapy, as well as their minimal side effects, drug interactions, and clinical utility in numerous pathophysiologic states common to the elderly, enhance the suitability of calcium channel blockers in treating mild to moderate hypertension in this subgroup. This is particularly relevant for those patients who have concomitant conditions, such as diabetes, chronic obstructive pulmonary disease, or peripheral vascular disease, and for whom many of the more traditional antihypertensive drugs are either contraindicated or might cause a worsening of the disease.

Aged↗

PubMed1995

Calcium channel blockers and renal dysfunction in arterial hypertension.

Beside effective systemic blood pressure control, calcium channel blockers exert several effects on glomerular haemodynamics (namely, preglomerular vasodilatation at the early stage of the hypertensive process) and on cellular mechanisms of glomerular sclerosis (namely, inhibition of mesangial mechanisms of growth) that may provide a renal protective effect in patients with essential hypertension and, in turn, may prevent or attenuate the development of nephrosclerosis (Table 3). However, up to now, there have been relatively few attempts to corroborate this assumption in clinical practice. Furthermore, more clinical studies have been conducted with the dihydropiridine class of calcium channel blockers. Thus, prospective, long-term ongoing studies will help to delineate the long-range consequences of the renal actions of the different class of calcium channel blockers in essential hypertension.

Calcium Channel Blockers↗

PubMed1998

Accidental ingestion of sustained release calcium channel blockers in children.

We examined the effects of small ingestions of sustained release calcium channel blockers (SR-CCBs) in young children and characterized current recommendations regarding monitoring after a suspected ingestion. A 2-part study was performed of pediatric calcium channel blocker (CCB) ingestion: first a telephone survey of 33 randomly selected Poison Control Centers (PCCs) from around the US concerning their recommended management of a small ingestion of sustained release calcium channel blocker in a child, and then a 5-y retrospective review of local cases of CCB ingestions in children under 4 y-of-age. The number of hours of medical observation recommended by the PCCs varied from > or = 24 h (n = 15, 45%) to < 6 h (n = 6, 18%). The retrospective chart review revealed that 19 of 29 local cases involved a SR-CCB, and 6 of these were thought to have ingested only 1 tablet. Observation time varied from > 24 h to < 6 h in the 17 cases seen in an emergency department. No symptoms or vital sign abnormalities were reported in any case. Recommendations regarding duration of observation varied from < 6 h to 24 h. Ingestion of a few SR-CCB tablets was not associated with symptoms, suggesting that admission and 24-h monitoring may not be necessary under those circumstances.

Accidents, Home↗

PubMed1996

Effects of T-type, L-type, N-type, P-type, and Q-type calcium channel blockers on stimulus-induced pre- and postsynaptic calcium fluxes in rat hippocampal slices.

The contribution of T-, L-, N-, P-, and Q-type Ca2+ channels to pre- and postsynaptic Ca2+ entry during stimulus-induced high neuronal activity in area CA1 of rat hippocampal slices was investigated by measuring the effect of specific blockers on stimulus-induced decreases in extracellular Ca2+ concentration ([Ca2+]o). [Ca2+]o was measured with ion-selective electrodes in stratum radiatum (SR) and stratum pyramidale (SP), while Ca2+ entry into neurons was induced with stimulus trains (20 Hz for 10 s) alternately delivered to SR and the alveus, respectively. The [Ca2+]o decreases recorded in SR in response to SR stimulation represented mainly presynaptic Ca2+ entry (Capre), while [Ca2+]o decreases recorded in SP in response to alvear stimulation were predominantly based on postsynaptic Ca2+ entry (Capost). Ethosuximide and trimethadione were ineffective in concentrations up to 1 mM. At 10 mM, they reduced Capost and, much less, also Capre. Nimodipine (25 microM) reduced Capost and, to a minor extent, Capre. omega-Agatoxin IVA (0.4-1 microM) and omega-contoxin MVIIC (1 microM) also reduced both Capre and Capost, but with a stronger action on Capre. omega-Conotoxin GVIA (3-8 microM) reduced Capost without effect on Capre. We conclude that during stimulus-induced, high-frequency neuronal activity Capost is carried by P/Q-, N-, and L- type channels and probably a further channel type different from these channels. Capre includes at least P/Q- and possibly L-type channels. N-type channels did not contribute to Capre in our experiments. Since ethosuximide and trimethadione were only effective in high concentrations, their action may be unspecific. Thus, T-type channels do not seem to play a major part in Ca2+ entry in this situation.

