Inhibition of Cerebral Vasoconstriction by Dantrolene and Nimodipine

Abstract

Introduction-Cerebral vasoconstriction is associated with increased cytosolic Ca 2+ concentration in vascular smooth muscle, presumably due to Ca 2+ influx and Ca 2+ release from intracellular stores. We tested the hypothesis that dantrolene (a blocker of Ca 2+ -induced Ca 2+ release from the ryanodine receptor channel on the sarco-endoplasmic reticulum) would potentiate the action of nimodipine (a voltage-dependent L-type Ca 2+ channel blocker, considered standard therapy for SAH) in inhibiting the vasoconstriction of isolated cerebral arteries.

Subtype identification and functional characterization of ryanodine receptors in rat cerebral artery myocytes

“…8A) is consistent with findings in other rat arterial smooth muscle preparations, including aorta, superior and inferior mesenteric (59), coronary (70), and main pulmonary arteries (80), but not basilar arteries (65). Our real-time PCR data, however, show that RyR2 is the most abundant transcript in rat cerebral artery myocytes, with RyR3 less highly expressed and RyR1 barely detected (Fig.…”

“…8B). Using PCR, it has recently been reported that only RyR3 RNA can be detected in rat basilar arteries (65). In both this study and ours, animals of same species, strain, and age were used.…”

“…Consistent with this role of RyR in vascular smooth muscle, several vasoconstrictors, including UTP and ␣ 1 adrenergic agonists, inhibit RyR-mediated Ca 2ϩ sparks in arterial myocytes (28,50). In addition, it has been recently reported that RyR inhibition and VDCC blockade synergistically inhibit basilar (but not femoral) artery constriction, raising speculation that pharmacological targeting of RyRs could be of therapeutic use in cerebral artery spasm (65). Despite the importance of RyRs in the physiology, pathophysiology, and pharmacology of cerebral artery smooth muscle, the molecular identity, subcellular location, and ion current phenotype of these native channels have not been determined.…”

Search for Genetic Variants in the Ryanodine Receptor 1 Gene in Patients with Symptomatic Cerebral Vasospasm after Aneurysmal Subarachnoid Hemorrhage

“…On the other hand, there are clinical indications that the specific RyR1 antagonist Dantrolene Ò may attenuate cerebral vasoconstriction [24,25]. So far, RYRs had been implicated in several diseases of skeletal muscle (RYR1) and heart muscle (RYR2) [26].…”

Dantrolene for cerebral vasospasm after subarachnoid haemorrhage: a randomised double blind placebo-controlled safety trial

“…Dantrolene, an already US Food and Drug Administration (FDA) approved ryanodine-receptor (RyR) blocker, is a promising pharmacological agent for improving outcomes after aSAH given its dual mechanism; it is neuroprotective,2 3 and in animal models inhibits cerebral vasoconstriction alone and exponentially more in combination with nimodipine 4. In fact, the common pathway for cVSP and neurotoxicity is the continuous elevation of intracellular Ca 2+ , resulting from the influx of extracellular Ca 2+ and, to a much higher degree, release from the largest intracellular Ca 2+ -store, the endo/sarcoplasmatic reticulum, mediated by the RyR 5 6.…”