Inhibition of Cerebral Vasoconstriction by Dantrolene and Nimodipine

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. 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 mu M) and/or nimodipine (30 nM). Femoral artery was examined for comparison. 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. 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.