Animals↗

PubMed1997

Effect of different calcium channel blockers on inhibitory junction potentials and slow waves in porcine ileum.

The effect of several calcium channel blockers was evaluated: (i) on spontaneous electrical and mechanical activities and (ii) on the response to electrical field stimulation. The study was carried out on whole-thickness preparation of porcine ileum. Glass microelectrodes were used to record membrane potential from smooth muscle cells. Resting membrane potential was -60 +/- 2mV (n = 18) and preparations generated spontaneous slow waves. Electrical field stimulation (EFS) was applied using different parameters. The amplitude and duration of inhibitory junction potentials (IJPs) increased with EFS strength. IJPs were abolished by tetrodotoxin (1 microM). Nifedipine (1 microM) did not modify the amplitude or duration of IJPs. The frequency of slow waves was not modified, however a slight but significant (p < 0.001) reduction in slow wave duration was observed. Mechanical activity was abolished in presence of nifedipine within approximately 6 min. omega-agatoxin IVA (50 nM) or omega-conotoxin MVIIC (100 nM), respectively a P-type and a Q-type calcium channel blockers, did not modify slow wave and IJP characteristics. In contrast, in presence of omega-conotoxin GVIA (100 nM), a N-type calcium channel blocker, or omega-conotoxin MVIIC (1 microM), IJPs were completely abolished. These data suggest that, in porcine ileum, N-type but not P-,Q- or L-type calcium channels are involved in the release of the non-adrenergic non-cholinergic neurotransmitters mediating IJPs. L-type calcium channels underlie electrical mechanical coupling but are not involved in slow wave generation.

Animals↗

PubMed1996

The safety of calcium channel blockers in human pregnancy: a prospective, multicenter cohort study.

OBJECTIVE: Our purpose was to examine the potential teratogenicity of calcium channel blockers. STUDY DESIGN: Six teratogen information services prospectively collected and followed up 78 women with first-trimester exposure to calcium channel blockers. Pregnancy outcome was compared (by paired t text of chi2 analysis) with that of a control group matched for maternal age and smoking. RESULTS: There was no increase in major malformation (2/66=3.0% [calcium channel blockers] vs 0% [nonteratogenic controls], p=0.27); a fivefold increase was ruled out (baseline 2%, alpha = 0.05, beta = 0.20). The defects reported were attributable to maternal diabetes or coingestion of teratogens. The increase in preterm delivery 28% [calcium channel blockers] vs 9% [nonteratogenic controls], p=0.003), attributed to maternal disease by stepwise regression, was the most important factor responsible for the observed decrease in birth weight (mean -334 gm vs nonteratogenic controls, p=0.08). CONCLUSION: This study suggests that calcium channel blockers do not represent a major teratogenic risk.

Abnormalities, Drug-Induced↗

PubMed1986

Cardioprotective actions of a new calcium channel blocker in acute myocardial ischemia.

The ability of anipamil, a calcium channel blocker, to protect ischemic myocardial tissue was investigated in pentobarbital anesthetized cats. Two bolus injections of anipamil (1.0 mg/kg i.v.) or their vehicle (i.e., 95% ethanol) were given 30 and 150 min post-ligation of the left anterior descending coronary artery. Anipamil significantly reduced the elevated S-T segment elevation and T wave amplitude suggesting a moderating influence on cellular ischemia. The drug also significantly blunted the loss in myocardial creatine kinase activity and amino-nitrogen concentrations from ischemic myocardial tissue, compared to cats receiving only the vehicle. These changes are suggestive of a cardioprotective effect of this calcium channel blocker. Since no significant change in the pressure rate index was seen with anipamil, a decrease in myocardial oxygen demand does not appear to be the major mechanism of the cardioprotective action of the agent. Therefore, anipamil protected the heart from ischemic damage, possibly by a direct cytoprotective action.

Animals↗

PubMed1988

Differential effects of calcium channel blockers and stimulants on morphine withdrawal in vitro.

The effects of calcium channel blockers and stimulants on naloxone-precipitated morphine withdrawal in morphine-dependent ileum were evaluated in vitro. Both verapamil and diltiazem (0.01-1 microM) inhibited the naloxone-induced morphine withdrawal contractures in a concentration-dependent way. The effect of diltiazem was stereo-specific. On the other hand, the calcium channel stimulant, Bay k 8644 (0.01 microM), significantly increased the naloxone-induced contractures of morphine-dependent ileum. These results suggest a role for calcium channels in morphine withdrawal in vitro.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1998

Electrophysiologic assessment of calcium channel blockers in transplanted hearts: an experimental study.

