Double Action of Nicardipine on Serotonin Release from Rat Platelets

Baudouin-Legros, Maryvonne; Dard, B; Guicheney, Pascale; Meyer, Philippe

doi:10.1097/00005344-198709000-00006

Cited by 6 publications

(5 citation statements)

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“…These data include the observations that platelets do not have high affinity dihydropyridine binding sites, K* rich solutions fail to evoke an increase in lCu'*7, valinomycin is not inhibitory to platelet activation, and agonists evoke only small (5)(6)(7)(8)(9)(10) as alpha receptor inhibition (25,26), inhibition of serotonin uptake (28)(29)(30), elevation of cAMR and inhibition of PAF binding (24). These mechanisms cannot explain the liposome data since no agonist interaction is required and no cyclase activity is present in this purified system.…”

Section: Discussionmentioning

confidence: 98%

Effect of Calcium Channel Blockers on Platelet GPIIb-IIIa as a Calcium Channel in Liposomes: Comparison with Effects on the Intact Platelet

Rybak

Renzulli

1992

Thromb Haemost

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SummaryThe platelet membrane glycoprotein IIb-IIIa complex is essential for platelet aggregation and functions as a fibrinogen receptor on the activated platelet. When incorporated into phospholipid vesicles, this glycoprotein complex can function as an apparent calcium channel which facilitates the transit of calcium across a phospholipid barrier. In order to further evaluate this calcium channel, the effect of calcium channel blockers of the dihydropyridine (nifedipine and nicardipine), arylalkylamine (verapamil) and benzothiazipine (diltiazem) classes were evaluated on GPIIb-Illa liposomes with encapsulated fura-2 (a fluorescent calcium indicator). Nicardipine, verapamil, and nifedipine significantly inhibited calcium influx into GPIIb-IIIa liposomes; however, this required 190 μM, 400 μM, and 140 μM drug, respectively. These concentrations are 10-1,000 fold greater than those clinically obtainable. In contrast, diltiazem at concentrations >220 μM and amiloride at concentrations >800 μM showed no inhibitory effects. When aspirinized platelets were activated with 30 μg/ml bovine fibrillar collagen, both nicardipine and diltiazem produced a decrease in both the initial rise and maximum cytoplasmic calcium concentration. Parallel experiments were performed to assess the effects of verapamil, nicardipine, and diltiazem on platelet aggregation in platelet rich plasma. Nicardipine, 190-380 μM, induced a prolongation of the lag phase, but no effect on the final degree of platelet aggregation to collagen. Similar inhibition of platelet aggregation was seen with diltiazem and verapamil although the effect of diltiazem was less pronounced particularly at higher concentrations of collagen. No effect was seen on aggregation with 32 μM ADP which is release independent, or on the primary wave of low dose ADP induced platelet aggregation. Verapamil (200 μM) and nicardipine (>190 μM) partially inhibited the secondary wave of 3.2 μM ADP aggregation. In contrast, diltiazem (400 μM) had limited effect on ADP induced aggregation. Similarly, both nicardipine and verapamil markedly inhibited platelet aggregation to 6 μM epinephrine; however, diltiazem had no effect. These data demonstrate that the GPIIb-IIIa calcium channel is selectively inhibited by different classes of calcium channel blockers. This inhibition requires concentrations much higher than that to inhibit classic voltage gated calcium channels and may be by a different mechanism. Further evaluation will determine whether this differential inhibition of the GPIIb-IIIa calcium channel is related to differences observed in platelet aggregation.

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Section: Discussionmentioning

confidence: 98%

Effect of Calcium Channel Blockers on Platelet GPIIb-IIIa as a Calcium Channel in Liposomes: Comparison with Effects on the Intact Platelet

Rybak

Renzulli

1992

Thromb Haemost

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“…Many mechanisms have been advocated to explain these properties. Calcium antagonists can prevent the influx of calcium with ensuing activation of receptor‐triggered phospholipase C, protein kinase C, and phospholipase A 25 , 27 ; they may also increase intracellular cyclic adenosine monophosphate levels, 28 antagonize calmodulin activation, 29 reduce thromboxane A 2 synthesis, 30 , 31 reduce serotonin uptake and release, 32 , 33 inhibit platelet‐activating factor, and neutralize glycoprotein IIb/IIIa, which acts as both a surface receptor for platelet aggregation and a calcium channel 34 . These antiplatelet properties may justify the increased risk of bleeding that has been observed among surgical patients 5 , 6 .…”

Section: Discussionmentioning

confidence: 99%

Use of calcium antagonists and hemoglobin loss in hospitalized elderly patients: A cohort study

