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Inhibition of Cerebral Vasoconstriction by Dantrolene and Nimodipine

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Abstract

Introduction

Cerebral vasoconstriction is associated with increased cytosolic Ca2+ concentration in vascular smooth muscle, presumably due to Ca2+ influx and Ca2+ release from intracellular stores. We tested the hypothesis that dantrolene (a blocker of Ca2+-induced Ca2+ release from the ryanodine receptor channel on the sarco-endoplasmic reticulum) would potentiate the action of nimodipine (a voltage-dependent L-type Ca2+ channel blocker, considered standard therapy for SAH) in inhibiting the vasoconstriction of isolated cerebral arteries.

Method

Sprague–Dawley rat basilar and femoral arteries were analyzed for ryanodine receptor expression by immunofluorescence and PCR. Vasoconstriction of basilar artery ex vivo was measured in a wire myograph while exposed to serotonin (5-HT) or endothelin-1 (ET-1) in the presence or absence of dantrolene (10–100 μM) and/or nimodipine (30 nM). Femoral artery was examined for comparison.

Results

Basilar and femoral arteries express only the ryanodine receptor 3 (RyR3) isoform. In both basilar and femoral arteries, dantrolene significantly inhibited the constriction to 5-HT, whereas it poorly affected the constriction to ET-1. The inhibitory effect of dantrolene on 5-HT was substantially increased by nimodipine, inducing a 10-fold increase in the 50% effective concentration of 5-HT and a 46% reduction in maximum basilar constriction. In femoral artery, dantrolene modestly affected constriction to phenylephrine and there was no interaction with nimodipine.

Conclusion

Dantrolene has synergistic effects with nimodipine against 5-HT-induced vasoconstriction in isolated cerebral arteries. Dantrolene–nimodipine interaction will require testing in a pathophysiological model but might provide treatment for reducing SAH-related vasospasm or other 5-HT-related vasospastic syndromes, such as Call-Fleming syndrome.

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Acknowledgment

Dr. John Sims is supported by NIH 1 K08 NS049241-01A2.

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Authors and Affiliations

  1. Department of Radiology, Massachusetts General Hospital, Harvard Medical School, CNY149 Rm64212A, 13th St, Charlestown, MA, 02129, USA

    Salvatore Salomone, Guray Soydan, Michael A. Moskowitz & John Randall Sims

  2. Department of Neurology, Division of Neurocritical Care and Acute Stroke, Massachusetts General Hospital, Harvard Medical School, CNY149 Rm64212A, 13th St, Charlestown, MA, 02129, USA

    John Randall Sims

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  1. Salvatore Salomone
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Correspondence to John Randall Sims.

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Salomone, S., Soydan, G., Moskowitz, M.A. et al. Inhibition of Cerebral Vasoconstriction by Dantrolene and Nimodipine. Neurocrit Care 10, 93–102 (2009). https://doi.org/10.1007/s12028-008-9153-0

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