The effects of calcium channel blockers on automaticity, conduction, and refractoriness were studied in a model of heterotopic heart transplantation in dogs, which combined an innervated heart (recipient) and a denervated one (donor). Following the surgical procedure, 0.2 mg/kg verapamil (n = 10), 0.15 mg/kg diltiazem (n = 10), or 5 microg/kg + 30 microg/kg/h nifedipine (n = 10) was administered intravenously. In basal situation and after drug administration, each heart was assessed for AV interval, cycle length, sinoatrial conduction time, atrioventricular node antegrade block point, and atrioventricular node and ventricular refractory periods; electrocardiographic PR and QT intervals and QRS complexes; systemic arterial, pulmonary artery, central venous, and pulmonary capillary wedge pressures; and cardiac output. The depressor effects of these calcium channel blockers on automaticity, refractoriness, and conduction were more intense in the transplanted hearts, very possibly because of the absence of adrenergic reflexes mediated by the autonomic nervous system; in particular, verapamil produced a great depression of sinus automaticity in a large number of cases.

Animals↗

PubMed2004

Antihypertensive effects of long-acting calcium channel blockers on hemodialysis days--a randomized crossover trial between benidipine and nifedipine CR.

BACKGROUND/AIMS: Since antihypertensive effects of most calcium channel blockers largely depend on their plasma concentrations, a rapid increase in blood pressure may occur as circulating levels of such blockers decrease after hemodialysis. Thus, the effects of benidipine and nifedipine CR (extended-release coated tablets, Adalat CR), which are long-acting calcium channel blockers, on post-hemodialytic blood pressures were investigated. METHODS: A randomized crossover trial was carried out with 10 hypertensive patients on chronic maintenance hemodialysis. Patients were assigned to receive benidipine (4-8 mg/day) or nifedipine CR (20-40 mg/day), and after 4 weeks, 24-hour ambulatory blood pressure monitoring was performed on the day of hemodialysis and blood samples were obtained before and after hemodialysis to measure plasma concentrations of the blockers. The calcium channel blockers were then exchanged in each patient and the same protocol was repeated. RESULTS: The pattern of fluctuation of blood pressure differed markedly between the treatment with benidipine and nifedipine CR. Under treatment with nifedipine CR, rapid increase in blood pressure was observed after hemodialysis, while blood pressure remained at favorable levels with benidipine. Plasma concentrations of the blockers were significantly decreased by hemodialysis. CONCLUSION: Benidipine exerts more sustained antihypertensive effects than expected from its disposition in plasma. The stable depressor effects of benidipine even after hemodialysis may contribute to favorable control of blood pressure in this population.

Aged↗

PubMed1993

Calcium channel blockers in heart failure.

The rationale for the use of calcium channel blockers in patients with chronic heart failure lies in their vasodilator action, antiischemic effect, ability to lessen left ventricular diastolic dysfunction and data showing their effect in preventing progression of myocardial dysfunction in animals with cardiomyopathy. Despite initial studies reporting improvement of the hemodynamic profile with nifedipine, further evaluation showed variable results, with hemodynamic worsening seen in up to 29% of patients. Longer-term controlled studies evaluating symptoms and clinical status demonstrated worsening chronic heart failure in approximately 25% of patients within 8 weeks of nifedipine therapy. Although diltiazem has a lesser myocardial depressant effect and its short-term use was associated with less frequent hemodynamic and clinical worsening, long-term exposure to the drug in a large group of patients with chronic heart failure due to left ventricular systolic dysfunction after myocardial infarction resulted in an increased incidence of cardiac events, with worsening heart failure and death. The use of verapamil in a similar patient cohort showed the loss of its demonstrated protective effect in patients with clinical evidence of heart failure. In an attempt to improve the safety of calcium channel blockers, the following approaches were suggested: 1) use of second-generation drugs with less myocardial depressant effect; 2) concomitant use of angiotensin-converting enzyme inhibitors to prevent reported neurohormonal activation; and 3) development of drugs with favorable neurohormonal effects. These approaches led to mixed results.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium Channel Blockers↗

PubMed2001

L-type calcium channel blockers and EGTA enhance superoxide production in cardiac fibroblasts.