Zuccalà

Cocchi

Pahor

et al. 2000

Clinical Pharmacology & Therapeutics

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Objective To assess the association between in‐hospital use of calcium antagonists and incident reduction in hemoglobin levels, as well as the impact of individual baseline risk for gastrointestinal bleeding on such an association. Methods The association between calcium antagonists and hemoglobin decrease >1.2 g/dL was examined in 6721 patients enrolled in a collaborative pharmacoepidemiology study who did not take calcium antagonists before admission and with baseline hemoglobin ≥12 g/dL. Among these participants, 1076 patients started taking calcium antagonists during their hospital stays. Demographic variables, comorbid conditions, medications, and objective tests that were associated with incident hemoglobin loss in separate age‐ and sex‐adjusted logistic regression models were examined as potential confounders in a summary model. Higher risk for gastrointestinal bleeding was defined by diagnosis, treatment for peptic disease, or both. Results Hemoglobin decrease was detected in 24% of participants who started treatment with calcium antagonists and in 19% of other patients (P < .0001). In addition, use of calcium antagonists was independently associated with increased probability of hemoglobin loss (odds ratio [OR], 1.22; 95% confidence interval [CI], 1.03 to 1.45; P = .018) after adjusting for potential confounders. Treatment with calcium antagonists was associated with hemoglobin loss in patients with higher baseline risk for gastrointestinal bleeding (OR, 1.67; 95% CI, 1.26 to 2.22; P < .0001) but not among other participants (OR, 1.02; 95% CI, 0.82 to 1.25). Conclusion Starting treatment with calcium antagonists is associated with a reduction in hemoglobin levels during a hospital stay. However, the increased risk of hemoglobin loss seems to be limited to patients with diagnosis or symptoms of peptic disease. (Clin Pharmacol Ther 2000;67:314–22.) Clinical Pharmacology & Therapeutics (2000) 67, 314–322; doi:

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“…Release: Although the mechanism(s) of regulation of platelet 5-HT levels has not been established, one hypothesis is that an equilibrium between platelet 5-HT uptake and release is responsible for steady-state levels of 5-HT. Platelets release 5-HT in response to several agonists in plasma, including thrombin (Baudouin-Legros et al, 1987). colleagues (1970, 1971) studied 5-HT "efflux" from the platelets of autistic children.…”

Section: Bloodmentioning

confidence: 99%

“…A study has not been reported in which release of 5-HT in response to drugs such as thrombin (Baudouin-Legros et al, 1987) has been measured in autistic subjects. Impaired stimulated release of 5-HT from platelets remains a possible mechanism of hyperserotonemia.…”

Section: Bloodmentioning

confidence: 99%

Autism: Review of neurochemical investigation

Cook

1990

Synapse

171

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The neurochemistry of autism, the most well-validated childhood neuropsychiatric disorder, has been studied extensively over the past three decades. Autism is of interest neurochemically because it represents a relatively homogeneous disorder with a triad of social, communicative, and intellectual developmental disturbance. Because a sufficient animal model has been lacking and relatively few diagnosed people with autism have died, most investigation has been of peripheral fluids and tissues. The most consistent finding has been that over 25% of autistic children and adolescents are hyperserotonemic. However, after 29 years of investigation, the mechanism of hyperserotonemia has not been determined. Hyperserotonemia has been found to be familial. Elevated plasma norepinephrine has also been a replicated finding. Cerebrospinal fluid (CSF) opiate activity has been found to be elevated in two studies. Plasma cyclic adenosine monophosphate (cAMP) has been found to be elevated in autistic children. A high rate of nonsuppression after dexamethasone and blunted or delayed growth hormone response to L-dopa have been found. Abnormal cell-mediated immunity has been replicated consistently in autism. Although several pharmacological trials have been conducted and shown promise in initial open trials, only "typical" antipsychotic drugs have shown replicable chronic ameliorating effects in double-blind trials. However, chronic neurotoxicity (tardive dyskinesia) has also been revealed. Findings of morphological changes in the cerebellum have been replicated. Findings in need of replication include diminished platelet function, increased baseline CSF homovanillic acid, decreased nerve cell adhesion molecule serum fragment, blunted prolactin response to fenfluramine, amelioration of symptoms by naltrexone and bromocriptine, reduced electroretinographic (ERG) b-wave amplitude, and morphological changes in the hippocampus, amygdala, and septal nuclei. In addition to refining and replicating past findings, future directions that may be fruitful include investigation of neurochemical aspects of platelet function, of interactions between monoaminergic systems, of phosphatidylinositides, and of pharmacological response to "atypical" antipsychotic agents and relatively selective serotonin receptor subtype agonists or antagonists.

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Double Action of Nicardipine on Serotonin Release from Rat Platelets

Cited by 6 publications

References 0 publications

Effect of Calcium Channel Blockers on Platelet GPIIb-IIIa as a Calcium Channel in Liposomes: Comparison with Effects on the Intact Platelet

Effect of Calcium Channel Blockers on Platelet GPIIb-IIIa as a Calcium Channel in Liposomes: Comparison with Effects on the Intact Platelet

Use of calcium antagonists and hemoglobin loss in hospitalized elderly patients: A cohort study

Autism: Review of neurochemical investigation

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