Concomitant administration of dantrolene and nimodipine significantly improves cerebral blood flow perfusion in a rat model of cerebral‐induced vasospasm

Abstract

A cerebral vasospasm (CVSP) is a potent vasoconstriction of the cerebral vasculature, and the primary cause of morbidity and mortality following a hemorrhagic stroke. The middle cerebral artery (MCA) is one of the most common vessels affected by CVSPs. Experimental evidence shows that concomitant administration of dantrolene (a ryanodine receptor blocker) and nimodipine (a Ca+2 channel blocker) has synergistic effects in reducing vasospasms in aortic rings from Sprague Dawley rats. To determine if the effects observed in the systemic vasculature extend to the cerebral circulation, we investigated the effect of intravenous administration of dantrolene (2.5 mg/kg) and nimodipine (1 mg/kg and 2 mg/kg) on MCA blood flow velocity (BFV). Using a PeriFlux 5000 Laser Doppler System, we measured BFV before and after administration of the drugs 7 days after induction of cerebral vasospasms in Sprague Dawley rats. A reduction in blood flow velocity indicates that vascular reactivity decreases and blood perfusion increases. Mean blood pressure (MBP) and heart rate (HR) were also measured. Individual administration of these drugs resulted in similar reductions in BFV (34% with dantrolene, n=6, p<0.05; 32% with nimodipine 2 mg/kg, n=6, p<0.05). Moreover, dantrolene combined with 1mg/kg of nimodipine decreased BFW by 48% (from 435.70 ± 21.50 to 284.30 ± 26.10 perfusion units, n=6, p<0.05). Similarly, dantrolene combined with 2 mg/kg of nimodipine, reduced BFW by 54% (from 536.00 ± 32.60 to 367.80 ± 40.90 perfusion units, n=6, p<0.05). Although when combined with 2 mg/kg of nimodipine, dantrolene significantly increases HR, the combination of dantrolene and 1mg/kg of nimodipine, did not alter MBP or HR. Thus, our results indicate that concurrent administration of 2.5 mg/kg dantrolene and 1 mg/kg nimodipine significantly reduce BFV in the MCA without altering systemic hemodynamic parameters. By reducing vascular reactivity synergistically, these drugs may improve cerebral blood perfusion. Therefore, adding dantrolene to current standard pharmacological therapies with calcium channel blockers (CCB) may allow a dosage reduction of CCB and minimize the systemic secondary effects of these drugs. Furthermore, if our findings with rats are applicable to humans, the combined use of dantrolene and nimodipine at optimal doses may be effective in reducing CVSPs.