Since the recognition of the importance of calcium ions to cardiac contractility, the effects of alterations in calcium homeostasis on cardiac myocyte function have attracted immense attention. However, the possibility that changes in extracellular calcium concentration or the administration of calcium channel blockers may exert significant effects on cardiac fibroblasts has not hitherto been explored. This communication presents evidence, for the first time, that EGTA, calcium-free incubation and L-type calcium channel blockers increase endogenous superoxide production in adult rat cardiac fibroblasts. A combination of ryanodine and EGTA was found to have an even greater effect. The observations indicate that extracellular calcium levels influence endogenous superoxide production in cardiac fibroblasts and support the postulation that myocardial fibroblasts may contribute to the cardiac effects of calcium channel blockers and alterations in extracellular calcium concentration.

Animals↗

PubMed1996

Spinal antinociceptive action of an N-Type voltage-dependent calcium channel blocker and the synergistic interaction with morphine.

BACKGROUND: Four different voltage-dependent calcium channels (L-, N-, T-, and P-types) are distinguished in the central nervous system. Both L- and N-type calcium channels have been implicated in the release of neurotransmitters from sensory neurons in the spinal cord. It has been demonstrated that intrathecal L-type calcium channel blockers, which alone do not exhibit any antinociceptive effects, potentiate the antinociceptive effect of intrathecal morphine. The current study was designed to investigate the antinociceptive effects of the intrathecally administered N-type calcium channel blocker, omega-conotoxin GVIA (omega-CgTx). The interaction between morphine and omega-CgTx at the level of the spinal cord also was examined. METHODS: In male Sprague-Dawley rats, lumbar intrathecal catheters were chronically implanted. Tail flick and mechanical paw pressure tests were used to assess thermal and mechanical nociceptive thresholds, respectively. Morphine, omega-CgTx, or a combination of morphine and omega-CgTx was administered intrathecally, and the nociceptive thresholds were determined. Isobolographic analyses were used to define the nature of the functional interactions between morphine and omega-CgTx. RESULTS: Intrathecal omega-CgTx produced antinociception in a dose- and time-dependent manner. Isobolographic analyses revealed that intrathecal omega-CgTx and morphine interacted synergistically in both nociceptive tests. CONCLUSIONS: This study indicates the importance of the N-type calcium channel in the spinal cord on nociception and suggests the functional interaction between the N-type calcium channel blocker and opioid at the level of the spinal cord.

Analgesics↗

PubMed1994

Protective effects of calcium channel blockers in carbon tetrachloride-induced liver toxicity.

The effects of calcium channel blockers, verapamil, nifedipine and diltiazem, on CCl4-induced liver damage were determined. A single dose of CCl4 (0.5 ml/kg p.o.) led to a five-fold increase in liver calcium content. The toxic effect of CCl4 was also observed in other hepatic processes: the protein synthesis rate in the liver showed an important decrease, liver glycogen content and bile flow was decreased, and lipid peroxidation was approximately doubled. The plasma levels of cholesterol, triglycerides and transaminases (AST and ALT) also increased. When the calcium channel blockers were administered 2 hr prior to and 7 hr after the administration of the toxic agent at doses of 25 mg/kg (diltiazem) and 10 mg/kg (nifedipine and verapamil), the liver showed a significant reestablishment of several of these parameters: a considerable reduction in liver calcium content, a decrease in AST and ALT levels, and a significant increase in protein synthesis rate. There was also a partial inhibition of lipid peroxidation.

Animals↗

PubMed2001

Calcium channel blockers as tocolytics.

This article reviews the clinical and basic science investigations regarding the safety and efficacy of calcium channel blockers as tocolytic agents. The authors reviewed the English language literature on the pharmacology and clinical applications of calcium antagonists in obstetrics. A MEDLINE (1966-2000) search was performed with the terms "calcium channel blockers," "randomized controlled trial," "preterm labor," "calcium antagonist," "tocolysis," and "nifedipine." References from these data sources were then used to find additional studies. Animal data and clinical trials in humans were included. The safety of these agents was researched in published data from the nonobstetric as well as obstetric literature. The calcium channel blockers most commonly used as tocolytics are nifedipine and nicardipine. These agents act to inhibit calcium influx across cell membranes, thereby decreasing tone in the smooth muscle of the vasculature. They act as profound vasodilatory agents and have minimal effect on the cardiac conduction system. Numerous randomized clinical trials have shown them to be as effective as beta-mimetics and magnesium in achieving tocolysis. When used for tocolysis, calcium antagonists have fewer maternal side effects than other tocolytics and have no adverse effect on fetal outcome.

Animals↗

PubMed1994

Pineal perfusion with calcium channel blockers inhibits differently daytime and nighttime melatonin production in rat.

In a previous study we have shown that the response of perifused pineal glands to calcium was different according to the circadian stage at which the glands were removed. This difference may be explained by circadian changes in calcium channel function. Therefore in the present study we documented the effects of calcium channel blockers in perifused rat pineal glands removed in the middle of the light and dark spans (7 and 19 HALO (hours after light onset), in a L/D 12:12 regimen). Moreover, we have studied the effect of calcium channel blockers on adrenergically stimulated pineal glands removed 7 HALO. Inorganic (Co2+ and Cd2+) and organic (nifedipine and diltiazem) calcium channel blockers at 10(-4) mol/l all significantly reduced melatonin production and this inhibition was more effective with the glands removed 7 HALO. In a concentration of 10(-)5 mol/l, only Cd2+ and diltiazem reduced melatonin production significantly in pineal glands removed 7 HALO. Verapamil at 10(-4) and 10(-5) mol/l showed no significant effect on melatonin production in glands removed both during the light and dark spans. Mn2+ at 10(-4) mol/l (but not at 10[-5] mol/l) appeared to stimulate melatonin production in glands removed both during the light and the dark (significant increase only with glands removed during the dark). Cobalt showed an immediate short inhibitory effect on both isoproterenol and norepinephrine-stimulated melatonin release, whereas nifedipine showed a significant inhibition only on isoproterenol-stimulated melatonin release. These results strongly suggest a circadian stage dependence of the pineal gland response to some calcium channel blockers and the involvement of calcium in the release of melatonin from pinealocytes.

Animals↗

PubMed1995

[Cardiovascular effects of a calcium channel blocker in hypoxia caused by altitude].

OBJECTIVE: High altitude pulmonary oedema can be successfully treated and prevented by calcium channel blockers. Moreover, calcium entering in the cells could explain the congestive phenomena of acute mountain sickness (AMS). These findings led us to study the action of a calcium channel blocker, isradipine, in the prevention of non-complicated AMS. METHODS: In a double blind randomized study, 20 healthy volunteers received 5 mg of isradipine (n = 6) or placebo (n = 6) for 8 days. After 5 days of treatment in normoxia, the subjects were rapidly transported to an altitude of 4350 m. The efficiency of the treatment was then estimated by the AMS symptom score, haemodynamic parameters and renal function. RESULTS: The administration of isradipine did not significantly modify AMS symptom score nor most of other parameters measured in high altitude hypoxia. Heart rate was an average of 15 b/min lower in the isradipine group, probably because of a direct action of isradipine on the sinus node. Otherwise, the effects of hypoxia were similar in both groups and were in accordance with the literature. There was no clear explanation for the increase in cardiac output and stroke volume when the subjects moved from supine to standing position. Renal blood flow, measured by Doppler or para-aminohippuric acid clearance was not modified by hypoxia. Cerebral blood flow was elevated, due to the direct vasodilator effect of hypoxia. However this increase did not seem to be the main mechanism responsible for the congestive phenomena. On the other hand, the increase in capillary permeability (demonstrated by the increased transcapillary escape rate of albumin, and albuminuria) appeared to play a major role in the pathogenesis of AMS and high altitude cerebral oedema. Isradipine had no protective effect on these phenomena and its use should be restricted to the treatment of high altitude pulmonary oedema.

Adult↗

PubMed2006

Synthesis and SAR of novel 2-arylthiazolidinones as selective analgesic N-type calcium channel blockers.

A series of new N-type (Ca(v)2.2) calcium channel blockers derived from the 'hit' structures 2-(3-bromo-4-fluorophenyl)-3-(2-pyridin-2-ylethyl)thiazolidin-4-one 9 and its 2-[4-(4-bromophenyl)pyridin-3-yl]-3-isobutyl analogue 10 is described. Extensive SAR studies using a range of synthetic approaches resulted in novel, patented compounds with IC50 values of up to 0.2 microM in an in vitro IMR32 assay, and selectivities for N/L of up to 30-fold. The new compounds described have potential in treatment of neuropathic pain.

Analgesics↗